PHYSIOLOGICAL REVIEWS Vol. 72, No. 1, January 1992 Printed in U.S.A.

Physiological Actions of

R. J. HUXTABLE Department of Pharmacology, University of Arizona College of Medicine, Tucson, Arizona

I. Introduction ...... 101 II. Physicochemical Considerations ...... 102 III. Biochemical Considerations ...... 104 A. Distribution of taurine ...... 104 B. Metabolism of taurine ...... 107 IV. Nonmetabolic Actions of Taurine ...... 108 A. Osmoregulation ...... 108 B. Calcium modulation ...... 114 C. Phospholipid interactions ...... 119 D. Protein interactions ...... 123 E. Interactions with ...... 129 V. Metabolic Actions: Taurine as ...... 130 A. Antioxidation: story ...... 130 B. Radioprotection ...... 133 C. detoxification ...... 134 VI. Metabolic Actions: Taurine as Precursor ...... 135 A. Antioxidation: chloramine story ...... 135 B. Radioprotection by taurine ...... 136 C. Energy storage (phosphagen) ...... 136 D. Metabolism and energy production ...... 138 E. Surfactant and detergent actions ...... 139 F. Xenobiotic conjugation ...... 141 G. Isethionic acid and anion balance ...... 141 H. Taurine-containing peptides ...... 142 I. Other taurine metabolites ...... 142 VII. Conclusions ...... 142

I. INTRODUCTION carries a functional significance above and beyond the presence of GABA in bacteria. The osmoregulatory ac- Z-Aminoethane sulfonic acid, or taurine, is a phylo- tions of GABA in the latter species are superseded by its genetically ancient compound with a disjunct distribu- neurotransmitter function in the former. A moment’s tion in the biosphere. It is present in high concentration thought will multiply these examples. Thus it can be in algae (159, 649, 748) and in the animal kingdom, in- readily deduced that, in considering the physiological cluding insects and arthropods, but is generally absent significance of taurine, it, in all likelihood, will exhibit or present in traces in the bacterial and plant kingdoms. polyvalent functions. In many animals, including mammals, it is one of the Taurine was so named because it was first isolated most abundant of the low-molecular-weight organic con- from the bile of the ox, Bos taurus (134). The modern era stituents. A 70-kg human contains up to 70 g of taurine. of research on taurine may be considered to have been One is not tumbling into the abyss of teleology in think- introduced by the seminal and thorough review of Ja- ing that a compound conserved so strongly and present cobsen and Smith (338), which appeared in this journal in such high amounts is exhibiting functions that are in 1968. At that time, the functions suggested for tau- advantageous to the life forms containing it. rine were limited to bile salt synthesis, osmoregulation As the phylogenetic tree is ascended, substances in marine invertebrates, energy storage in marine tend to accrete functions. The adaptive advantages pro- worms, and neuroinhibition in the central nervous sys- vided by serotonin in bananas (Muss sapienturn), norepi- tem (CNS). Since then, the increase in the range of phe- nephrine in Solarium, and dopamine in the giant sa- nomena with which taurine has been associated has guaro cactus (Cereus giganteus) are extended to addi- been little short of astounding. Phenomena currently tional phenomena when these same compounds are associated with taurine are listed in Table 1. The pur- found in the mammalian brain. The presence of y-ami- pose of this review is not to examine these phenomena nobutyric acid (GABA) in the brains of higher animals per se but to elucidate the mechanisms by which taurine

0031-9333/92 $2.00 Copyright 0 1992 the American Physiological Society 101 102 R. J. HUXTABLE Volume 72

TABLE 1. Some biological actions of taurine

Action References Action References

Cardiovascular system Retina Antiarrhythmic 185,253, 652,747 Maintenance of structure and 590, 741 Positive inotropy at low calcium 183,186,187,362, 643 function of photoreceptors, outer Negative inotropy at high calcium 183,187 segments, and tapetum lucidum Potentiation of digitalis inotropy Summarized in 315 Antagonism of calcium paradox 145,402 Liver Hypotensive (central and 1, 3, 68, 198-201, 322, 323, 539, peripheral action) 581, 699, 829 Bile salt synthesis 243,244 , 293 Retardation of lesion development 33,510 in calcium overload Reproductive system cardiomyopathy Increased resistance of platelets to 248 Sperm motility factor 529,580 aggregation Muscle Brain Muscle membrane stabilizer 284,300 Anticonvulsant 63,151,217,286,288,552 Modulator of neuronal excitability 13,123-126,191,232,233,350, General 538 Maintenance of cerebellar function 55,'738-740 Modulation of neurotransmitter 8, 29, 115, 279, 321, 382, 419, Antinociceptive against chemical 697 and hormone release 577a, 633,676,678,762,814 stimuli Osmoregulation 261,329,349,357,433 Thermoregulation 12, 59, 105, 106, 215, 276, 361, Stimulation of glycolysis and 147,409,527,673 460,532,634,698,700 glycogenesis Antiaggressive actions 491,492 Attenuation of 617 Central regulation of 69,202,207,271,808 hypercholesterolemia cardiorespiratory responses Cell proliferation and viability 280,605 Alteration of sleeping duration 168,319,505,509 Antioxidation 592,688,756,758,823 Resistance to anoxia/hypoxia 185,438,483,689 Regulation of phosphorylation 453,466 Altered learning 10,483, 662 Xenobiotic conjugation 155,281,340-343,347,352 Altered motor behavior 46,205,353,459,614,615 Antitremor actions 213 Suppression of drinking 275,761 Suppression of eating 761

may be acting and how the same mechanism expressed Smith in publishing a complete and exhaustive review of in different settings may affect apparently unrelated the taurine area has vanished irretrievably, entombed physiological phenomena. I have, perhaps unwisely, within a voluminous literature. For those who want listed conclusions at the end of each section. The need more information, the literature on taurine can be pur- for brevity in language and the desire to avoid qualify- sued through the numerous reviews and symposia pro- ing nearly every statement inevitably gives these con- ceedings that have appeared since 1976 (45,87,247,286, clusions an assurance that may be lacking in the pri- 288,291,297,298,305,311,327,338,416,549,551,598,672, mary literature. In attempting to make the information 735, 823). digestible to the general reader, I may have trodden on a few toes of the taurine specialists. However, there are enough toes in the area that a few can be spared in a II. PHYSICOCHEMICAL CONSIDERATIONS good cause. If nothing else, I hope the conclusions stimu- late further investigations by those desirous of disprov- The biological actions of a compound are an inevita- ing them. ble consequence of its physicochemical properties. Tau- Despite the impressive progress of the past two de- rine is an that differs from the more familiar cades, an understanding of the mechanisms underlying substances of that class in being a sulfonic rather than a the effects of taurine has been slow to evolve. However, carboxylic amino acid and in being a P-amino acid recent investigations have narrowed the gap between rather than an a-amino acid. Compared with carboxyl- observation and understanding, and one can be confi- ate groups, the sulfonate group is a strong acid, having dent that a further review of this topic in this journal in an acidic dissociation constant (pK,) equivalent to that another 20 years will reveal an advance in mechanistic of a mineral acid, such as hydrochloric acid (Table 2). insight sufficient to systematize in a rational way the The high acidity makes taurine almost completely zwit- biological actions of taurine. terionic over the physiological pH range. In contrast, a It is a measure of the progress made over the last 22 significant fraction of carboxylic amino acids exist un- vears that anv hoDe of competing with Jacobson and ionized over this range (Fig. 1). At pH 7.4, the fractions January 1992 PHYSIOLOGICAL ACTIONS OF TAURINE 103

TABLE 2. Physical constants of neuroactive amino acids 100

Solubility, mM Ionization Constants Isoelectric 25°C 100°C pK, pK2 pK3 Point

Taurine 838 1.5 8.82 5.16 3,329 8,948 2.34 9.60 5.97 Aspartate 37.6 518 1.88 3.65 9.60 2.77 Glutamate 58.4 952 2.16 4.32 9.96 3.24 ,& Freely soluble 3.55 10.24 6.89 GABA Freely soluble 4.03 10.56 7.30 Asparagine 226 4,170 2.02 8.80 5.41 Glutamine 246 2.17 9.13 5.65

GABA, y-aminobutyric acid. [Modified from Huxtable (290).] of @-alanine and GABA having unionized acid functions are 125 and 340 times greater than the fraction of tau- rine. The zwitterionic nature of taurine gives it high water solubility and low lipophilicity. Consequently, compared with carboxylic amino acids, diffusion through lipophilic membranes is slow for taurine. Fig- ure 2 illustrates this for the uptake of taurine and the structurally analogous ,&alanine by the isolated per- Concentration (mlvl) fused heart. Both substances exhibit saturable active FIG. 2. Transport of lipophilic amino acid, P-alanine, and lipo- transport with similar kinetic properties. However, phobic amino acid, taurine, into isolated Lagendorff-perfused rat nonsaturable uptake for taurine (i.e., diffusion) is negli- heart. There is a nonsaturable component to transport of @-alanine, indicating membrane diffusion. [From Huxtable and Sebring (316).]

gible compared with the nonsaturable uptake of ,&ala- nine. The impermeability of biological membranes to taurine probably underlies the extraordinarily high concentration gradients that may be maintained across such membranes. For the retina, a taurine gradient of 400:1 is maintained (586). For brain cells, this may be as high as 500:l. For Ehrlich ascites cells in culture, the gradient ranges to 2,000:1 (102), and for HeLa cells it ranges up to 7,000:1(624). The poor permeability of tau- rine also permits ready renal regulation of the whole body content in mammals, as reuptake from the tubular fluid is a function of a hormonally controlled active transport system (95-97, 192, 345, 659). Hormone- and neurotransmitter-controlled regulation of active trans- port processes have also been established in the heart and salivary gland (283), the pineal gland (810,811), as- trocytes (267), and glial cells (479). To maintain such concentration gradients by high- capacity, high-affinity uptake systems in the face of sig- nificant diffusion out of the cell would place an unaccept- able energy demand on the cell. Sodium ions are co- transported with amino acids (297). Depending on the Taurine system and the observer, for each taurine molecule 1===5= transported, between 1 and 3 Na+ are carried. This Na+ 7.0 7.2 7.4 7.6 7.8 is pumped back out via the Na+-K+-ATPase, hydro- PH lyzing 1 ATP per 3 molecules of Na+. The diffusion FIG. 1. Effect of pH on degree of ionization of acid function in rate shown for P-alanine on Figure 2 is ~212 taurine, ,&alanine, and y-aminobutyric acid (GABA). Number of un- nmol l min-l . mmol-l l g dry wt? The taurine concen- ionized functions per lo6 molecules is shown. tration in the rat heart is ~40 mM. If taurine diffused 104 R. J. HUXTABLE Volume 72

TABLE 3. Structural and ionic properties of taurine, HH 0 ,&alanine, and aminoethane phosphonate H \ I I / N-C,-C,-X----O / Average. Bond Angles, O H I I \ HNH CNH Around C, Around Cz 0x0 cxo HH o FIG. 3. Type structures for @aminooxyacids, taurine (X = S), Aminoethanephosphonate 111.0 108.0 112.0 111.9 111.7 107.1 P-alanine (X = C), and aminoethane phosphonate (X = P) (see Table 3). Taurine 110.3 108.7 109.3 109.3 112.5 106.2 ,&Alanine 108.4 112.4* 108.4-t 127.0 116.5 Bond Lengths, nm and thus has a lower isoelectric point than taurine. P-Al- anine does not mimic the Ca2’ modulatory action of tau- C-XX-O* C-C C-N N-H$ Cl--$ Cz-H* rine on phospholipid membranes and does not compete with taurine for its low-affinity phospholipid-binding Aminoethane site (692). phosphonate 0.180 0.153 0.151 0.148 0.095 0.102 0.102 Taurine 0.178 0.146 0.152 0.148 0.085 0.096 0.096 The sulfur in taurine is in the form of a sulfonate @Alanine 0.155 0.129 0.155 0.148 and may be further oxidized to sulfate. The lowest oxi- dation state for sulfur is -2, and the highest is +6. The Ionization Constants sulfur in taurine, at +4, has a free energy content of ~260 kJ/mol relative to sulfate (Fig. 4). However, ani- PK PK, Isoelectric point mals are unable to garner metabolically this energy of Aminoethane phosphonate ? ? oxidation, resigning to bacteria the responsibility of Taurine 1.5 9.08 5.29 completing the natural redox cycle of sulfur (292). @Alanine 3.6 10.36 6.99 Aminomethane sulfonate ? 5.75 III. BIOCHEMICAL CONSIDERATIONS For numbering see Fig. 7. Data for bond lengths and bond an- gles: aminoethane phosphonate (566), taurine (567), and ,&alanine (348). Ionization constants from Ref. (11). pK,, pK,, acidic and basic dissociation constants, respectively; X, variable element. A. Distribution of Taurine *x-cl-&. t N-&-Cl. $ Averages. The distribution of taurine can be summarized in the statement that it is present in high concentrations throughout the animal kingdom, except for the proto- out at the same rate as ,&alanine, to maintain a concen- zoans, but is low or absent in the other kingdoms. tration of 40 mM taurine the heart would need to pump Although there is a body of literature on the trans- 17 pmol Na+ . min-l l g dry wt? This is equivalent to 5.7 port and metabolism of taurine in bacteria (see sect. pmol ATP or almost 2 pmol 02. This may be compared VIC), little information is available on the taurine con- with the O2 consumption of the working rat heart of 36.8 centrations in bacteria. It appears, however, that tau- pm01 l min-l l g dry wt-’ (540). Furthermore, because the maximum rate (Vmax) of taurine transport in the rat heart is -32 nmol . min-’ .g dry wt-’ (308), the amount of the taurine transporter protein would have to be in- creased >250-fold to counteract such diffusion rates. As a result of its zwitterionic nature, taurine has a 209 kJ high dipole. Its isoelectric point falls between that of carboxylic w-amino acids, such as glycine, ,&alanine, 0 SO and GABA, and that of acidic amino acids, such as aspar- tate and glutamate (Table 2). The membrane modula- 178 kJ l/2 s*o3 tory actions of taurine and its interactions with Ca2+ k and other cations probably stem from its unique ionic characteristics. 151 kJ The overriding significance of the ionic properties so;- of taurine is supported by the inability of isosteres of , taurine to substitute for it in various biological phenom- +4 ena. Aminoethane phosphonate and ,&alanine are two 258 kJ compounds that sterically resemble taurine (Table 3; Fig. 3). Despite the similarity, aminoethane phospho- nate has no affinity for the taurine transport system or, +6 indeed, for any other site at which taurine interacts. FIG. 4. Free energy of oxidation of sulfur. Each step down re- Aminoethane phosphonate differs from taurine in being moves 2 electrons with indicated drop in free energy. Sulfur in taurine a dibasic acid, i.e., it has two acidic replaceable protons, is at oxidation state of +4. [From Huxtable (294).] January 1992 PHYSIOLOGICAL ACTIONS OF TAURINE 105 rine is found in certain bacteria in relatively low molluscs are, in general, high in taurine (15,16,160,430, amounts. In Bacillus, for example, taurine concentra- 607,616,772,794). Concentrations have been reported to tions increase during cell growth, reaching a maximum range from 12 pmol/g wet wt in an unidentified species of 0.6 pmol/g protein (536). However, taurine is obtained of shrimp to 41 pmol/g wet wt in a clam (600). The pe- from the incubating medium and not biosynthesized. ripheral nerve of the crab, Carcinus maenas L., has 75.5 In the plant kingdom, taurine occurs in traces, aver- pmol/g wet wt of taurine, and the ganglions are equally aging -0.01 pmol/g fresh wt of green tissue according high (160). However, concentrations of certain other to one report (424). This is ~1% of the content of the amino acids are also high. Aspartate concentrations are most abundant free amino acids. Marine algae (sea- higher than taurine in the peripheral nerves of both weeds) are an exception. In Japan, processes have been crabs and lobsters. Taurine concentrations in marine patented for the extraction of taurine from seaweed invertebrates were thoroughly reviewed in 1971 (15). (748). Yields were not reported. However, seaweeds in The insects comprise another class high in taurine. general have relatively high concentrations of taurine, It is the most abundant free amino acid in the nervous concentrations falling in the range of 0.015-0.998 pmol/ system (671). Honeybee brains contain 34.4 pmol/g wet g wet wt, depending on the species (358). Taurine and its wt (193), and brains of stable flies, Stomoxys calcitrans, derivative N-(1-carboxyethyl)taurine are reported to contain 37.3 pmol/g dry wt (266). Fly ganglions are even have a widespread distribution in red but not in brown higher at 110 pmol/g dry wt. or green algae (420). Again, however, no concentrations Spiders are unusual in having higher concentra- are given. tions of taurine than of glutamate in their CNS. Taurine Mushrooms, lichens, mosses, and ferns contain no can comprise up to 34% of the total free amino acid pool, more than 0.001-0.007 pmol/g wet wt (358). Taurine has being particularly high in spiders using vision for orien- been found in pumpkin seeds at concentrations of 0.013 tation (521). pmol/g wet wt and in nuts such as walnuts and almonds In fish, taurine is common. Indeed, some of the con- in concentrations ranging up to 0.046 pmol/g wet wt centrations reported are remarkably high: 83 pmol/g (600). Others were unable to detect taurine in a range of wet wt in the dark muscle of the yellowtail, Seriola quin- food grains and nuts, including rice, corn, wheat, barley, queradiata, for example (660). Tilapia contains a more lentils, and peanuts (597). Concentrations of ~0.005 modest 9.1 pmol/g. The heart of the rainbow trout, pmol/g dry wt were found in black beans. SaZmo gairdnerii (Richardson), contains 48.7 pmol/g, Methodological difficulties obtrude in the measure- and the gills contain 35.2 pmol/g of taurine compared ment of such low concentrations of taurine. In some of with 0.73 pmol/g in plasma (219). Although not directly the reports, it is unclear as to whether or not glycero- stated, these values are probably based on wet weight. phosphoethanolamines interfered with the assay (130, The second most abundant free amino acid in the heart 745). In brain tissues, the coelution of such substances is glutamate, with only 2.2 pmol/g. can give erroneously high values for taurine and in plant Although taurine concentrations are generally low extracts can lead to a false identification (383). Typi- in reptiles, olive sea snakes, Aipysurus Zaevis, have cally, taurine concentrations in the brain as measured plasma concentrations of 130 PM, and garter snakes chromatographically will fall following acid hydrolysis (Thamnophis) excrete high concentrations of taurine of a sample (130,745), as such a treatment cleaves gly- (53). Frog brains have only 0.05 pmol/g wet wt (193). cerophosphoethanolamine to and glycer- Birds, like fish, contain exceptionally high taurine ophosphate. We have found no taurine in beans (Mexi- concentrations in erythrocytes, typically 100 times the can black, white, or tan) or peanuts (R. J. Huxtable and concentrations found in mammals (708). Pigeon erythro- C. Bergland, unpublished observations). In extracts of cytes, for example, contain 17 mM taurine. Concentra- beans, a major peak elutes close to, but clearly different tions are maintained by transport rather than by biosyn- from, the retention time for taurine. However, in the thesis. absence of appropriately run standards, the peak could In mammals, taurine is near ubiquitous in distribu- be misidentified as taurine. “Spiking” samples with a- tion, with tissue concentrations typically in the micro- glycerophosphoethanolamine showed that the unknown mole per gram wet weight range. Body fluids, such as peak did not coelute. Its identity remains unestablished. plasma, cerebrospinal fluid, and extracellular fluid, A further problem lies in the potential for plant contain much lower concentrations, typically in the contamination by mammalian effluvia. One wet thumb range of lo-100 PM. The highest concentrations are print contains 1 nmol of taurine (236). This amount may usually found in the heart or brain, but the bulk of the be compared, for example, with the analytical range of taurine is in the musculature. In the heart, taurine com- 0.1-0.3 nmol employed by the high-performance liquid prises up to 60% of the total free amino acid pool. Con- chromatographic method used in one recent paper re- centrations range from 3.5 pmol/g wet wt in cows to in porting concentrations in plants (600). Grains, seeds, excess of 30 pmol/g in rats (284). and other plant products may be contaminated with tau- Numerous reports are available on taurine concen- rine by rat droppings, insect remains, or poor handling trations in the brain and spinal cord (6,7,47,48,112,120, by laboratory personnel. Reported values may therefore 228,254,355,426,551,555,557,558,568-570,610-613,625, be taken as representing upper limits of taurine content. 705,781,836). In adult brain, taurine concentrations are Among the invertebrates. marine arthropods and tvgicallv slightlv higher or slightlv lower than GABA 106 R. J. HUXTABLE Volume 72 concentrations. Glutamate concentrations, however, are phibians typically have concentrations one-third to one- consistently higher. Microdistribution of taurine within fourth those of mammals, the frog having 10 pmol/g wet a given structure tends to be uniform (836). In rats, tau- wt retina. rine is high in the cerebral cortex and cerebellum. The The layered organization of the retina makes it pos- olfactory bulb is another region rich in taurine. sible to dissect and analyze separately the various cells All cell types in the CNS appear to contain taurine. of which it is comprised (108,109,579,832). About two- destroys neuronal cell bodies while sparing thirds of the retinal taurine is localized in the photore- glialcells (114,237,435,445,601,731,751). Injected uni- ceptor layer. The concentration is highest in the outer laterally into rat striata, kainate produces a 14% de- nuclear layer, 95% of the volume of which is photore- crease in whole tissue taurine content relative to the ceptors, the other 5% being glia (595). Localization in unlesioned side and a 29% fall in taurine content of the the photoreceptor layer is confirmed by measurements brain P, fraction (a synaptosomal and mitochondrial on animals lacking photoreceptors, either due to in- fraction) (629, 828). Measurements of tissue taurine herited dystrophies or to experimental manipulations. concentrations following selective destruction of cere- In the so-called RCS rat (from their discovery at the bellar granule or stellate cells also indicate the presence Royal College of Surgeons, London), the photoreceptor of taurine in a number of cell types (642). In rabbit cere- layer degenerates over the first several weeks of life. bral cortex, taurine, along with other neuroactive amino Concomitantly, retinal taurine concentrations fall to acids, was reported to be present in higher concentra- 25% of those in normal rats (679, 681). Similarly, tau- tions in glia and synaptosomes than in neuronal cell rine concentrations are low in the retinas of mice with bodies, the perikarya (696). Glial tumors also contain dystrophy (109, 578, 579). Taurine concentra- taurine (434). tions fall in parallel with photoreceptor cell degenera- The highest concentrations of taurine occur in de- tion in Irish setter dogs with rod-cone dysplasias (680). veloping brain, at which time the concentrations of Treatment with the excitatory , glutamate other free amino acids tend to be low (131). With devel- and kainate, destroys the inner layer of the retina with- opment, taurine concentrations fall, with levels in out affecting the photoreceptor layer. Such treatment adults being about one-third those of neonates. This leaves taurine concentrations unaffected (601, 661). pattern has been observed in humans (434, 737), mon- The developmental changes in taurine in the retina keys (641, 737), mice (384), rabbits (91), and rats (127, differ considerably from those in the brain in that tau- 287,310,732,733). This developmental pattern is true in rine concentrations increase in temporal correspon- insects also. Taurine concentrations in the brain of the dence with the formation of the photoreceptor layer and moth, Mamestra cmfigurata, rise ZO-fold between the the development of electroretinogram amplitude (583). pupal stage and metamorphosis (61). Secretory structures, such as the pineal, pituitary, Pinched-off nerve terminals, or synaptosomes, and neurohypophysis, contain extremely high concen- have been well-studied preparations (64,131,383). Syn- trations, ranging to in excess of 60 pmol/g wet wt (120, aptosomal taurine concentration is about the same as 220,225,228,369,464,785). whole tissue concentration. Synaptosomal concentra- In a given species, taurine concentrations are most tions of nearly all other amino acids are lower than variable in the liver where the concentrations are af- whole tissue concentrations, leading to a relative synap- fected by the dietary content. Rabbits and guinea pigs tosomal enrichment in taurine. Synaptic vesicles con- have low hepatic concentrations of taurine (91, 821). tained within synaptosomes are even more enriched in Newborn rabbits have concentrations of taurine in liver taurine. Thus, in bovine cerebral cortex, taurine concen- 100 times greater than adult rabbits (91). tration is 25.6 pmol/g protein, this being 9.9% of the In summary, perhaps the most striking observation ninhydrin-positive material in the preparation. Corre- concerning the distribution of taurine is its generally sponding figures for synaptosomes are 11.0 pmol/g pro- high concentration in cells lacking cell walls and its al- tein (12.9%) and for synaptic vesicles 55.9 pmol/g pro- most complete absence from cells having cell walls. In tein (37.4% ) (383). In bovine medulla, taurine comprises mammals, taurine is particularly high in excitable tis- 10.3% of ninhydrin-positive material in whole tissue sues, especially in secretory structures. and 33.8% in synaptosomes. However, synaptic vesicles contain x0.04 pmol taurine/g whole brain, which is only a few percent of the total taurine content of the brain. I. Conclusions on distribution of taurine In all species examined, the concentrations of tau- rine in retina exceed those of the brain (585,591). Reti- I) In the plant kingdom, the distribution of taurine nal concentrations are high even in species low in tau- is sporadic and where found the concentrations are low rine in other tissues. In mammals, concentrations are (nmol/g wet wt). fairly constant from species to species, with baboons Z) In the animal kingdom, except for the proto- having 29 pmol/g wet wt retina, guinea pigs 32 pmol/g zoans, the distribution of taurine is ubiquitous and the wet wt retina, cats 43 pmol/g wet wt retina, rats 50 concentrations are high (pmol/g wet wt). pmol/g wet wt retina, and rabbits 52 pmol/g wet wt 3) In general, taurine concentrations are high in retina (585, 591, 792). Mice are exceptional in having species having cells lacking rigid cell walls and are low only 16 bmol taurine/g wet wt retina. Reptiles and am- or absent in species having cells with rigid cell walls. January 1992 PHYSIOLOGICAL ACTIONS OF TAURINE 107

4) In animals, taurine concentrations are high in Sulfur dioxide is rapidly metaboli zed to first sulfite and platelets, electrically excitable tissues, and secretory then sulfate, which is excreted in the urine. structures (up to ~60 pmol/g wet wt). Concentrations The hypotaurine originating from the other tine of are low in extracellular fluids (low PM) and are low or the fork is oxidized further to taurine. In mammals, tau- variable in other tissues. rine is either excreted as such or in the form of bile salts such as taurocholate. The free energy associated with the oxidation of sulfur is wasted in animals, as they are B. Metabolism of Taurine unable to couple it to ATP synthesis. Sulfur passing through the transaminase pathway is merely excreted. Taurine was for a long time generally considered to The pathway through taurine, however, salvages the be the inert waste product of sulfur metabolism in ani- sulfur for other uses before it is excreted. Animals such mals. Although a long list of actions of taurine has now as cats, humans, and certain monkeys that are unable to been established (Table I), in a sense one of the adjec- synthesize meaningful quantities of taurine must rely tives is correct and the other partially so. Taurine is chemically inert. It is biochemically inert in animals in on a dietary source of this supposedly “waste” sulfonic the sense that the greatest proportion of taurine is ex- amino acid. creted unchanged. It is, in animals, one of the end prod- The mammalian handling of taurine is a small part ucts of sulfur metabolism. The phrase end products is of the biological sulfur cycle. In the biosphere, sulfate is used advisedly, despite its superfluistic construction, as reduced to sulfide by microorganisms and reoxidized to the word waste perhaps carries pejorative connotations either sulfate or taurine by animals, microorganisms, one might wish to avoid. and plants. The taurine excreted from animals is oxi- Detailed discussions of taurine biosynthesis can be dized by certain microorganisms to sulfate to complete found in recent reviews (293,297). Mammals are capable the cycle (292). only of sulfur oxidation, not reduction. Reduced sulfur, In species other than mammals, taurine biosynthe- in the form of the sulfur-containing amino acids methio- sis has been poorly studied. If the skate, Raja erinacea, nine and cysteine, is therefore an essential component is an exemplar, fish lack decarbox- of the diet. Sulfur catabolism occurs by two routes, fork- ylase and are unable to synthesis taurine (367). Embry- ing from the oxidized metabolite of cysteine, cysteine onic skates are unable to convert [14C]cystine to taurine, sulfinic acid (Fig. 5). Cysteine sulfinate is produced in relying instead on a transport system for extracting tau- the liver by cysteine dioxygenase (EC 1.13.11.20) (4’71, rine from the egg yolk (216). The skate is also unable to 725). It is rapidly metabolized further in all mammals metabolize taurine; it obtains it from the environment by transamination to P-sulfinyl pyruvate and in some and releases it back into the environment (366). mammals by decarboxylation to hypotaurine. ,&Sulfinyl In conclusion, most reduced sulfur, ingested in the pyruvate spontaneously decomposes while still bound form of and cysteine, is oxidized in mam- by its parent to sulfur dioxide and pyruvate. mals through cysteine sulfinate to sulfate. A small per-

CHgSCH2CH2FH+JH2 C02H Methionine

Aspartate Cysteine H02SCH2TH-NH2 H02SCH2CH2NH2 Aminotransferase Sulfinate 1 k02H 1 Decarboxylase 1 1 Hypotaurlne L Cysteine Sulfinate

Salts 44 H03SCH2CH2NH21 -----b H2S03 Bile SO2I Taurine

Sulfite Oxidase

+ +6

I ---b Excretion

FIG. 5. Hepatic catabolism of sulfur amino acids in mammals. Bulk of sulfu .r amino acids is oxidized to cystei ne sulfinate. Further oxidation to sulfate is ubiquitous. Certain mammals also divert part of flow through cysteine sulfinate toward syn.thesis of taurine. Taurine is excreted as such or in form of bile salts such as taurocholate. 108 R. J. HUXTABLE Volume 72 centage is metabolized to taurine. Certain carnivorous the wall prevents SWpelling. The cellulose walls plant or omnivorous mammals, with their greater specializa- cells permit internal turgors as high as 50 atm in some tion, have lost, or are losing, the ability to produce tau- species. Organisms without cell walls face the dual rine, relying instead on nutritional sources to maintain problems of protecting body fluids from osmotic their body loads. Despite this, quantitatively, the vast changes in the environment and osmoregulating cells in bulk of taurine in the biosphere is formed in the animal the face of concentration differentials across the plasma kingdom. In most species, cell, organ, and whole body membrane. Multicellular organisms, such as molluscs, taurine concentrations are regulated by transport, bio- that can avoid changes in exterior osmolarity (i.e., mos- synthesis and metabolism being of minor import. mol/l solution) by such behaviors as shell closing still have need for intracellular osmotic regulation. Isosmotic intracellular regulation is indispensable I. Conclusions on metabolism of taurine for viability for single-celled organisms lacking cell walls or for multicellular organisms in which the osmo- I) Mammals metabolize sulfur amino acids through larity of body fluids approximates that of the environ- cysteine to cysteine sulfinate to sulfate. Mammals also ment. In general, marine invertebrates have body fluids metabolize cysteine sulfinate to taurine. However, the isosmotic with sea water. In extracellular fluids, os- capacity to do this is highly variable by species. motic balance is achieved primarily with inorganic 2) Mammals unable to decarboxylate sufficient cys- salts, while intracellular regulation is achieved with a teine sulfinate must rely on a dietary source of taurine. mixture of salts and organic substances. The later evo- 3) Taurine is excreted as such or in the form of tau- lution of anisosmotic extracellular regulation of body rocholate or related bile salts. Some mammals have lost fluids (i.e., the osmolarity of extracellular fluids being the ability to conjugate taurine to form bile salts (see held constant in the face of varying environmental os- sect. VIE and Table 5). molarity) partially relieves responsibility from the in- tracellular mechanism in vertebrates. The osmotic pressure of a cell is determined by the IV. NONMETABOLIC ACTIONS OF TAURINE total osmolarity of cytoplasmic solutes. These solutes consist of inorganic ions, low-molecular-weight organic The nonmetabolic actions of taurine are those that compounds, and macromolecules. Osmoregulation in- are not a result of a process in which taurine is either volves alterations in the concentrations of substances in produced or metabolized. the first two classes. Typically, in response to a hypo- or hyperosmotic stress, changes in concentration occur in selected members of both classes. In particular, K+ or A. Osmoregulation Cl- accumulation or release is usually involved in os- moregulation (80, 654). However, with inorganic ions The phylogenetically oldest function for taurine the requirements for osmoregulation and the regulation and, next to bile salt synthesis, the one on a surest exper- of membrane excitability are not coincident, constrain- imental footing, is that of osmoregulation. This is ing the osmoregulatory role of inorganic ions. clearly an important function in numerous, but not all, In marine invertebrates and cartilaginous elasmo- invertebrates and fish. There is increasing evidence that branch fishes (i.e., sharks and rays), organic substances it may be a similarly important function of taurine in contribute ~60~70% of the total cell osmolarity. The mammals. composition of the organic substances employed can Simultaneous with the evolution of cells arose the vary widely. Intracellular urea varies from 2 mM in the requirement for osmoregulation. Membrane excitabil- hagfish, Myxine glutinosa, to 422 mM in the coelocanth, ity derives from ionic imbalances across the membrane. Latemeria chalumae, while free amino acids vary from If the consequential osmotic imbalance were left un- 44 mM in the freshwater teleost, Platichthysjlesus, to corrected, alterations in cell volume would result due to 331 mM in the hagfish (368). Depending on the species, the free permeability of plasma membranes to water. other important osmoregulators include trimethyl- Increased cell volume leads to membrane rupture, while oxide, , and ,&alanine. In mammals, the both increases and decreases in cell volume cause con- largest contribution to the osmolarity of a cell is pro- centration changes in a plenitude of cell constituents vided by inorganic ions. Osmotic regulation is provided and disruption of the biochemical processes sustaining by organic osmolytes, which typically contribute lo- viability. 20% to the total intracellular osmolarity. Cells can use one of three strategies for handling What are the characteristics of an ideal osmoregu- osmotic stresses. Osmotic changes can be ignored (by latory organic substance? The cytosolic concentration means of a cell wall), avoided (as in the shell-closing must change in concert with the osmolarity of the cell behaviors of certain molluscs), or adapted to (by modifi- exterior. Changes in concentration must not drastically cation of cellular concentrations of water, inorganic alter cell membrane potential, enzyme activities, or ions, and organic osmolytes). Organisms with cell walls, other cell processes. To satisfy these requirements, the such as plants and most bacteria, can ignore osmotic osmotic change must be close to electrogenically neu- changes within a certain range because the rigidity of tral. To avoid interference with an osmoregulatory January 1992 PHYSIOLOGICAL ACTIONS OF TAURINE 109 function by competing metabolic demands, ideally one 250 175 would want a metabolically inert or nonessential com- pound. Furthermore, the energy expenses of synthesiz- ing the compound, maintaining high concentration gra- dients across the cell membrane, and changing concen- 200 trations in response to osmotic changes must all be minimized. Thus a zwitterionic compound(s) is indi- 50 cated, for a neutral compound would be liposoluble and r 150 require energy for maintenance of high cell concentra- E tion gradients. The requirement of inexpensive synthe- sis can be met by using a metabolic waste product such L 2 as taurine or urea. For adjusting the concentration gra- 7 100 dient across the membrane, a selective transport system is needed, one that is sensitive to osmotic changes. Cells can be categorized according to the low-mo- lecular-weight organic compounds they use for osmo- 50 regulation. Some species, such as certain molluscs, use primarily taurine. Other species use taurine to adapt to limited osmotic changes but, in addition, adjust the con- centrations of other cell osmolytes in response to severe osmotic stress. Still other species, such as the blue crab, Callinectes sapidus (Zll), use a mixture of osmolytes, Sea water salinity, including taurine. Finally, certain cells do not use tau- FIG. 6. Relationship between salinity and total body concentra- rine at all to respond to osmotic stresses. Examples in- tion of taurine (crosses) and total ninhydrin-positive substances clude bacteria, where other nonessential amino acids (NPS; closed circles) in mussel MytiZus edulis. Note that with increas- ing salinity, taurine constitutes increasing percentage of total ninhy- such as glutamate, , and GABA serve as os- drin-positive substances. [From Lange (430). Reprinted with permis- moregulatory substances (513), and the mollusc, Ano- sion by Pergamon Press.] donta, where phosphate and K+ are the major osmotic substances. Among the amino acids, the largest varia- tion under osmotic stress is always provided by the non- versa. Such moves are marked by osmoregulatory shifts essential amino acids (210,682, 683). in cell constituents. In many cases, taurine is the constit- Taurine meets the requirements for a biologically uent showing the largest shift (30,111,196,197,329,349, perfect osmoregulator almost ideally. It is transported 359,433,790). In clams such as Noetia ponderosa, taurine by a system unique to ,&amino acids, the transport is is the major osmotic amino acid, its concentration vary- Na+ dependent (i.e., responsive to ionic changes), and ing from 68 pmol/g dry wt in adductor muscle to 356 the transport is responsive to other osmotic substances, pmol/g dry wt in gills. In the latter structure, taurine such as glucose (31,779). Extremely high intra- to extra- plus hypotaurine comprise 80% of the free amino acid cellular concentration gradients for taurine can be pool. When N. ponderosa blood cells are moved from maintained due to its lipophobic properties, and the use seawater to 50% seawater, the fall in cell taurine con- of taurine as an osmoregulator “spares” metabolically centrations provides 86% of the osmotic change (21). important amino acids. It is hardly surprising, there- Taurine is also prominently involved in osmoregulation fore, that an osmoregulatory action of taurine was the in the mussel, Mytilus e&,&s (632, 665). As salinity in- first biochemical function to evolve for it and that this creases, the percent contribution of taurine to the nin- action has been conserved so strongly from amoebas hydrin-positive pool also increases. At a salinity of 5 through the mammals. parts per thousand (ppt), taurine is undetectable. At a The involvement of taurine in maintaining osmotic salinity of 30 ppt, taurine constitutes 28% of the ninhy- balance was suggested in 1915 to account for the high drin-positive pool (Fig. 6) (430). In the shellfish Crassos- taurine content of the echinoderm Astropecten auran- trea, as salinity increases, the cell concentrations of tiacus (Grey) (401). An osmoregulatory function for tau- both taurine and glycine increase (478). Taurine pro- rine appears to have been first proposed by Krogh (404). vides >50% of the osmotic increase in mudflat snails, Typically, taurine concentrations are high in marine Nassarius obsoletus (Say), exposed to increased salin- molluscs (421, 715), low in molluscs living in brackish ity (357). water, and absent in land and freshwater molluscs (32, In euryhaline teleosts (an infraclass of bony ray- 715). Volume regulation by taurine has subsequently finned fishes), the osmolarity of body fluids changes been established in systems as diverse as euryhaline with environment. Serum osmolality (i.e., mosmol/kg species (178), avian erythrocytes (403, 708, 719), and solution) in the flounder, for example, drops from 364 to mammalian cells (252, 655, 658). 304 mosmol/kg on transfer from seawater to freshwa- Euryhaline species are aquatic organisms that are ter. In the stickleback, Gasterosteus aculeatus, the corre- able to adapt to marked changes in salinity: they can sponding drop is from 340 to 290 mosmol/kg (431). Isos- move from saltwater to brackish or freshwater and vice motic intracellular regulation therefore occurs as the 110 R. J. HUXTABLE Volume 72 environment changes. Typically, this is largely achieved 50 by changes in taurine content. Taurine is particularly A important in osmoregulation of the fish heart (181,790, 791). Taurine comprises in excess of 50% of cardiac free amino acids in teleost species such as flounder (Ha- 4o tichthysjlesus) or skate, and changes in taurine content z accounts for about one-half of the osmolar adjustment $ in the cell (790). When the osmolality of flounder plasma y* 30 decreases by 17%, the fall in ventricular taurine pro- z vides 40% of the total osmotic adaptation, with K+ pro- g viding 16% (791). As plasma osmolality shifts, so does + 2. the concentration ratio for taurine between plasma and [ erythrocytes (197). A 100 mosmol/kg fall in the plasma (L is accompanied by an 80% drop in erythrocyte taurine concentration, providing 30% of the total osmotic re- 10 sponse. The fall in GABA is even more marked. How- ever, GABA provides only 17% of the total osmotic re- P sponse (194). Taurine excretion from the little skate, oh- Raja erinacea, is increased under hyposmolar condi- 1 1.1 1.2 1.3 tions (366). On transfer from sea water to 50% sea Relative cell volume water, the muscle of the little skate shows marked drops FIG. 7. Cell volume and amino acid permeability. As relative vol- in free amino acid, urea, and trimethylamine oxide con- ume of murine Ehrlich ascites cells is increased, there is marked and centrations (180). linear increase in taurine permeability (A). Change in glycine perme-- An area of progress in the taurine field ov ‘er the ability (B) is much less marked and nonlinear. Incubation media con- tain 10 PM taurine (X), 1 mM glycine (o), or 0 glycine (0). [From Hoff- past decade sterns from the realization that cell osmo- mann and Lambert (261).] regulation is probably a significant function of taurine in mammals also. In mammalian heart (760) and brain (759), taurine can be the organic osmolyte present in highest concentration. The largest shift in osmolar and amino acid accumulation are all linked phe- equivalents within a cell in response to osmotic stress is nomena. contributed by taurine. This is as true of mammalian Taurine concentrations are typically high in mam- cells responding to a change in cell environment as of malian sperm and seminal fluid, and it is possible that marine organisms responding to a change in salinity taurine is serving an osmoprotective function. In ham- (181,212,259, 768). Thus dilution of the incubation me- sters, fluids in the reproductive tract are hyperosmolar, dium results in a release of taurine by a Na+-indepen- having values of up to 400 mosmol/kg (344). Hyposmotic dent mechanism (261). A 30% increase in cell volume in conditions kill sperm, but chimpanzee sperm are pro- Ehrlich ascites cells produces a 600% increase in perme- tected by the addition of 2 mM taurine (580). ability to taurine but only a 50% increase in permeabil- The high-affinity transport system for taurine in ity to g ,lycine An osmotic change from 300 to 150 mos- mice myocytes responds sensitively to changes in osmo- mol/kg leads to an 87% fal 1 in cell taurine co ncentration larity (31). Rats with hereditary diabetes insipidus are and a 1,500% rise in buffer taurine concentration. In chronically dehydrated. Water deprivation leads to in- other words, the concentration gradient across the cell creased taurine concentrations (per g protein) in mus- membrane for taurine drops from 757:1 to 7:l. The per- cle, brain, and platelets, suggesting an osmoregulatory meability of the membrane to taurine is a linear func- function for the compound (541). tion of cell volume (261; Fig. 7). The loss of taurine from isolated retinas varied in- Ehrlich ascites tumor cells behave as almost per- versely with osmolarity; the greater the osmolarity the fect osmometers. Taurine is the most significant ninhy- lower the efflux (687). The excitotoxin-induced release drin-positive substance lost during volume regulation, of taurine from retina is stimulated by both K+ and Cl- but even bigger changes occur with K+ and Cl- (260). On (593). As the edema produced by excitotoxins is thought shifting the cells from a 300 mosmol/kg solution to one to be a consequence of passive influx of Cl- accompany- of 225 mosmol/kg, there is a loss of 21.8 mM ninhydrin- ing increased Na+ conductance, Cl-enhanced taurine positive substances from the intracellular milieu but a efflux may be a link between cell volume changes and loss of 47.2 mM inorganic ions (Na+, K+, and Cl- com- the initiation of an osmoregulatory response. bined). However, the steady-state distribution of amino Taurine has often been shown to protect various acids across the cell membrane varied with the concen- functions of retinal rod outer segments. Rod cells are tration gradient of K+ and Na+ across the membrane one of two types of photoreceptors in the retina, the (260). Ion transport is powered by a Na+-K+-ATPase, other type being cone cells. The outer segments of rod and amino acid transport is Na+ dependent. Thus energy cells can be readily isolated. Each outer segment con- consumption, ion gradients (hence cell excitability), sists of from l,OOO-2,000 disks, stacked like dinner January 1992 PHYSIOLOGICAL ACTIONS OF TAURINE 111 plates, surrounded by a membrane (66). The rod outer affected at decreased osmolalities of up to 50 mosmol/ segment is biochemically hyperactive. New disks are kg. If osmolality is decreased further, then an increased continuously biosynthesized at one end of the rod and release of other amino acids is found (437). Perfusion are continually shed from the other end in groups of with a 105 mosmol/kg buffer led to a rapid 15-fold in- 8-30 (838, 839). The protective effect of taurine is com- crease in taurine concentrations. On switching to a plex and appears to involve not only osmoregulatory but standard Krebs Ringer bicarbonate buffer, taurine con- antioxidant and ion regulatory activities. centrations promptly reverted to normal. Systemic Light exposure causes an increase in diameter in water intoxication (ZOO ml/kg ip) also led to increased rod outer segments (158), probably secondary to alter- extracellular taurine concentrations in the brain within ations in ionic fluxes. Taurine, which is found in these 60 min. Results such as these suggest that the osmoreg- structures in high concentration, may be a regulator of ulatory actions of taurine in mammals have both an these volume changes. intracellular and an extracellular component; in the Under certain conditions, ferrous sulfate causes face of an osmotic imbalance, the taurine concentration peroxidation, swelling, and disruption of rod outer seg- in the intracellular compartment alters inversely to the ments (590). Swelling can occur secondarily to lipid per- taurine concentration in the extracellular compart- oxidation (90, 819). Taurine and zinc sulfate together ment. protect against the swelling without affecting malon- In the continuing biological demonstration that ev- dialdehyde formation, an index of degree of peroxida- erything is connected to everything else, disturbances in tion. @-Alanine also protected against the swelling, sug- osmoregulation are involved in the response of brain gesting an osmoregulatory action of these P-amino acids. cells to excitotoxins and the response of photoreceptors The brain is particularly vulnerable to osmotic dis- to light. Excitotoxins are neuroexcitatory acidic amino turbances (517, 572, 713). Cerebral edema is a serious acids such as kainate, glutamate, N-methyl-D-aspar- condition, leading to seizures and other sequelae, that is tate, or cysteate. They kill neurons. The cell depolariza- hard to treat (22,26,27,133,743). Taurine has anticon- tion these agents produce is accomplished by increased vulsant actions in a wide variety of experimental seizure Na+ entry. There is a resulting passive Cl- entry. Water states (286). These actions may stem, in part, from its enters to counteract the osmotic action of Cl-, the cells osmoregulatory action, although an endogenous anti- swell, and lysis may result (657). In general, conditions action has yet to be demonstrated for tau- that lead to swelling of brain cells result in a stimulated rine. The mammalian brain alters cell amino acid con- efflux of taurine. These conditions include seizures centrations in response to both hypo- and hyperosmotic (796), excitotoxins (78,445,788), ischemia (51), and hypo- conditions, decreasing them in the former and increas- glycemia (763). ing them in the latter condition (50). During the regula- The taurine-depleting agent, guanidinoethane tory phase, astrocytes under hyposmolar conditions sulfonate, can replace taurine as an osmoeffector in the show a marked and unique increase in taurine efflux, brain (768). which depletes cell taurine content by up to 64% (623a). In summary, osmoregulation is not a function Astrocytes swell when incubated in as little as 10 PM unique to taurine. In fish and in marine invertebrates, taurine, perhaps because too much enters the cell (797). taurine serves a prime osmoregulatory function, i.e., the The toxicity of taurine is usually assumed to be negligi- variations in taurine content of a tissue are sufficient to ble, but such findings suggest that exposure to high account for a significant proportion of the osmotic ad- amounts of taurine may carry cryptic risks. The swell- justment of that tissue. In mammals, the osmotically ing of astrocytes leads to a proportional depolarization induced variations in taurine content in general account of membrane potential (365). This is an indication that for only a few percent of the osmotic change required. the osmoregulatory and electrical activities of cells are Taurine, to fulfill an osmoregulatory function, must do interdependent phenomena. The frequently studied ef- so by modification of the movement of other osmotically fects of taurine on ion currents may thus be closely con- active substances, such as ions or water. It has been nected with its osmotic actions (297). Taurine is also pointed out that in the brain there is a linear correlation toxic to cultured cerebellar cells from kittens, lowering from mammal to mammal in the taurine content and survival rate (770). In mice cells, however, taurine sup- the cerebral metabolic rate or rate of glucose consump- ports cell survival. tion (780). As glucose entry and metabolism are accom- Water intoxication both increases extracellular tau- panied by the entry of water, it has been suggested that rine concentrations and decreases intracellular levels taurine is involved in the removal of this water. On the (720, 795). A decrease in extracellular osmolality of as other hand, the correlation between glucose consump- little as 10 mosmol/kg leads to detectable increases in tion and taurine is heavily weighted by two small spe- taurine concentrations. A 15-fold increase is seen at a cies, rats and mice, with high metabolic rates. Other 105-mosmol/kg decrement. small species should be considered to strengthen the Microdialysis of the brain with hyposmotic solu- correlation. In general, phenomena such as seizures or tions resulted in marked increases in extracellular tau- hypoxia that interfere with cell water balance in the rine concentrations (720,795). No other amino acid was brain also alter taurine balance. 112 R. J. HUXTABLE Volume 72

1. Taurine uptake 100 “0 The transport and release of taurine are processes -80 integrally involved in any osmoregulatory function. These phenomena have been reviewed in detail re- cently (297). The increase in cell taurine content produced by hy- perosmolar conditions appears to be achieved primarily by active transport of taurine into the cell (31). This is a Na+-dependent process, with Na+ being cotransported into the cell. The coupling to Na+ supplies the energy for transport, inasmuch as the concentration gradient the 0 I I I I I I 1 Na+ is running down is maintained by a membrane- 0 80 160 240 320 bound Na+-K+-ATPase. An increase in the extracellular Time (min) Na+ concentration may also serve as a signal that the osmotic strength is rising. In addition, taurine uptake is FIG. 8. Taurine efflux and cell osmolality. Flounder erythrocytes were transferred from medium of 330 mosmol/kgH,O (open circles) to stimulated by extracellular Cl- (345, 820, 841). In fish medium of 225 mosmol/kgH,O (closed circles). Na+ was held un- renal tubules, replacement of Cl- led to a fall in the Vmax changed at 113 mM and taurine at 0.3 mM. Lowered osmolality pro- for taurine transport (820). duces immediate and marked stimulation in rate coefficient for tau- The incomplete resorption of taurine by renal prox- rine efflux. [From Fugelli and Thoroed (195).] imal tubules and the dependence of resorption on various hormonal and second messenger signals allow the kidneys to regulate the whole body taurine burden in As is typical of cells exposed to hyposmolar conditions, mammals (129,345). Thus, in rats, the rate of exchange the erythrocytes initially swell and then revert to the of taurine between body organs is faster than the turn- initial cellular volume as volume-adjustment mecha- over rate from the whole anima 1, indicating that excre- nisms come into play. In this system at least, stimula- tion is the rate-limiting step rather than release into the tion of taurine release is stimulated neither by the re- circulation (287). For example, rats fed a diet containing duction in ionic strength nor cell swelling but by the 0.4% taurine had half-lives of exchange of 4.9 days for reduction in external osmolali tY* visceral organs, 5.5 d.ays for the brain, and 11.4 days for The increased taurine release induced by hyposmo- whole body turnover lar solutions is antagonized by the diuretic (720, 721). This raises the seductive idea that the os- motic actions of taurine are related to its effect on Cl- 2. Taurine release flux. However, this requires further investigation. The effect of K+ on taurine release has generated The drastic drop in erythrocyte taurine content considerable confusion, perhaps because of the failure produced by hyposmolar conditions is a consequence of a to make a distinction between a cause and an effect. marked stimulation in taurine efflux. The permeability Exposure to high K+ concentrations depolarizes excit- of the plasma membrane to taurine rises, and, due to the able cells, and there is a tendency to equate the response steep concentration gradient across the membrane, tau- with the cause and to assume that any consequence of rine efflux increases. That this is the mechanism is high K+ treatment is due to depolarization. In fact, K+ shown by the finding that both the influx and efflux rate produces many effects, including stimulation of energy are stimulated (although, because of the concentration metabolism, glycogenolysis, and alterations in cyclic difference across the membrane, the mass transfer is nucleotide concentrations, protein phosphorylation, and out of and not into the cell) and that the influx is not Na+ protein synthesis (77,179,258,461,712). Potassium also dependent (195). This indicates both the lack of identity induces cell swelling (354, 798, 799). of this erythrocyte system with the normal Na+-active In many systems, K+-evoked release of taurine ap- transport process that maintains cell taurine concen- pears to be related more to the increased Cl- flux than to trations and its lack of energy dependency, i.e., taurine the depolarization. Chloride flux is accompanied by the is entering the erythrocyte by diffusion rather than by passive entry of water. Potassium-evoked release of tau- carrier transport. The signal for the permeability rine from synaptosomes and cerebellar granule cells is change could be water movement, osmotic change per se, Cl- dependent, the substitution of gluconate for Cl- pre- or stretch of the plasma membrane. venting K+-evoked release (663, 684). Gluconate also In the rectal gland of the shark, Squalus acanthias, prevents the synaptosomal swelling accompanying K+- the permeability to taurine is increased by K+ (841). A induced depolarization in Cl-containing media. Potas- 30% decrease in medium osmolarity leads to a l&fold sium-evoked release of GABA, on the other hand, is un- increase in taurine efflux from chick retina (603). The affected by Cl- or hyperosmolar conditions. In cerebel- efflux rate of taurine from flounder erythrocytes in- lar cortical neurons, however, Cl- removal only mildly creases some 40-fold within a few minutes of buffer os- attenuates K+-induced release of taurine (684). Cultured molality being dropped by 75 mosmol/kg (195; Fig. 8). astrocytes in isosmotic media swell in proportion to the January 1992 PHYSIOLOGICAL ACTIONS OF TAURINE 113

K+ concentration of the media. However, the volume in- 390, 439-442, 445, 446, 518, 788). The taurine-releasing crease is abolished in low Cl- media or in hypertonic effect of the agonist quisqualate is completely osmoti- media. The release of taurine is proportional to the de- cally sensitive, being abolished under hyperosmolar gree of swelling rather than to the concentration of K+ conditions (519). The action of kainate is partially osmot- (604). Similarly, the K’-induced swelling of chick ret- ically sensitive, whereas the action of N-methyl-D- inas is prevented by omission of Cl-, as is the increased aspartate is unaffected by osmolarity. Thus excitatory release of taurine (146). The osmotically induced release amino acid-induced release of taurine appears to be par- of taurine is not achieved by reversal of active trans- tially due to cell swelling and to be partially osmotically port. The importance of Cl- is shown by the finding that insensitive. N-methyl-D-aspartate-induced release of inhibitors of Cl--HCO, exchange block release of tau- taurine is reduced in the absence of Ca2’ (439), as is rine (364). Release is also, however, dependent on opera- neuronal cell death produced by this excitotoxin (206). tion of the Na+-H+ exchanger (722). Cell acidification At least for N-methyl-D-aspartate, the effects are re- leads to swelling. This occurs in Cl-free medium in ceptor mediated, as the receptor antagonist 2-amino-5- which there is an outflow of Cl- from the cell. Thus the phosphonovalerate abolishes the induced release of tau- Cl- dependence of osmotically released taurine may be, rine (518). to one degree or another, a response, in fact, to a cellular A problem with many of the studies on taurine ef- pH shift. flux is that they measure the release of preloaded Potassium-evoked release of taurine occurs at K+ [3H]taurine (364, 497, 663). What in fact is being mea- concentrations below those at which the release of glu- sured in such an experiment is an increase in cell perme- tamate or GABA is affected (497, 723), i.e., at nondepo- ability, and, in the absence of other measurements, from larizing concentrations of K+. Taurine efflux is stimu- the measurement of radiolabel one cannot be sure of the lated by K+ from glial cells also (497). Release occurs direction of mass transfer. However, in one of the few even if nondepolarizing concentrations of K+ are used studies in which a direct comparision has been made, a but not with depolarizing concentrations if a hyperos- good correlation was found between the K+-evoked re- molar buffer is used. Compared with depolarization-in- lease of preloaded [3H]taurine and endogenous taurine duced release of amino acids, K+-evoked release of tau- from mouse brain slices, except for a more rapid attenu- rine is slower, of lesser magnitude, and continues after ation of release of the labeled taurine (554). Another K+ concentrations have been normalized (214,270,390- lesson from release experiments is that different cell 392, 396,448,497, 593, 627, 718). All of this is consistent types respond differently to various stimuli. To avoid with K+-evoked release of taurine being primarily an confusing oneself and others, therefore, it is important osmotic response to the Cl-induced cell swelling rather to use well-defined preparations. On the other hand, it is than a depolarization-induced response. also important to remember that cells in culture may A lack of dependence on Ca2’ under certain circum- not behave the same as they do in situ. stances of K+-evoked release of taurine also suggests The importance of taurine in osmoregulation helps release is not neurotransmitter like (113, 177, 238, 269, explain the ubiquity of its distribution in a way other 399,422,498,508,593,604,630,701). It has been claimed putative functions, such as that of neurotransmission, that taurine release from cerebellar neurons is Ca2’ de- do not. Furthermore, a primary osmoregulatory func- pendent at 40 mM K+ but Ca2’ independent at higher K+ tion also explains the absence of taurine (or the low concentrations (619). However, others have shown that amounts) in the walled cells of the bacterial and plant K+-induced release of taurine from cerebellar granule kingdoms. cells is a function of cell swelling rather than of Ca2’ (619,620). Taurine release is inhibited by Mg? Thus the 3. Conclusions on taurine and osmoregulation decrease in taurine release seen when Ca2’ is replaced with 10 mM M$+ (619) is probably due to M$+ inhibi- 1) The biophysical and biochemical properties of tion rather than Ca2+ dependency. This may explain why taurine make it an excellent candidate for osmoregula- the Ca2+-channel antagonist is without effect tion. on the K+-evoked release of taurine from cultures of 2) Taurine is a major osmolyte in marine inverte- cerebellar astrocytes, although replacement of Ca2’ by brates and fish. The importance of taurine as an organic M2+ leads to an inhibition of release (620). osm olyte, however, varies wi .th species. Depend .ing on The adenosine 3’,5’-cyclic monophosphate (CAMP)- the species, other osmolytes assume greater or lesser induced increase in taurine transport and taurine efflux importance. is independent of Ca2’ (34,283,498,701). It is, however, 3) Osmotic stress in mammalian tissues leads to inhibited by increased osmotic pressure (498). Confus- large changes in taurine concentrations. As organic os- ingly, in cultured cerebellar astrocytes, K+-evoked re- molytes are quantitatively less important in mammals, lease of taurine is inhibited by dibutyryl CAMP (618). changes in taurine concentrations per se are insufficient Excitotoxic amino acids produce cell edema due to to osmoregulate cells. To establish an osmoregulatory stimulation of Na+ entry through voltage-activated function in mammals, it is necessary to show that tau- channels followed by passive entry of Cl- and water (99, rine affects either water movement or ion fluxes suffi- 657). Such amino acids have also been well established ciently to restore osmotic equilibrium across the cell to increase efflux of taurine from excitable cells (79,339, membrane. 114 R. J. HUXTABLE Volume 72

0 10 m&l, Bullfrog heart Read et al. (ISSO)

0 10 mM, Guinea pig heart Khatter et al. (lQ81)

A 4, 20 mM Guinea pig ventricle Franconi et al. (1982) FIG. 9. Dependence on Ca2’ con- centration of inotropic response to tau- rine. Three independent studies are sum- marized. Shown are transformations of original data from Refs. 183, 362, 643. Lower the Ca2’ concentration, greater the inotropic response to taurine. At su- pranormal concentrations of Ca2+, posi- tive inotropic response to taurine disap- pears or is reversed to negative inotro- pit response.

0.5 1.0 2.0 2.8 Calcium Concentration (mM)

B. Calcium Modulation outer laminae of the sarcolemmal glycocalyx. The inner lamina of the glycocalyx consists of a glycoprotein inte- There is considerable evidence that taurine modu- grated with the plasma membrane and joined to the lates many Ca2+ -dependent processes (296,297,3X& 327, outer lamina by the cross-linking of sialic acid residues 330,419,534,538,584,594). This is most clearly shown in with Ca2’ (188). As the Ca2+ pool becomes depleted, the the heart where the contractile response is a function of two layers separate, forming blebs and impairing the the rate and extent of entry of extracellular Ca2’ during barrier to Ca2+ movement. In the subsequent presence of the plateau phase of the action potential and where re- physiologically normal concentrations of Ca2+, too much laxation is a function of the rate and extent of removal Ca2+ reaches -the external aspect of the bilayer cell of cytoplasmic Ca2+. The contractile responses serve, membrane and too much enters. The observation of therefore, as Ca2’ detectors. The Ca2’ modulatory ac- greatest significance is that taurine is protective even if tions of taurine in the heart have been reviewed only present during the reperfusion period, i.e., after the (315, 327). membrane damage has occurred. It is, therefore, not af- Interest in the cardiac actions of taurine has been fecting the degree of damage but is ameliorating the high since the seminal work of Read and Welty (644, consequences of this damage. This is a similar phenome- 806) 30 years ago. Taurine has a plenitude of effects on non to that observed in skeletal muscle sarcoplasmic the heart that appear to be Ca2’ related. It has been well reticulum following phospholipase C treatment. This established that taurine is positively inotropic in hearts cleaves off the charged headgroups of phospholipids and exposed to subphysiological concentrations of Ca2’. Con- leads to a diminution in the Ca2’ binding and transport- versely, taurine is negatively inotropic in hearts ex- ing capacity of the organelle. Taurine antagonizes the posed to supraphysiological concentrations of Ca2+ (183, diminution in the Ca2’ handling capacity without af- 186, 187, 362, 804; Fig. 9). Taurine affords protection fecting the degree of headgroup hydrolysis by phospho- against the Ca2+ paradox (402), Ca2+-overload cardiomy- lipase C (300). opathy (33, 804), and arrhythmogenesis (94, 326, 644, A related phenomenon is the oxygen paradox. 747, 805). Taurine also antagonizes the negative ino- Reexposure to normal oxygen concentrations after a pe- tropy of Ca2’ channel antagonists. riod of hypoxia leads to enzyme leakage, Ca2+ overload The Ca2+ paradox is of particular interest. Hearts of the cell, and ventricular arrhythmias. Taurine pro- exposed to Ca2+- free conditions for more than a few min- tects against all these consequences (185). Taurine also utes suff er severe damage when reexposed to physiologi- protects against the sh ortening in the plateau phase of tally normal con centrations of Ca2’ (hence the para- the cardiac slow action potential produced by anoxia or dox). During the Ca2’ -free period, Ca2’ bound with high hypoxia, apparently by protecting against the inactiva- affinity to sites on the sarcolemma leaks away. This tion of Ca2+ channels (669). high-affinity Ca2’ pool holds together the inner and More recently, relaxation times and contraction du- January 1992 PHYSIOLOGICAL ACTIONS OF TAURINE 115 ration have been found to be significantly prolonged in stitial space. Free cytosolic Ca2’ concentrations are 103- papillary muscle of hearts taurine depleted by means of lo6 times less. Hence high-affinity binding and trans- guanidinoethane sulfonate (428). This is a consequence port of Ca2’ [i.e., dissociation (&) or Michaelis constant of a prolonged plateau phase of the action potential, i.e., (K,) in the PM range] are physiologically relevant only a prolonged Ca2’ entry phase. within the cell for extrusion of Ca2’ or transport into In congestive heart failure, there is an increase in cell organelles. Low-affinity processes (i.e., K, or K, in cardiac taurine content (301). The increased taurine the mM range), on the other hand, are relevant only for load derives from transport and not biosynthesis and is binding to the outside of the cell, for transport into the due to an adrenergic stimulation of taurine influx (103, cell, or for similar processes within cell organelles such 283, 303). Congestive failure is usually the consequence as mitochondria or sarcoplasmic reticulum in which of a prolonged period of cardiac overload, during which high Ca2’ concentrations can accumulate. Calcium there has been high adrenergic tone. The adrenergic entry into the cell proceeds down a concentration gra- stimulation of transport is, in turn, mediated via an in- dient and does not directly require energy (although crease in CAMP concentrations but is not due to an al- channel entry requires channel activation). Calcium re- tered ion flux produced by the cyclic nucleotide (34). moval from the cytoplasm proceeds against a concen- There is a cardiotonic action of taurine in experi- tration gradient and, directly or indirectly, requires en- mental congestive heart failure, produced in rabbits by ergy. Entry into the cell occurs through voltage- or re- damaging the aortic valve (40). Taurine, given orally, ceptor-regulated channels or via exchange processes, had an inotropic action and reduced mortality. such as Na’-Ca2’ exchange. Voltage-operated channels Taurine has been claimed to be of benefit in the are phosphorylated by CAMP-dependent or phospho- treatment of congestive heart failure in humans, either lipid-dependent protein kinases (405). Receptor-oper- by itself or as an adjunct to digitalis therapy (37-39, ated channels have been poorly studied but appear to be 749). It is now used for this purpose in Japan. Taurine opened by 1,4,5-inositol triphosphate, itself the product has been claimed to be of benefit in patients resistant to of a kinase (635). Both kinds of channels, therefore, have therapy with digitalis and diuretics (36). The inotropic an indirect energy requirement in that ATP is used as a actions of digitalis are due to an increased rate and by the kinases involved in their regulation. amount of delivery of Ca2’ to the myofibrillar contrac- Movement of Ca2’ from the cytosol requires a Ca2’ tile proteins. Presumably taurine, by whatever mecha- pump, such as the ones present in mitochondria, sarco- nism it acts, is achieving the same result. However, the plasmic reticulum, or the cell membrane. These various cardiac actions of taurine are not mediated via the ,&- processes involved in Ca2’ movements are quite differ- adrenergic receptor (187, 667), the histamine H, recep- ent, and in considering the actions of taurine on Ca2’ tor (187), changes in CAMP concentrations (667), or the movement, one must be aware of which process is being Na+-K+-ATPase enzyme (9). affected. The common dilated cardiomyopathy seen in house The Ca2+-modulatory actions of taurine involve ei- cats is associated with low concentrations of taurine in ther or both a modification of Ca2’ availability to sys- the circulation (628). Supplementation of animals with tems sensitive to Ca2’ or a modification of the sensitiv- taurine prevents or reverses the development of disease. ity to Ca2+, i.e., there is an alteration in intensity of Low taurine concentrations are also associated with di- either the signal or the response. Changes in signal in- lated cardiomyopathy in the fox (524). tensity include alterations in the rate and amount The taurine derivative taumustine, or Z-bis-(Z- of change in cytosolic Ca2’ concentrations during ex- chloroethyl)aminoethane sulfonic acid, is an antitumor citation-contraction or excitation-secretion coupling. agent having a number of toxic side effects. Taurine Changes in response intensity include alterations in af- does not affect the antitumor action but decreases the finity of Ca2+ -binding sites on troponin or calmodulin or neurotoxicity and pulmonary embolism associated with alterations in Ca2+ dependence of myosin ATPase and taumustine (623). Both these phenomena are Ca2’ re- other Ca2+-dependent ATPases. Current evidence indi- lated. Thus the decrease in embolus formation may be cates that the major effect of taurine involves an alter- due to a modulation of Ca2+ availability in platelets. ation in Ca2’ delivery (104, 315, 729). Although the brain has not been as well studied as the heart from this regard, a number of the central ac- The possibility of direct chelation of taurine and tions of taurine appear to be Ca2’ related. These include Ca2+ has been refuted by elegant 13C-nuclear magnetic the anticonvulsant actions (231, 331, 588) and interac- resonance (NMR) studies (144, 145, 324). The action of tions with opiates (118, 333, 334, 827). The excitotoxin- taurine on Ca2+ movements thus appears to be indirect. induced release of taurine may protect cells from Ca2’ The question reduces itself to in what way and under toxicity independent of an osmoregulatory function what conditions does taurine alter the membrane bind- (439, 519). However, Lehmann (436) found that taurine ing and transport of Ca2’. did not modify the toxicity of N-methyl-D-aspartate. 2. Eflects of taurine on calcium, wzovements I. Calcium binding and transport: general comments Extracellular Ca2+ concentrations are in the milli- At first sight, the actions of taurine on Ca2+ move- molar range: -2.4 mM in plasma and -1 mM in inter- ments appear confusing and inconsistent. However, 116 R. J. HUXTABLE Volume 72 these actions can be largely rationalized if careful con- ing the lack of functionality of inward-operating Ca2+ sideration is given to the preparation employed and the pumps in exterior membranes. The absence of the mito- incubation conditions, such as the Ca2+ concentration, chondrial marker enzyme cytochrome oxidase from rod composition of buffer, and presence of energy source. outer segments showing ATP-dependent Ca2’ transport Furthermore, most studies employ radiolabeled 45Ca2+ has been interpreted as indicating the preparation was to follow the movement of Ca2’ from one compartment not contaminated with mitochondria (599). However, to another. Movement of radiolabel does not necessarily the mitochondrial inhibitors ruthenium red, oligomy- mean that mass transfer is occurring in the same direc- tin, and dicyclohexylcarbodiimide all inhibited the ef- tion, i.e., increased 45Ca2+ uptake from cytosol to mito- fect of taurine in this preparation. Others have also chondria may reflect an increase in mitochondrial per- shown that the taurine stimulation of Ca2+ transport is meability such that the gross movement of Ca2’ is out- inhibited by these mitochondrial agents and also by the ward from the mitochondria. mitchondrial inhibitor atractyloside (469). Mitochon- That taurine has marked effects on the kinetics of dria are much more active in transporting Ca2’ than are Ca2’ in whole tissue has been shown by a number of purified synaptosomes (419). The lower the Ca2’ concen- investigators. Rat hearts perfused with 2.5 mM 45Ca2+ tration, the greater the activity of mitochondria relative for 15 min retained more radioactivity in the presence of to synaptosomes, a transporting ratio of 14:l being seen 8 mM taurine (104). During a Z-min Ca2+-free washout, at 10 PM Ca2’. In most cases, therefore, it is safe to more radioactivity effluxed from the taurine-exposed assume that, regardless of the preparation, high-affin- hearts; however, more remained in the heart at the end ity transport of Ca2+ is occurring into a subcellular or- of the washout. Similar observations have been made on ganelle. guinea pig heart (143). Taurine also increases the abso- Typically, bicarbonate-dependent stimulation of lute content of Ca2+ in guinea pig ventricular strips su- Ca2+ transport is observed employing 50 mM bicarbon- perfused at low Ca2+ concentrations (183, 186). At Ca2’ ate and 10 PM Ca2’ (412,469) or 25 mM bicarbonate and concentrations of 22.7 mM, however, taurine lowered 20 PM Ca2’ (599). These buffers are supersaturated with the Ca2+ content of strips (183). Here, in the absence of regard to Ca2’ salts, as is made apparent by salt precipi- taurine in the superfusate, the taurine content of the tation if the buffers are stored for l-2 days. Bicarbonate strips declines. One action of taurine in the superfusate, exists in aqueous solution in equilibrium with carbon- therefore, is to maintain tissue levels of taurine. ate, the pK, for bicarbonate being 9.75. The solubility of Calcium transport in the submillimolar range can calcium carbonate is -0.15 mM. Thus the solubility of be considered high-affinity transport. Typically, high- Ca2’ is

The other variable modifying the action of taurine Ca2+ concentration needed for half-maximal tension is Na+ concentration. In the absence of Na+, Remtulla et from 3.02 to 2.51 PM, a 17% decrease (729). al. (648) and Sebring and Huxtable (691) report that taurine decreases Ca2’ binding. The effect of taurine is due to a decrease in the affinity of Ca2+ binding from 4. Conclusions on taurine and calcium 0.20 mM in Tris buffer to 0.29 mM in Tris plus 10 mM taurine (691). The B,,, was unchanged. However, Conclusions that can be drawn as to the biochemi- Ca2+-binding affinity is much lower in the presence of cal actions of taurine on calcium movements are as fol- Na+. In the presence of Na+, taurine increases Ca2’-bind- lows. ing affinity from 4.6 to 1.9 mM. In guinea pig cardiac I) In the presence of a precipitating anion, taurine sarcolemma, on the other hand, it has been claimed that increases the Ca2’ storage capacity of the sarcoplasmic taurine stimulates the low-affinity binding of Ca2’ reticulum and, possibly, mitochondria and other intra- (362). Sodium competes for cation-binding sites with cellular organelles. Ca2’ and modifies Ca2+ entry or efflux via the Na’-Ca2’ 2) Taurine stimulates the pumping rate of Ca2+-ac- exchanger. In the absence of Na+, the latter becomes a tivated ATPase pumps, perhaps by increasing the turn- Ca2’-Ca2’ homoexchanger. over rate of the pump secondary to a membrane modifi- In the presence of ATP but in the absence of bicar- cation. bonate and Na+, taurine stimulates Ca2+ uptake in bull- 3) Taurine modifies the high-affinity binding of frog and hamster sarcolemma. Stimulation is not seen Ca2’ to the plasma membrane, increasing the affinity in sarcolemma of the cardiomyopathic hamster (807), an but decreasing the binding capacity. This effect of tau- animal known to have structural and biochemical de- rine is antagonized generally by cations, including Ca2+ fects in the sarcolemma. Stimulation appears to be de- itself. pendent on Ca2+ concentration, the effect being seen in 4) Taurine decreases the passive diffusion of Ca2’ general at concentrations of 21 mM. across the membrane. The release of Ca2’ from intracellular storage sites 5) Taurine modulates Ca2’ channel activity by two is also affected by taurine. Taurine potentiates - means: secondarily to an alteration in the properties of induced contractures of skinned cardiac fibers (729). Ca2+-binding sites on membrane acidic phospholipids Caffeine acts by releasing Ca2’ from the sarcoplasmic (thereby modifying Ca2’ delivery to the channel) and by reticulum. A significant aspect of this finding is that a direct effect on a hydrophilic site near or on the chan- taurine only needs to be present during the Ca2’ loading nel that is also influenced by Ca2’ channel antagonists phase, i.e., taurine does affect the action of caffeine per (thereby modifying the kinetics of channel opening or se but increases the size of the caffeine-mobilizable Ca2’ closing). pool. A further significant observation is that the effect Conclusions that can be drawn as to the pharmaco- of taurine is Ca2+ dependent. Contractures are stimu- logical or physiological actions of taurine on calcium lated by taurine when cells are loaded at 0.2 PM Ca2’ but movements are as follows. are inhibited by taurine when cells are loaded at 0.47 PM I) Taurine has the dual ability to increase Ca2+ Ca2’. The effect of taurine also depended on the degree availability under conditions of low Ca2’ availability of loading of the sarcoplasmic reticulum. As the degree but to protect against Ca2’ overload under conditions of of loading increased, so the dose-response effect of tau- high Ca2’ availability. rine shifted to the right (i.e., toward higher taurine con- 2) Taurine mildly increases the Ca2’ sensitivity of centrations). This results in taurine increasing caffeine- various Ca2+ -dependent processes. induced contractures when concentrations of Ca2’ in the 3) Both the positive and negative inotropic effects sarcoplasmic reticulum are low but decreasing contrac- of taurine parallel the effects of taurine on Ca2’ binding tures when Ca2’ concentrations in the sarcoplasmic re- to cardiac cell membranes and Ca2’ entry through the ticulum are near maximal. Again, there is a physiologi- slow Ca2’ channel. cal correlate to a biochemical observation. It has been shown that Ca2+ itself antagonizes the stimulation of Ca2’ binding produced by taurine (691). A further inter- C. Phospholipid Interactions locking observation is that increased osmolarity antago- nizes the effect of taurine. Membrane Ca2’ is bound primarily to the acidic phospholipids of the phosphatidylserine and phosphati- dylinositol classes. High-affinity binding of Ca2’ can be 3. Effect of taurine on calcium detectors observed to vesicles prepared from acidic phospholipids or to vesicles prepared from mixtures of phospholipids As well as affecting Ca2+ availability, taurine alters that include the acidic phospholipids. Negligible binding the response of Ca2’ detector systems in the cell. Thus it of Ca2’ occurs to neutral phospholipids. increases the binding of Ca2’ to myosin ATPase, in- As discussed, the effects of taurine on the mem- creases the Ca2+ sensitivity of myofibrils (729), and brane binding of Ca2’ have been well established. It has slightly alters the interaction of Ca2+ and calmodulin also been shown that taurine has similar actions on the (694, 695). In skinned myofilaments, taurine alters the binding of Ca2’ to artificial vesicles prepared from phos- 120 R. J. HUXTABLE Volume 7.2 pholipids present in the same ratio as is found in rat TABLE 4. Comparison between taurine binding to heart sarcolemma (296, 314, 316). In other words, tau- biological membranes and arti$cial phospholipid vesicles rine increases the binding affinity for Ca2’ to phospho- lipids but decreases the B,,, of binding. If vesicles pre- Artificial Biological Phospholipid pared from single classes of phospholipids are exam- Membranes Membranes ined, taurine is found to have a significant effect only on the binding of Ca2’ to phosphatidylserine. A point of Taurine binding affinity, 14.1 SL-filtration 28.8 interest is that the stimulation of binding is greater in mM 19.2 SL-centrifugation the mixed vesicles containing both acidic and neutral 33.4 P,B Hill coefficient 1.90 SL-centrifugation 1.52* phospholipids than would be predicted from the effect 3.26 SL-filtration 1.9t of taurine on vesicles of pure phosphatidylserine. Tau- 3.8* rine (20 mM) stimulates the binding of 1 PM Ca2’ to the Scatchard curve Bell shaped Bell shaped latter by 38%. In phospholipid vesicles mimicking the Binding antagonists Cations Ca2+ > Na+ > K+ Ca2+ > Na+ > K+ composition of rat heart sarcolemma, however, a stimu- Hypotaurine Yes Yes lation of 85% is observed. These vesicles contain 1.025% P-Alanine No No phosphatidylserine. On the basis of the Ca2+-binding val- Guanidinoethane No No ues for the individual phospholipids, it is possible to sulfonate predict a binding value for the mixed vesicles. The cal- SL, rat heart sarcolemma; P,B, rat brain synaptosomes. Original culated value for Ca2’ binding of 17 pmol/mg phospho- data from Refs. 296, 316, 317, 691, 692. * Heterogeneous phospho- lipid is close to the experimentally observed value of 21 lipid vesicles containing cholesterol. t Homogeneous phosphati- pmol/mg phospholipid. The stimulation seen with tau- dylcholine vesicles. $ Homogenous phosphatidylserine vesicles. rine (38 pmol/mg phospholipid), on the other hand, is much greater than the calculated value (19 pmol/mg phospholipid), i.e., the presence of both neutral phospho- independently found a similar low-affinity lipids (phosphatidylcholine and phosphatidylethanol- on cardiac sarcolemma, showing positive amine) and the acidic phospholipid phosphatidylserine and Na+ inhibition. All these binding characteristics in the same vesicle has a synergistic effect on the tau- were reproducible in phospholipid vesicles lacking pro- rine-induced stimulation of Ca2+ binding. tein (Table 4). From this it can be reasonably concluded How is taurine achieving these effects? A bigger that the low-affinity binding site for taurine present in mystery than necessary has been made of the binding of biological membranes is phospholipid in nature. Bind- taurine to membranes, particularly brain membranes ing affinity is increased by the addition of cholesterol to (for review see Ref. 297). When a correction is made for the liposome, i.e., it is affected by membrane fluidity. In the release of endogenous taurine, only two taurine- mixed vesicles, the addition of 50% cholesterol in- binding sites can be seen in brain synaptosomal P,B creased affinity from 64 to 29 mM. In vesicles prepared membranes, a high-affinity site with a & of 25 PM and a from single classes of phospholipids, the highest affin- low-affinity site of 33 mM (313). In rat heart sarco- ity of binding was found with the neutral phospholipids. lemma, the corresponding low-affinity site has a J& of Insignificant binding occurred to phosphatidylinositol 19 mM (692). The high-affinity site thus has a & similar (316). These binding affinities are in keeping with the to that of the K, for taurine transport. In addition, the structural analogy between taurine and the charged high-affinity site is Na+ dependent, and the binding of headgroups of the neutral phospholipids (Fig. 10). Tau- taurine is antagonized by taurine transport antagonists rine may form a low-afi nity charge complex with neu- such as guanidinoethane sulfonate. No equivalent high- tral phospholipids in membranes, thereby altering affinity binding site for taurine is found in phospholipid membrane architecture, fluidity, and properties. As cat- vesicles. This site can, therefore, be reasonably equated ions antagonize the binding of taurine, this implies that with the proteinaceous taurine transporter. High-affin- association with the phosphate grouping is of more sig- ity binding proteins for taurine have been partially puri- nificance than association with the amine grouping of fied from pig and rat heart ventricle (410, 411). Their the phospholipid headgroup. involvement in taurine transport has been shown by in- The effect of taurine on membrane Ca2’ binding has corporating the purified protein into proteoliposomes been explained in terms of an increased affinity of Ca2+ where, under appropriate conditions, the reconstituted binding with a decreased B,,, of binding. However, neg- system will transport taurine. ative cooperativity of taurine on Ca2’ binding would Binding to the low-affinity site, on the other hand, produce an equivalent shift. The two situations are de- is inhibited by cations such as Na+, Ca2+, and, to a lesser scribed by different mathmatical models: the first, bind- extent, K+ (692). The affinity of the low-affinity synapto- ing = B,,,/[l + (K&S)], and the second, binding = B,,,/ somal-binding site for taurine increases from 33 mM in [l + (Kd/S)nl ( w here S is substrate concentration and n the presence of 140 mM Na+ to 5.8 mM in the absence of is the Hill coefficient). However, the underlying mecha- Na+. The transport inhibitors, guanidinoethane sulfo- nism is not necessarily different. Taurine itself binds nate and @alanine, are without effect on low-affinity with positive cooperativity, implying that the binding binding. Binding showed positive cooperativity and of a taurine molecule to a given site increases the prob- yielded a bell-shaped Scatchard curve. Hirai (255) has ability of an adjacent site being occupied relative January 19% PHYSIOLOGICAL ACTIONS OF TAURINE 121

0 repolarization, there is a rebinding of taurine to the A 0 R-0-f-OCH,~HNH, membrane resulting in a greater affinity of binding of OQ co: Ca2+. The overall effect would appear to be accelerated rates of both the onset and offset of Ca2+-dependent phe- nomena, such as excitation-contraction and excitation- secretion coupling. 0 0 The above sequence is in part speculation and in B o=h4,CH,NH, I part based on biochemical observation. It is in keeping 0” with the known pharmacological actions of taurine and provides the beginnings of a rational basis for under- standing the physiological importance of this singular C 0 amino acid. 8 A glycoprotein binding taurine with low affinity R-0-bOCH,CH,NH,I Oe has been isolated from heart (101, 410). This has been postulated to be involved in the cardiac actions of tau- FIG. 10. Type structures for phosphatidylserine (A), taurine (B), rine. The binding of taurine shows positive cooperati- and phosphatidylethanolamine (C), illustrating similarity between vity. Hypotaurine is a potent inhibitor of taurine bind- taurine and charged headgroups of phospholipids. ing, whereas @-alanine is without effect. This mimics the effect of th.ese analogues on the phospholipid low- affinity binding site. Equimolar guanidinoethane sulfo- to a nonadjacent site. The binding sites for Ca2’ and nate reduced taurine binding to 29%, whereas this ana- taurine mutually compete inasmuch as taurine modifies logue reduces low-affinity binding to the sarcolemma by Ca2+ binding and Ca2’ antagonizes taurine binding. The only 7% (692). Thus we have a situation in which recon- effect of taurine on Ca2+ binding can be well described stituted phospholipid vesicles and a glycoprotein iso- by a curve of the following type: binding = B,,,/[l + lated from the sarcolemma both exhibit taurine-binding (Kd/S)n], where n < 1, i.e., where there is negative coop- properties remarkably similar to those of the low-affin- erativity. In one experiment, for example, the effect of ity site on the sarcolemma. We can either accept that taurine on Ca2’ binding to brain synaptosomes could be two low-affinity sites showing positive cooperativity described either by a fit to the two-compartment model and having the same structure-activity requirements reside on the sarcolemma or that the glycoprotein and binding = Bmaxl 41 + Wd11s >I + %,x241 + Wd 21s >I phospholipid sites are one and the same. If the latter, then it must be concluded that the phospholipid site has with a residual mean square of 0.063 or by a fit to a the better claim, because we can be sure that the lipo- one-compartment negative cooperativity model with a somes contain no protein. residual mean square of 0.037. In other words, excellent A high-affinity taurine-binding site has been lo- fits are obtained with both models, but the fit is better cated on the sarcoplasmic reticulum, exhibiting a Kd of with the cooperativity model. The best fit was obtained 3.2 PM (636). It is difficult to ascribe significance to such with a Hill coefficient of 0.80 t 0.02. Thus a negatively a site when intracellular taurine concentrations are 103- cooperative effect of taurine on Ca2+ binding may be the IO4 times higher. obverse side of the coin to a positively cooperative effect The effect of taurine is part of a four-way interac- on its own binding, i.e., these two effects are part and tion: taurine binds primarily to neutral phospholipids in parcel of the same phenomenon. This, however, is a ten- a low-affinity process, Ca2’ binds solely to acidic phos- tative suggestion. pholipids in a high-affinity process, and the binding of It appears, therefore, that the Ca2’ modulatory site taurine modifies Ca2+-binding sites so as to reduce the is a low-affinity taurine-binding site on neutral phos- number of sites and to increase the affinity of the re- pholipids. The affinity for taurine is in the range of in- maining sites. tracellular concentrations of taurine, so this site is phys- Phosphorus-31 NMR studies on the binding of iologically relevant only within the cell. At low cyto- paramagnetic cations to phospholipid vesicles support plasmic Ca2’ concentrations (low PM), taurine increases the existence of a taurine-cation-phospholipid interac- the amount of phospholipid-bound Ca2+. However, the tion (296). In keeping with this, verapamil decreases the effect of taurine is antagonized by Na+ and Ca2’ itself. low-affinity binding of taurine to the sarcolemma in par- As the concentrations of these cations increase during allel to its antagonism of the taurine-induced increase the depolarization phase of the action potential, so tau- in binding affinity of Ca2+ (101). rine is displaced from the membrane, resulting in a de- There is a hydration shell around the polar head- crease in the binding affinity of Ca2’ and an accelerated groups of membrane phospholipids. Removal of this hy- release of Ca2’ into the cytoplasm. Sodium also com- dration shell alters the phase transition temperature petes for binding with Ca2’, so a rise in Na+ due to the and other membrane properties, such as Ca2’ transport opening of the fast Na+ channels also increases the re- (121). The low-affinity binding of taurine may perturb lease of Ca2’ from membrane binding sites. Conversely, this shell. The binding of taurine may also decrease the as cvtoplasmic Na+ and Ca2+ concentrations fall during packing densitv of headgroups and the strength of the 122 R. J. HUXTABLE Volume 7.2

1.000 - van der Waals interaction between lipid chains, as has .-0 been observed for the interaction of trehalose and phos- -6 pholipids. OL ; 0.925 - We can speculate that the direct effects of taurine .- on phospholipid membranes modify other lipid-depen- 5 dent phenomena, such as the operation of ion channels, 5 the regulation of membrane-bound , and pro- h; 0.850 - tein phosphorylation processes. Many membrane pro- .- F tein functions are modified by their lipid environment. 0 50.775 - For example, ion pumps and Na+-K+-ATPase are c 13 strongly affected by cholesterol (833). -c If various cell phenomena are strongly affected by zl the interactions of phospholipids and taurine, then one 0.700 f I I I I might expect some correlation between membrane phos- 0 50 100 150 200 pholipid composition and cytosolic taurine concentra- Taurine Concentration tions. Indeed, this might be the basis for the wide varia- (nmol.mg -’ Synaptosomal Protein) tion in taurine concentrations of excitable tissues, both FIG. 11. Correlation of taurine concentration and ratio of neutral between species and at different developmental stages phospholipids in synaptosomal P,B fraction of developing rat brain. within a species. Thus the rat heart contains 35 pmol/g [From Huxtable et al. (304). Reprinted with permission by Pergamon wet wt of taurine, but the cow heart contains only 4 Press.] pmol/g wet wt (285). The rat brain at day I of age con- tains 18.6 pmol/g wet wt of taurine, whereas at 56 days of age it contains 4.9 pmol/g wet wt (304). Synaptosomes points to a structural change in the cell membrane, per- of developing brain represent a good system in which to haps in the phospholipid composition. examine for correlations, since development is accompa- N-methyl-D-aspartate-induced release of taurine nied by large changes both in taurine content and in in the brain is Ca2+ dependent, and release is reduced in phospholipid composition. Taurine concentrations in the absence of Ca2’ (439). It is possible that Ca2+ antago- the synaptosome fall from 181 nmol/mg protein on day 1 nism of phospholipid binding of taurine is involved in of life to 31 nmol/mg protein on day 56 (304). A strong the release of taurine. With this phenomenon, as with so negative correlation was found between taurine concen- many others, there is mutual “feedback” between tau- tration and the ratio of phosphatidylethanolamine to rine and Ca2’ in that the addition of taurine reduces phosphatidylcholine in the membrane (304; Fig. 11). Ca2’ influx and hence the resulting taurine release. Furthermore, synaptosomal taurine concentrations also Phospholipid vesicles and bilayer membranes fuse correlate with the rate of phospholipid , a under osmotic swelling (110). An osmoregulatory action process that converts phosphatidylethanolamine to of taurine, therefore, indirectly markedly affects phos- phosphatidylcholine (P. Lleu and R. J. Huxtable, unpub- pholipid behavior. Membrane fusion is involved in hor- lished observations). mone and neurotransmitter release, exocytosis, and the During development, there is also an alteration in insertion of proteins into plasma membranes. The inhib- the transport and diffusion characteristics of brain itory effect of taurine on transmitter release may, at membranes. The possibility is being investigated that least in part, be related to an inhibition of membrane the altered taurine concentrations are due to altered fusion. As Ca2’ speeds the rate of membrane fusion, the transport and diffusion through the membrane, which Ca2+-regulatory action of taurine may also be involved. in turn are a simple function of the phospholipid con- These two phenomena provide a mechanistic basis for tent. Phospholipid composition is well known to affect the much discussed “membrane stabilizing” actions of the activity of membrane proteins, including transport taurine (284, 300). proteins, and the ability of molecules to diffuse through Cryoprotection, or protection of cell functions the membrane is also affected by phospholipid composi- under low-temperature conditions, is a phenomenon tion. Increased incorporation of polyunsaturated fatty closely related to osmoregulation. Taurine is cryopro- acids into cell membranes of neuroblastoma cells led to tective in intertidal bivalves such as MytiZu,s (4729, ap- marked increases in the Vmax for glutamate transport parently by protecting phospholipids against fusion and and a smaller increase in the Vmaxfor taurine transport leakage. The binding of taurine to phospholipid head- (43). Guinea pigs maintained on 0.4% taurine in drink- groups affects bilayer fluidity and phase transition tem- ing water showed a marked decrease in hepatic phos- peratures (467). phatidylcholine content (82). Other actions of taurine that may involve lipid in- The effect of taurine on membrane transition tem- teractions include its antiaggregating effects on plate- perature may also be a consequence of phospholipid in- lets. Platelets are highly enriched in taurine. The plate- teraction and altered membrane fluidity (467). lets of taurine-deprived cats are twice as sensitive to The alterations in Ca2’ transport and in Ca2+-stimu- collagen-induced aggregation, whereas human platelets lated ATPase activities in taurine-depleted hearts are incubated with taurine are more resistant to aggrega- not rectified by incubation with taurine (239). This tion (248). On raising taurine content from 2.0 to 4.2 Jarmar-y 1992 PHYSIOLOGICAL ACTIONS OF TAURINE 123

~mol/106 platelets, the threshold for aggregation in- Whether or not taurine is a neurotransmitter is a, creased from 0.88 to 2.12 pg collagen/ml platelet-rich question still vigorously debated. The demonstration of plasma. Platelet activation involves the eversion of high-affinity Na+-independent binding sites for taurine acidic phospholipids onto the outer aspect of the mem- would be consistent with this amino acid having a trans- brane, followed by cross-linking via Ca2’ to y-carbox- mitter function. Over a physiological concentration ylglutamate residues on various coagulation factors. It range of taurine, no such high-affinity Na+-independent is possible that taurine is inhibiting the phospholipid binding of taurine is observed (313,474,476,514). How- changes leading to exposure of acidic phospholipids. ever, some groups have claimed the presence of such binding with affinities in the nanomolar range (385,386, 393,394,473,824). Thus 99% of the endogenous taurine I. Conclusions on taurine and phospholipids was removed from mouse brain synaptosomes by a com- bination of multiple freezings, thawings, washings, and I) There is a low-affinity binding site for taurine on detergent treatments (394). Sodium-independent bind- the neutral phospholipids of the membrane, with an af- ing of taurine was demonstrated in this well-pummeled finity within the intracellular range of taurine concen- preparation having a Kd .of 0.11 PM and a B,, of 0.13 trations. pmol/mg protein. Binding occurred with positive coop- 2) Taurine has a negative cooperative effect on the erativity (388,394). This affinity may be compared with high-affinity binding of Ca2+ to phosphatidylserine, re- the extracellular concentrations of taurine in the brain sulting in increased affinity of binding for Ca2+ and a as determined by microfiber dialysis. Depending on the decreased B,,,. brain region, these range from 6 to 20 PM (235,451). At a 3) The effect of taurine on the phospholipid binding concentration of 6 PM taurine, >98% of the binding sites of Ca2’ is antagonized by Ca2+ and Na+. The antagonistic will be occupied. If positive cooperativity with a Hill action of Na+ is, in turn, antagonized by ATP. coefficient of 2 is assumed (393), then the proportion of 4) The Ca2+-modulatory actions of taurine are man- sites occupied increases to 99.97% {i.e., binding = B,,/ ifested, at least in part, via the low-affinity binding site [1 + (KJS)‘]}. F rom the binding constants (388), it is for taurine. possible to estimate that t0.001% of the taurine in the brain can be bound to Na+-independent sites. Others have found even higher affinities, up to 0.027 PM (824). Typically, Na’-independent binding for GABA is D. Protein Interactions lo-100 times more abundant (473). Corresponding af- finities for GABA are 1.2 PM for Na+ dependent and 0.37 Given the ubiquity of taurine in mammalian cells PM for Na’-independent binding (156) compared with and the high concentrations which obtain, it is not un- an extracellular GABA concentration of 0.1 PM (664). At reasonable to expect to find taurine-dependent phe- this concentration, ~21% of the Na+-independent sites nomena involving interactions with proteins. Indeed, will be occupied. Thus the GABA-binding sites have neu- taurine has a plethora of effects that might be the con- rochemical relevence not obvious for the taurine-bind- sequence of protein interactions, including the neuro- ing sites. Sodium-dependent binding is lo-fold greater transmitter-like effects. Protein interactions could be than Na+-independent binding, but freezing and thaw- indirect, secondarily to alterations in the lipid environ- ing abolishes Na+-dependent binding while doubling ment produced by the lipid binding of taurine, or direct, Na+-independent binding (156). involving the binding of taurine to protein. Effects could When taurine concentrations are depleted by result from the antagonistic actions of taurine, i.e., its means of guanidinoethane sulfonate (308), Na’-indepen- binding blocking the binding of a biologically active li- dent binding sites show increased affinity for taurine, gand, or from the agonistic actions of taurine, the bind- the Kd falling from 0.54 to 0.10 PM (386). ing of taurine producing some direct consequence. The These studies show that brain membranes can be sticking point in investigations in this area, however, is manipulated to express a low degree of Na+-indepen- that such protein binding of taurine has yet to be unam- dent binding of taurine (394). The physiological rele- biguously demonstrated. vance of such binding remains to be demonstrated. Such Extracellularly, binding affinities must be within drastic treatment of tissue is necessary for binding ac- an order of magnitude of the measured taurine concen- tivity to be expressed that it is questionable whether the trations (6-20 PM) for variations in binding to be physio- binding sites exist in vivo or whether they are an arti- logically meaningful. As discussed in section IVC, tau- fact of the treatment. If they exist, what is the relevance rine binding of this order that has been well character- of sites of such high affinity that they are half saturated ized can be equated with the transport site for taurine. at taurine concentrations of -1% of those actually oc- Intracellularly, for modulation of protein activity to oc- curring in brain extracellular fluid (235)? cur, binding constants within the range of intracellular The Na+-independent binding demonstrated for tau- taurine concentrations are presumably required. rine is much less than that found for GABA (388, 394, Higher affinity sites would be permanently occupied. 473,774). There is the further question, therefore, as to Such sites, however, could be involved in protein stabili- whether the observed binding is to sites unique for tau- zation. rine or to sites that also bind GABA. Binding is blocked 124 R. J. HUXTABLE Volume 72 by the glycine antagonist, , or the GABA an- binding of the Cl- ionophore t-butylbicyclophosphoro- tagonists , , and homotaurine, sug- thionate to the GABA, receptor complex (638). As inhi- gesting that binding could be to either glycine or GABA bition of binding has been correlated with the opening of sites. The electrophysiological actions of taurine are typ- the Cl- channel, the action of taurine suggests that it ically explained on the basis of taurine acting at recep- stimulates Cl- flux by interacting with the recognition tors for GABA, glycine, or taurine. The area has been site for GABA on the GABA* receptor complex. The recently reviewed (297). The relevant point for this re- available knowledge does not establish, but does not dis- view is how good the evidence is that these actions of prove, that taurine is acting at a proteinaceous site. In taurine are mediated by protein binding. It would take a terms of the lipid interactions of taurine, it is notewor- Judge Jeffreys to hang on the basis of the available evi- thy that GABA binding appears to be regulated by dence. Both biochemical (binding) and electrophysiologi- membrane phospholipids. Treating brain membranes cal studies must concur in the demonstration of a “tau- with phospholipase C or glycerophosphoethanolamine rine receptor.” increases the affinity of GABA binding (463). Further- Taurine noncompetitively blocks the binding of more, whereas taurine inhibits the binding of flunitra- GABA to postsynaptic binding sites, GABA exhibiting a zepam to synaptosomes (P2 fraction) at 0-4”C, taurine decreased B,,, with no change in & (221,257,328,487- stimulates binding at 37OC (638). This suggests that the 489,576). This implies that taurine is not binding at the effect of taurine is modified by a phase change in the same site as GABA. It displaces the binding of GABA to membrane. both high- and low-affinity sites, with half-maximal in- The higher affinities reported in some of the papers hibitory concentrations (IC,) of 30 and 700 PM, respec- cited are likely to be inaccurate due to a failure to take tively (488, 489). Others have found taurine to be less into account the release of endogenous taurine from the active in antagonizing the binding of GABA (257). Tau- membrane preparations being used. It is difficult to rine appears to be rather more effective at the GABAB prepare membranes free of releasable taurine, and even site, having an IC,, of 5 PM (398). If taurine is capable of well-washed preparations can release sufficient taurine inhibiting GABA binding, one would imagine it should to raise taurine concentrations by an order of magni- not be too difficult to demonstrate direct binding of tau- tude at nominal concentrations under 10 FM (313). rine, but so far this demonstration has been elusive. The failure to date to demonstrate receptor binding Taurine also appears to modify the postsynaptic re- for taurine raises the major question as to how its elec- sponses to GABA. A characteristic of trophysiological actions are expressed. These have been binding in the brain is that GABA stimulates binding in assumed to be mediated by interactions at protein re- washed, but not unwashed, membranes. Thus GABA ceptor sites controlling ion fluxes. Kudo et al. (406) have stimulates the binding of and proposed subtypes of taurine receptors in the frog spinal to the benzodiazepine-binding site on the GABA recep- cord based on electrophysiological responses. Mathers tor-Cl- channel complex. Taurine inhibits GABA stimu- et al. (503) have concluded that there are three types of lation (328, 488, 490, 514). The half-maximal effective taurine receptors in the spinal cord: depolarizing, hy- dose (ED,& concentrations found range from 7 (514) to perpolarizing, and glycine types. Others report that the 780 PM (488, 489). Again, the inhibition is noncompeti- taurine antagonist (TAG; or 6-aminomethyl-3-methyl- tive (328). The antagonistic effect of taurine cannot be 4H,l,2,4-benzothiadiazine-1,1-dioxide) antagonizes the overcome by increasing the concentration of GABA, in- depolarizing actions of taurine and P-alanine in the frog dicating the effect is not due to competition at the spinal cord without affecting the action of glycine or GABA-binding site (328). Here, taurine is acting as a GABA (582). Thus there is a degree of evidence that at partial agonist of the GABA-benzodiazepine receptor least in the spinal cord there may be specific receptors complex, affecting the GABA recognition site but not for taurinelike substances. However, the demonstration directly affecting the benzodiazepine-binding site. The of binding of the appropriate type and structure-activ- fact that diazepam binding is increased by taurine in the ity requirements is an absolute requirement for valida- presence of suggests that taurine inter- tion of the existence of a receptor. acts with the -binding site (328). Abundant reports of the neuroinhibitory actions of There is confusionover the action of taurine on ben- taurine start with the findings of Curtis and co-workers zodiazepine binding in the absence of GABA. Some (123, 125, 126). The evidence is good both peripherally workers find that taurine causes a reduction in the B,,, and centrally that these actions of taurine are the result of flunitrazepam binding but an increase in the affinity of a stimulation of Cl- current (117, 226, 227, 543, 556, (514). This parallels the action of taurine on Ca2’ bind- 559, 744). This leads to hyperpolarization of the cell ing. However, there is a difference of opinion on the membrane. dose-response relationships. The IC,, for inhibition of The degree of hyperpolarization produced by tau- flunitrazepam binding has been claimed to be between rine decreases as the membrane potential is made more 12 and 32 PM (514) and to be 30-50 mM (488,818). Thus, negative. At sufficiently negative potentials, the effect although it is clear that taurine interacts with the benzo- reverses and taurine produces a depolarization or hypo- diazepine-GABA-Cl- channel complex, it is not at all polarization. The crossover potential is the “reversal clear how it is acting. There is a recent report that tau- potential.” A reversal potential occurs with taurine in rine inhibits. in a bicuculline-dependent manner. the guinea pig hippocampal slices at -55 to -67 mV (840), in January 19% PHYSIOLOGICAL ACTIONS OF TAURINE 125 guinea pig Purkinje cell dendrites at -125 mV (560), and altering the physical properties of the membrane lipids in lobster axon at -85 mV (226). Neuronal CA3 pyrami- surrounding the channel. Taurine has no effect on the dal cells and granule cells that are syn aptically stimu- action of the first agent but antagonizes, both in vivo lated fro m resting potentials of -65 mV are hyperpolar- and in vitro, the reduction in Cl- current produced by ized in the presence of taurine. At a resting potential of diazacholesterol (116). The effect is rapid and is thus -80 mV, both cell types are depolarized. At -72 mV, unconnected with the synthesis of new channel proteins. there is a biphasic response to taurine, with an initial The authors conclude that taurine is interacting with a hyperpolarizing response being followed by a depolariz- lipid environment near the receptor with the effect of ing response. The action of taurine on cerebellar Pur- increasing the open probability of the channel. Thus the kinje cells is similarly due to an effect on Cl- conduc- effect of taurine on Cl- conductance may be a conse- tance. Here, however, a reversal potential of -125 mV is quence of the lipid binding of taurine rather than of a found (559-562). direct protein interaction. The differing reversal potentials in various prepara- Taurine and Cl- may mutually interact in the CNS tions are due to the effect of the K+ concentration on the in that taurine transport can be both Na+ and Cl- de- Cl- gradient. The hyperpolarizing action of taurine on pendent (75,96,515,523,773). Such dual dependency is pyramidal CA1 neurons has a reversal potential of be- seen in livers (75), placental brush-border membranes tween -65 and -70 mV (744). This is the same as for (523), renal brush-border membranes (96,773), and syn- Cl-dependent responses in hippocampal slices (14, 25, aptosomes (515). Microdialysis experiments on the 753, 754) and is positive to the K+-induced reversal po- brain have shown that extracellular taurine concentra- tential (753, 754). Earlier conclusions that taurine di- tions rise ZO-fold when an anion such as acetate is sub- rectly altered K+ conductance may be in error (226,563). stituted for Cl- (721). Other amino acids were unaf- Recently, Okamoto et al. (559), working with Purkinje fected, apart from an increase in phosphoethanolamine cells, concluded that the apparent dependency of the re- (447). It was not established whether the increased con- versal potential on K+ concentration was an effect sec- centrations were a result of increased release or de- ondary to an alteration in internal Cl- concentration creased reuptake, although it was proposed to be en- produced by the external change in K+ concentration. hanced release (721). The increase in extracellular tau- Thus an increase in K+ conductance is either absent or rine concentrations is due to the use of weak acids to only a minor part of the action of taurine. replace Cl- rather than due to the decrease in Cl- con- A reversal of electrophysiological action is also tent per se (499). The cell permeability of weak acids seen at low Cl- concentrations. The taurine-induced hy- leads to an increase in intracellular osmolality. The re- perpolarization of Purkinje cell dendrites decreases the sulting osmotically induced release of taurine would frequency of spontaneous firing (560). This inhibitory have the effect of counteracting the increase in cell vol- action reverses to an excitatory action at Cl- concentra- ume that would otherwise occur. Partial substitution of tions <4 mM (559). This is caused by a reversal of the Cl- with isethionate, an impermeant sulfonate anion, concentration gradient for Cl- across the cell mem- did not lead to an increase in extracellular taurine con- brane. If the transmembrane Cl- gradient is decreased centrations (499). However, intriguingly, the increase in by injecting Cl- into neurons, the hyperpolarizing re- taurine concentration produced by acetate is blocked by sponse to taurine converts to a depolarizing response the Cl- transport inhibitor furosemide (721). Whether (744). In keeping with this, on intracellular recording, this indicates that taurine transport is intimately asso- taurine-induced hyperpolarization is proportional to ciated with the Cl- channel or whether it is an indepen- the external Cl- concentration. dent action of furosemide remains to be established. In cultured spinal neurons of mouse, patch applica- In stimulating Cl- flux, taurine is similar in its neu- tion of taurine (5-40 PM) leads to stimulation of Cl- ropharmacology to the other w-amino acids, GABA and current with taurine activating Cl- channels with an glycine. There are some differences between the amino average life time of 1.0 ms (503). This is significantly acids. Typically, taurine has a slower onset of action shorter than duration of activation produced by GABA. than iontophoresed GABA (543, 565). y-Aminobutyric Taurine also has electrophysiological actions in acid increases the amplitude of cortical evoked poten- muscle (117,226,227). Rats given 5 mmol/day taurine ip tials within 30 s of application, whereas a response to for 14 days show a significant shortening in muscle ac- taurine takes -3 min to develop (656). In cortical neu- tion potential duration combined with an acceleration rons of cats, GABA hyperpolarized all cells, acting on in the rates of depolarization and repolarization (226). the soma. Taurine, acting on the dendrites, hyperpolar- Taurine produced a hyperpolarization of membrane po- ized less than one-half the cells (13). The hyperpolariz- tential in muscle fibers, both on preloading the animal ing effect of taurine on Purkinje cells had a more grad- and on direct addition to the tissue bath. ual onset and offset than the effect of GABA (834). The Additional light on the mechanism of taurine-in- different time course of action militates against, but duced changes in Cl- conductivity in striated m uscle has does not exclude, the possibility of taurine acting at been obtained from channel inhibitor studies. Anthra- GABA receptor sites. On exposure to taurine, a current cene 9-carboxylate lowers Cl- current by binding to a response is produced in Xenopus oocytes injected with site within the channel and occluding it. 20,25-Diaza- mouse brain mRNA (272). However, the response to tau- cholesterol, on the other hand, lowers conductance by rine is extremely weak compared with GABA. In the 126 R. J. HUXTABLE Volume 72 same system, taurine competitively antagonized the re- stimulation of Cl- current in cortical homogenates, but sponse to glycine (273). glycine is without effect (556). The taurine antagonist Although taurine stimulates Cl- current in cerebral TAG blocks frog spinal cord depolarization and the hy- cortical homogenates of mice, it inhibits the stimulation perpolarizing response of Purkinje cell dendrites pro- of Cl- current produced by GABA (556). y-Aminobu- duced by taurine without affecting the similar re- tyric acid is acting at GABA, sites, as shown by antago- sponses to glycine (562,830). However, taurine agonists nism by picrotoxin or bicuculline and by the lack of ef- such as taltrimide and antagonists such as TAG are fect of the GABAB antagonist baclofen. The authors’ highly lipophilic. It has yet to be established whether conclusion that taurine is a partial agonist at GABA* their taurinelike activities are expressed in lipid or pro- sites must be confirmed by kinetic analysis of the effect tein compartments. of taurine on the dose-response curve to GABA. Both glycine and taurine produce cardiorespiratory In guinea pig cerebellar slices, sites sensitive to ion- depression when applied to the ventral surface of the tophoresis of taurine, GABA, glycine, and @-alanine medulla (207). Their effects are blocked by both strych- differ, even though the actions of all four amino acids nine and TAG, indicating that the sites of action of the are blocked by picrotoxin or strychnine (564). If dis- two antagonists were similar. That they were not iden- tances are measured from the Purkinje cell body in mi- tical, however, was surmised from the observation that crons along the dendrite, sites at which spontaneous strychnine given in the absence of an amino acid was spike discharges can be suppressed are clustered at 0,80, without effect, whereas TAG given similarly produced 180, 220 and 280 pm, with sites on the cell body (0 pm) respiratory stimulation. The gradients of the dose-re- being basket cell synapses and the sites on the dendrites sponse curves to glycine and taurine also differed mark- being stellate neuron synapses. y-Aminobutyric acid- edly, which should not occur if their actions were me- sensitive sites were located at 0 and 180 pm, and tau- diated via the same receptor. Another group, however, rine-sensitive sites were located at 0, 80, and 220 pm. did not observe that TAG antagonized glycine-induced Alternate injections of each of a pair of amino acids onto cardiorespiratory depression (808). the same cell show that taurine- and glycine-sensitive Taurine competitively reduces strychnine binding sites or taurine- and ,&alanine-sensitive sites do not co- in brain stem (395), spinal cord (530), and retina (67), incide. whereas strychnine antagonizes taurine binding to Taurine modulates both the release of and the re- brain membranes (388) and reduces the depressant ac- sponse to GABA (514). The Ca2+-dependent, K+-stimu- tion of taurine in the brain stem without affecting the lated release of GABA from cerebellar slices is reduced action of GABA (232). These findings indicate a close by taurine in a dose-dependent manner (0.25-25 mM) relationship between binding sites for taurine and (537, 538). Taurine reduces Ca2+ efflux to a degree pro- strychnine. portional to the decrease in GABA release. In the ab- Taurine has been shown to interfere with the action sence of Ca2+, taurine has little effect on GABA release. of a number of proteins in addition to those of receptors If anything, basal GABA release is mildly stimulated by for neuroinhibitory amino acids. Although these effects taurine (390, 396). Its effect, therefore, is presumably may be presumed to be secondary to binding to these consequential on a decreased entry of Ca2’ and is thus proteins, such binding has not been demonstrated. Cal- probably due to interactions of taurine with membrane modulin is a Ca2’ -dependent protein that has two high- phospholipids. affinity and two low-affinity binding sites for Ca2+. Tau- Less work has been done on the relationship be- rine modifies some of the consequences of calmodulin tween glycine and taurine responses. Interpretation of activation, including decreasing the rate of the calmod- findings has relied heavily on the presumed specificity ulin-dependent decrease in adenylate cyclase activity of action of strychnine as a glycine antagonist. The ac- (673). As calmodulin stimulates the Ca2+-ATPase activ- tions of taurine that are blocked by strychnine have ity in the sarcolemma that is associated with the Ca2’ been interpreted as being mediated via a glycine recep- pump, such an effect of taurine may be involved in its tor (68, 232, 414, 415, 507, 693, 724, 775). Thus both gly- Ca2’ modulatory activities. In the brain, 10 mM taurine tine and taurine reduce the light-evoked release of ace- markedly decreases Ca2’ binding to calmodulin (694, tylcholine, taurine being five times as potent as glycine. 695), an action that has been suggested to be the link The actions of both agents are blocked by strychnine between taurine and ,&adrenergic responses. Kinetic (122). The stimulation of Cl- current in cultured neurons analysis reveals that the effect on Ca2+ binding is due to induced by taurine is abolished by strychnine but is un- a decreased Ca2+-binding affinity (695). The binding of affected by the GABA antagonist bicuculline (503). Ca2+ shifts the ultraviolet absorption spectrum of cal- In other experimental situations, however, the ac- modulin such that the difference spectrum is negative tions of the two amino acids can be clearly distin- between 270 and 290 nm. Taurine converts this to a posi- guished. Although the inhibitory actions of both glycine tive difference spectrum (695). The shift is caused by a and taurine on the frog spinal cord are antagonized by conformational alteration following Ca2+ binding that dendrobine and strychnine, the hyperpolarizing action increases the a-helical content and exposes tyrosine resi- of taurine is blocked at strychnine concentrations (0.1 dues to the solvent. Taurine must therefore be interfer- PM) that were without eflFect on glycine (406,407). Both ing with this conformational change, presumably by strychnine and taurine antagonize the GABA-induced binding, although this has not been established. January 1992 PHYSIOLOGICAL ACTIONS OF TAURINE 127

The insulin receptor is another postulated site of (333, 837) and antagonizes the -induced in- action of taurine (506). A number of effects of taurine on crease in growth hormone secretion (115). These effects glucose metabolism have been reported, including a hy- may be related to the antagonism by taurine of mor- poglycemic and antidiabetic action (142,762), increased phine-induced decreases in Ca2’ content of synapto- glucose uptake, potentiation of the actions of insulin somes. Taurine also may inhibit the release of endoge- (429), and enhanced glycogenesis, glycolysis, and glu- nous . Taurine, administered in drinking water, cose oxidation (147,409,527,673). If cardiac taurine con- increases ,&endorphin-like immunoreactivity in the hy- centrations are decreased with guanidinoethane sulfo- pothalamus (ZOO), one of the brain areas most sensitive nate or ,&alanine, cardiac glycolysis is increased second- to peripherally administered taurine (275). ary to a stimulation of phosphofructokinase activity Along with the other inhibitory amino acids, tau- (527). This, in turn, is a consequence of decreased citrate rine blocks the elevation in CAMP concentrations in concentrations. In the pancreas, increased glycolysis brain slices induced by cysteine sulfinate but not the has been ascribed to an increase in hexokinase activity elevations induced by aspartate or glutamate (41). In (EC 2.7.1.1). An increase in plasma taurine decreases addition, taurine also antagonizes the stimulatory ef- glycogenolysis (408,429). fects of norepinephrine, adenosine, and histamine on Binding of taurine to the purified insulin receptor hippocampal CAMP concentrations (41) . Furthermore, has been reported, with a Kd of 0.13 PM and a B,,, of 1.6 taurine antagonizes the stimulation of CAMP produc- nmol/mg protein (506). Binding was displaced by insu- tion in cockroach hemocytes induced by the insect neuro- lin. Again, the affinity presents a problem for a physio- transmitter octopamine and other phenylalkylamines logically meaningful modulatory action in that it is (246). The mechanism appears to be competitive inhibi- w 1% of extracellular taurine concentrations. However, tion of the receptor. Taurine also inhibits release of oc- in general, taurine has been claimed to have insulin-like topamine from the insect CNS, thereby modulating actions (140). Thus it markedly lessens the rise in serum aminergic function. Conversely to its effect on brain glucose concentrations following glucose loading (409). CAMP concentrations, taurine has been shown to in- This is caused by increased clearance by muscle, indi- crease cerebellar guanosine 3’,5’-cyclic monophosphate cating a membrane action of taurine. Taurine also po- (cGMP) concentrations (229). tentiates insulin release from the pancreas by a nonad- In the periphery, there are indications of an in- renergic mechanism (714). terrelationship between taurine and the sympathetic Insulin, in turn, increases the formation of taurine- system. In the heart, taurine antagonizes the stress-in- containing bile salts by an effect independent of in- duced increase in cyclic nucleotide content (486), its ef- creasing taurine transport (546). fect on CAMP being greatly reduced after ,&blockade. Interactions between taurine and carbohydrate me- The taurine-induced decrease in cardiac CAMP content tabolism have been observed in amoeba. Taurine in- appears to involve an effect on both adenylate cyclase duces encystation in HartmanneZZa (786). In association and phosphodiesterase (484). Taurin .e transpor t in the with this, taurine increases glycogenolysis, activating heart, salivary glands, and is uniquely stimu- glycogen phosphorylase while inhibiting glycogen syn- lated by &-adrenergic agonists or by agents that raise thetase and lowering CAMP concentrations. cell CAMP concentrations (34,35,283). This is the mecha- Taurine has a number of additional actions that nism whereby cardiac taurine concentrations are raised may be receptor or enzyme mediated. However, evidence in (666) and congestive heart failure (301). as to the mechanism of action is missing in all of these. In the brain and pineal, however, &-adrenergic activa- Taurine is antagonistic to a number of the actions tion leads to stimulated release of taurine (479,703,811). of morphine, an action that perhaps underlies its use in Adrenergically stimulated release occurs from glia cells various countries, including the United States, in the also, raising the possibility of an adrenergic modulation treatment of opiate addiction. Crave-Away, which is of neuronal-glial interactions (479, 702). The effects of sold as “an adjunct to standard therapy for chemical cyclic nucleotides on taurine movements are indepen- dependence” contains taurine as the major ingredient. dent of their actions on cytoplasmic Ca2+ concentrations Taurine counteracts -induced analgesia (118,335, (34, 701). SZ?), increases the ED,, for morphine (827), and re- Taurine also increases the turnover of CAMP in the duces wet dog shakes produced by [D-Ala2,Met5]en- heart, stimulating both adenylate cyclase and phospho- kephalinamide (837). Conversely, GABA increases mor- diesterase (484). As the latter is stimulated more than phine-induced analgesia. Taurine is antinociceptive, at the former, the consequence is a decrease in cardiomyo- least against writhing produced by intraperitoneal in- cyte CAMP concentration (484). As discussed in section jection of acetic acid. The opiate antagonist naloxone IvBZ, under conditions where taurine stimulates Ca2’ inhibited the effect of taurine, which suggests that the uptake in retinal membranes, it also inhibits protein opioid system is involved (697). Naloxone also blocks the phosphorylation by [T-~~P]ATP (453,466). It is tempting lowering of induced by taurine in deoxy- to associ ate all th .ese phenomena and to suggest that corticosterone acetate (DOCA)-salt hypertensive rats taurine s timulates CAMP-dependent phosphorylation of (ZOO). Taurine, on the other hand, was without effect in Ca2’ channels while also decreasing the average opening the hot-plate test. Taurine also attenuates abstinence time. signs to morphine and to [D-Ala2,Met5]enkephalinamide Although the transport and efflux of taurine are 128 R. J. HUXTABLE Volume 72 stimulated by CAMP, the inactivation of such stimula- Blood pressure is also lowered (201). In hypertensive tion does not appear to be due to a decrease in cellular humans, oral taurine administration lowers blood CAMP. In astroglial cells, increased CAMP concentra- pressure and attenuates sympathoadrenal tone (198). tions resulting from ,&adrenergic stimulation eventu- Peripheral administration of taurine also blocks the in- ally fall due to an increase in phosphodiesterase activ- creased turnover of norepinephrine in the hypothala- ity. However, CAMP concentrations decrease slower mus of DOCA/salt hypertensive rats (201). Central (in- than the fall-off in the rate of taurine excretion (702). tracerebroventricular) administration of taurine de- Taurine also activates cardiac guanylate cyclase ac- creases blood pressure, heart rate, and sympathetic tivity (485, 702). nerve activity in both hypertensive and normotensive Taurine lowered the elevation of cardiac cyclic nu- animals (68,322,323,581,829). Taurine also antagonizes cleotides in intact rats in response to stress. The effect the increase in blood pressure produced by centrally ad- on cGMP concentrations was blocked by , and ministered renin (3). It appears that taurine normalizes the effect on CAMP was attenuated by adrenergic overactivity of the sympathetic nervous system, possi- ,&blockers (486). This suggests that taurine affects bly by inhibiting neuronal influx of Ca2’. the coupling between receptor and second messenger Taurine also promotes natriuresis, increasing uri- system. nary kallikrein output and decreasing plasma atria1 na- Cyclic AMP-induced inhibition of phagocytosis is triuretic factor concentrations when given as a 3% solu- antagonized by taurine in chick retinal pigment epithe- tion in drinking water (274, 375). lial cells (545). Controlled phagocytosis is important in In the pineal, taurine stimulates N-acetyltransfer- maintaining the functional integrity of the retina. Rod ase activity, increasing the production of acetylsero- outer segments, like some manic and never-ending pro- tonin 40-fold and melatonin 25-fold (812). This effect cession, are synthesized at the rate of three to four per appears to be mediated ,&adrenergically, as it is blocked hour and march steadily outward to a phagocytotic stereospecifically by L-propranolol. Taurine produces doom (839). Melatonin is the extracellular messenger the same actions in denervated pineals, so its effect is stopping phagocytosis, and CAMP is its intracellular not due to release of norepinephrine. counterpart. It appears that the intracellular “stop” Taurine has been found to both stimulate and in- signal is cancelled by cGMP, and the extracellular stop hibit evoked release of norepinephrine. The effect seen signal is cancelled by taurine. Phagocytotic activity, depends on the endogenous taurine concentrations and therefore, is controlled by the taurine-to-melatonin ra- on the area of the brain examined, one study finding tio in the space around the photoreceptors. enhanced release from frontal slices and inhibited re- This action of taurine is reminiscent of its actions lease from occipital slices (382). Another study found in the slime molds. These bizarre organisms exist for that taurine increased norepinephrine concentrations part of the time as dispersed, single cells. For reproduc- in the midbrain but decreased them in the hypothala- tive purposes, cells aggregate into a fruiting body. Ag- mus, along with a decrease in turnover rate (12). The gregation is inhibited by glucose, but the inhibition is effect may also be concentration dependent, high levels overcome by taurine via a stimulatory action on cell of taurine inhibiting release (531). Greater stimulation CAMP concentrations (381, 504, 640, 786). is seen in taurine-depleted brains (382). A stimulatory Taurine decreases the number of binding sites for effect on K+-evoked release may be mediated via pre- the al-antagonist prazosin (182) and decreases the posi- synaptic cu-adrenergic receptors and also by increased tive inotropy of phenylephrine (measured in the pres- availability of Ca2’ for stimulus-secretion coupling (205, ence of propranolol to block ,&responses) (184). Taurine, 382). Evoked release has been shown to be inhibited by therefore, exhibits a-adrenergic antagonism. taurine in the cortex and superior cervical ganglion The effects of taurine on motor behavior and tem- (417, 531). Taurine also suppresses the K+-evoked re- perature regulation also appear to be mediated via a lease of norepinephrine from the superior cervical gan- catecholaminergic system (12, 205). glion and from cerebral cortical slices (531). It is with- Taurine is involved with purinergic systems. In as- out effect on spontaneous efflux. In addition, taurine troglial cells, incubation with adenosine leads to an in- inhibits the release of preloaded norepinephrine from crease in CAMP concentrations and a stimulation of tau- synaptosomes. rine release (480). The ,&blocker propranolol is without Few interactions of taurine and serotonin have effect, but the adenosine blocker isobutylmethylxan- been reported. Taurine increases the affinity but de- thine blocks these responses. Other studies indicate the creases the number of synaptic binding sites for spiper- involvement of the purinergic A, receptor. Purinergic one, a ligand for dopamine and serotonin receptors A, agonists increase the release of taurine but are with- (389). This is reminiscent of its action on the binding of out effect on CAMP content. Ca2’. Taurine also decreases the activity of striatal dopa- The various central and peripheral actions of tau- minergic neurons (240, 241). Taurine decreases seroto- rine on blood pressure regulation may also involve di- nin turnover in the hypothalamus (12). Taurine-induced rect interactions with protein. The increased norepi- hypothermia is reduced if brain serotonin content is low- nephrine turnover in the hearts of uninephrectomized, ered by p-chlorophenylalanine treatment (698). The au- DOCA hypertensive rats is suppressed to control levels thors concluded that taurine-induced hypothermia was by adding 1% taurine to the drinking water (200, 666). mediated, at least in part, via serotonergic mechanisms. January 1992 PHYSIOLOGICAL ACTIONS OF TAURINE 129

It has also been suggested that the stimulatory effect of binding is being observed rather than a consequence of a taurine on prolactin secretion is mediated serotonergi- general membrane action. tally (676). Somatostatin was released from isolated median Taurine decreases the release of acetylcholine from eminences incubated with 50 PM taurine (8). This effect, the abdominal ganglion of the cockroach PeripZaneta however, is not specific to taurine, being exhibited by americana (279), brain slices (531), the retina (122), the hypotaurine (200 PM) and cysteamine (50 PM). The most adrenals, superior cervical ganglia, and cerebral corti- potent compound was cysteic acid, which was effective cal slices (531). In the first system, the action of taurine at 0.1 PM. Taurine also increases the release of somato- is unaffected by TAG, high Ca2’ concentrations, or by statin (detected immunologically) from cultured rat ce- 4-aminopyridine, but it is blocked by theophylline, sug- rebral cortical cells (651). gesting an action via modulation of CAMP concentra- Growth hormone is a third hormone whose release tions. The coexistence of cysteine sulfinic acid decarbox- is stimulated by taurine (321). In addition, taurine an- ylase and choline acetyltransferase in motoneurons indi- tagonizes the central actions of angiotensin II and renin cates a possible physiologically relevant presynaptic on water intake, effects that it shares with GABA (3). action of taurine (92). In addition, taurine has postsyn- Taurine augments immune responses, although aptic actions, inhibiting noncompetitively carbamyl- next to nothing is known of the mechanism (501, 502, choline-induced contractions of frog gastrocnemius 686). It stimulates proliferation of lymphocyte T- and muscle (443). B-cells in response to mitogens and increases cytoplas- Taurine and glutamate concentrations in the brain mic Ca2+ concentrations in these cells (542). are strongly correlated, suggesting their cytoarchitec- In conclusion, actions of taurine that may be recep- tor mediated can be demonstrated, but proof of direct tural colocation (306, 641). An influence of taurine on effect at a receptor site remains to be obtained. the glutamate-GABA axis is indicated by the finding that taurine stimulates decarboxylase in There are, of course, macromolecular constituents in the cell apart from lipids and protein. The interac- the brain of the genetically epileptic rat (62). In guinea tions of taurine with nucleic acids have been poorly stud- pig cerebellar slices or rat cerebellar granule cells, tau- ied despite the known involvement of taurine with rine had little effect on the evoked release of glutamate growth (542, 596) and the highly charged nature of nu- (268,538). It inhibits glutamate-induced depolarizations cleic acids. One of the few reports on the interactions of in a number of systems (413-415). Of the currently ac- taurine and DNA found that taurine antagonized the cepted three receptors for excitatory amino acids, tau- NaCl-induced precipitation of the histone chromatin, rine was most potent in inhibiting the N-methyl-D- the nucleoprotein component of chromosomes (74). aspartate receptor, followed by the kainate and quis- qualate receptors (414). Its effect on responses to glutamate is noncompetitive, and taurine does not in- I. Conclusions on interactions of taurine and proteins terfere with the binding of glutamate (818). One of the best-studied effects of taurine on hor- 1) A convincing biochemical demonstration of bind- mones is the increase in circulating prolactin concentra- ing sites for taurine on proteins, other than the trans- tions produced by central administration of taurine port protein, has yet to be achieved. (321, 676, 678). This response is seen on the infusion of 2) As yet, there has been no convincing demonstra- taurine into the arcuate nucleus of the hypothalamus tion of Na+-independent binding in the CNS under con- (675) or the anterior pituitary gland (676-678). Infusion ditions that are physiologically relevant. Thus a neces- into other areas of the hypothalamus, or other areas of sary requirement to establish a neurotransmitter func- the brain, are without effect. This stimulatory effect of tion for taurine has yet to be satisfied. taurine is antagonized by TAG (577). Neither taurine 3) Electrophysiological evidence suggests that tau- nor TAG affected the pituitary secretion of luteinizing rine has activity at proteinaceous receptor sites for in- hormone. However, taurine does block the increased re- hibitory amino acids. Much of the evidence equally sup- lease of luteinizing hormone induced by the excitotoxin ports an indirect modification of receptor site activity. N-methyl-D-aspartate (633). This appears to be a func- There is no convincing evidence that taurine directly tion of the neurodepressant activity of taurine. binds to the GABA or glycine receptors. Low levels of taurine (0.25-l pmol) given intracere- ..$) Taurine stimulates Cl- flux and hyperpolarizes broventricularly stimulate prolactin release, whereas membranes. This action could involve both direct effects higher levels (4 pmol) do not, because at these levels on the Cl- channel or indirect effects on the membrane somatostatin release is enhanced (8, 321). Naloxone environment of the channel. blocks taurine-induced release of prolactin, while tau- rine given simultaneously with the Met-enkephalin de- rivative FR33-824 increases release above that induced E. Interactions With Zinc by either agent alone (321). This suggests that an opioid peptidergic system may be involved in the regulation of Zinc is another metal ion with which taurine inter- release. The low concentration at which taurine is effec- acts. Zinc deficiency leads to increased excretion of tau- tive suggests that a specific effect mediated via protein rine (277). Both substances act as membrane stabilizers. 130 R. J. HUXTABLE Volume 72

Ferrous sulfate damages the rod outer segments of the frog retina, leading to swelling, aggregation, and disruption of disk membranes. Zinc and taurine to- gether, but neither separately, protect against these Superoxid: consequences without affecting the degree of membrane \ peroxidation produced by Fe2+ (590). Instead, these le+ 2H+ agents prevent the excess passage of water and ions across the membrane that results from peroxidation. Damage is prevented if Na+ and Cl- are replaced with nonpermeant ions (597). Similarly, taurine and zinc H2°21 have a synergistic action in protecting cultured lympho- Hydrogen blastoid cells from retinol-induced loss of viability (605). peroxide Again, these agents protect from disturbances in os- le moregulation induced by membrane lipid peroxidation without affecting the extent of peroxidation. Thus, as in / other examples given, taurine protects from the conse- OH * &OH- quences of membrane damage without affecting the de- Hydroxyl gree of damage. The tapetum at the back of the eye reflects light passing unabsorbed through the retinal layer to allow another chance for absorption. Zinc and taurine are both necessary for the integrity of the membrane surrounding the tapetal rods. The highest zinc concen- OH- trations in dogs and cats are in the tapetum. Taurine Hydroxide deficiency leads to a loss of zinc from the membrane FIG. 12. Reduction of oxygen by 4 single electron steps. Three followed by membrane disruption and tapetal disorgan- intermediates, superoxide, peroxide, and hydroxyl radical, are respon- ization (741). sible for oxidative damage in cell. The antiepileptic actions of taurine may also have a zinc component, as suggested a number of years ago (44, 148). Zinc is involved in epileptogenesis (83), and sei- O2 + 4H+ + 4e --) 2H,O (0 zures induced by the excitotoxin kainate involve mobili- zation of zinc resulting in neuronal death (190). The overall reaction proceeds by four single elec- A zinc-taurine complex has been proposed to ac- tron steps, generating sequentially superoxide, hydro- count for some of the interactions of these agents (e.g., gen peroxide dianion, hydroxyl radical, and hydroxide see Ref. 778). However, the log stability constant for zinc ion as intermediates (Fig. 12). The first three interme- and taurine is low, 4.6 (quoted in Ref. 823). This may be diates are more reactive than oxygen itself and are pri- compared to a constant of 9.3 for the zinc-glycine com- marily responsible for the toxicity of oxygen. Hydrogen plex, for example. peroxide dianion is the dianion of a weak dibasic acid and is immediately protonated to hydrogen peroxide. This is a strong oxidant, but it reacts slowly except with V. METABOLIC ACTIONS: TAURINE AS PRODUCT such structures as complexes of transition metals. The highly reactive hydroxyl radical is indiscrim- inately reactive in biological systems, exhibiting bimo-

A. Antioxidation: Hypotaurine Story lecular rate constants in the range of 107-1010 M-l l s-l. Addition of the fourth electron yields the hydroxide ion, which is protonated to water. Oxidation of organic substances occurs in the step- In most tissues, protection from oxygen toxicity is wise reduction of oxygen to water. The initially formed provided by a combination of three enzymes, superoxide partially oxidized organic intermediates may undergo dismutase (EC 1.15.1.1), catalase (EC 1.11.1.6), and gluta- further reaction. Life, of course, depends on the con- thione (GSH) peroxidase (EC 1.11.1.9). Superoxide dis- trolled oxidation of organic substrates, with the free en- mutase speeds up manyfold the conversion of superox- ergy released being coupled to the energy-requiring pro- ide to hydrogen peroxide. The other two enzymes de- cesses that sustain the cell. However, the inherent oxi- stroy hydrogen peroxide. The heme enzyme, catalase, dizability of most cell constituents renders oxygen both converts hydrogen peroxide to water, using an appro- essential and toxic, and numerous mechanisms have priate electron donor. evolved to protect living systems from the deleterious At high concentrations of peroxide, peroxide itself actions of oxygen. can act as electron donor, i.e., dismutation occurs. The The complete reduction of oxygen to water requires selenoenzyme, GSH peroxidase, carries out a similar re- four electrons (e) action, with the electron donor being GSH. This is con- January 1992 PHYSIOLOGICAL ACTIONS OF TAURINE 131 verted to the disulfide form, from which GSH is regen- Hypotaurine oxidizing activity is found in many erated by the action of GSH reductase. No enzyme is tissues (85, 153, 166). These include ox retina (136), rat available for the removal of hydroxyl radical or hypo- spleen (622), and other organs (165, 550). Hypotaurine, chlorite. These substances are so reactive that such an also, is normally present only in low amounts. In the enzyme would be ineffective. Instead, the operation of brain, for example, hypotaurine concentrations are only the other enzymes described limits the formation of 1% those of taurine (611). There are two situations, how- these oxidants. Hypochlorite is also removed by reac- ever, in which millimolar concentrations of hypotaurine tion with taurine, as discussed in section VIA. occur: in the regenerating liver (734, 736) and in the Among the more vulnerable components of mem- male reproductive system (372, 373, 516). branes to oxidative insult are polyunsaturated fatty Seminal plasma is unusual among body fluids in acids. Hydroperoxides and cyclic peroxides that are that its osmolarity is determined primarily by organic formed interfere with membrane fluidity and mem- components. Semen is also high in unsaturated fatty brane function, and break down to yield malondialde- acids, which require protection from oxidation. Whole hyde, among other products (76,203, 631, 752) semen of guinea pigs contains 26 mM hypotaurine (494). In guinea pig seminal vesicles, hypotaurine concentra- R&H: CH - CH,- CH: CHR2 --) tion is 6.3 pmol/g, and in the prostate it is 4.6 pmol/g (values in this paragraph are probably based on wet OHC. CH, l CHO + other products (2) weight, although this is not stated in the cited papers) The high redox potential of partially oxidized sulfur (370). Taurine concentrations are about the same. intermediates could theoretically protect against oxida- Mouse seminal vesicles contain 2.1 pmol/g hypotaurine tive damage. Cysteine, cysteamine, hypotaurine, and compared with 6.5 pmol/g in the cauda of the epididymis taurine have been variously proposed to have such a (the cordlike structure on the back of the testes) and 5.9 protective function. Both hypotaurine and cysteamine pmol/g in the caput. The testes contain only 0.21 pmol/g oxidize spontaneously and are, chemically, powerful an- hypotaurine, but 1.8 pmol/ml are present in seminal tioxidants. Both are excellent scavengers for hydroxyl fluid (371). The mouse contains far higher concentra- radical and hypochlorite, but neither is particularly tions of taurine, however, with 41.9 pmol/g being pres- reactive toward superoxide (28,165). Rate constants for ent in seminal vesicles and 47.4 pmol/ml in seminal reaction with hydroxyl are 1.15 X lOlo M-l l s-l for hypo- fluid. Epididymal plasma from the cauda epididymis taurine and 5.9 X 10’ M-l l s-l for cysteamine. typically contains high concentrations of taurine plus Cysteamine is converted to hypotaurine enzymati- hypotaurine. Combined concentrations are 5.2 mM in tally by cysteamine dioxygenase (EC 1.13.11.19), an en- rams, 49.5 mM in rabbits, and 53.4 mM in boars (494). zyme analogous to cysteine dioxygenase (EC 1.13.11.20), Concentrations ranging between lo-l6 and lo-l5 mol the enzyme producing cysteine sulfinic acid (471, 825, taurine and hypotaurine per sperm have been reported, 826). Cysteamine dioxygenase is present in heart (302) respectively, although these numbers would be more in- and kidney (86, 150) but is absent from brain (418). A terpretable if given per milliliter or per gram (516). Hy- major objection to a physiologically relevant antioxi- potaurine was absent from human acrosomes, the cap- dant role for cysteamine is the low amounts present in like structure on the head of spermatozoa, and may not most tissues. These are on the order of 0.1-0.2 nmol/g be present in human sperm (784). Taurine, on the other wet wt in most tissues. Cysteamine is undetectable in hand, is one of the major free amino acids found in hu- the brain (318, 417). Radiotracer experiments have es- man acrosomes. tablished that [35S]methionine and [3,3’-3H]cystine are In boars at least, hypotaurine is located in sperm converted in (302). rather than in seminal fluid (777). Spermatozoa are Exogeno Iidly oxidized itinerant cells that must adjust to a continually chang- both in vivo and taurine ing environment in first the male and then the female (302). In the mouse, within 4 h, >90% of an administered genital tract. In men, it takes 2 mo for the primary sper- dose was converted to taurine. Conversion in the guinea matogonium to develop to the spermatozoon and an- pig is slower, but even so, 80-90% metabolism to taurine other 12 days for the latter to pass through the epididy- occurs within 18 h. In vitro, the rate of conversion to mis. Sperm are viable in the female tract for up to l-2 taurine is strongly dependent on sulfide. An initial prod- days. In certain mammals, such as bats, and in many uct is thiocysteamine. nonmammalian species, spermatozoa survive in the fe- Cystamine, the oxidative dimer of cysteamine, is male tract for several months (494). In view of the sus- transported into the lung by a two-component system, ceptibility of sperm to oxidative damage and their lack one component having a K, of 12 PM and the other a K, of normal enzymatic protection from partially reduced of 503 PM (452). High-affinity transport is inhibited by oxygen intermediates, it is intriguing to speculate that the pneumotoxin, paraquat. In the lungs, cystamine is hypotaurine provides a chemical defense. efficiently converted to taurine, apparently by a GSH- Mammalian sperm lack both catalase and a func- dependent process, as conversion is inhibited when GSH tional GSH reductase system (17). Although GSH re- is depleted. It has been suggested that this process pro- ductase activity can be measured, the absence of GSH in tects the lu ngs from oxidative stress (452). sperm renders the enzyme irrelevant in the metabolism 132 R. J. HUXTABLE Volume 72

of hydrogen peroxide. It may, however, be involved in ‘OH the metabolism of lipid hydroperoxides (265). The third enzyme, superoxide dismutase, on the other hand, is present in spermatozoa (264,520). Superoxide is toxic to sperm, causing lipid peroxidation and loss of motility. Due to protonation, the rate of peroxidation increases . OH @- Lc!2rlnecliate markedly with a decrease in pH. About one-third of the superoxide is generated in the sperm mitochondria; the rest is generated in the cytosol. Mammalian sperm are rich in plasmalogens, containing vinyl ether functions / that react with oxygen to generate superoxide. 0 At 24°C rabbit sperm generate superoxide at a rate II 0 of 0.2 nmol l min-l . lo* cells-l (264). In the presence of R-S-O cyanide, this rate increases to 1.8 nmol. min-l l IO8 . . cells-l due to inhibition of superoxide dismutase. The dismutase produces hydrogen peroxide. Rabbit sperma- Hypotaurine 0 tozoa make 0.8 nmol peroxide l min-l l lo* cells-l (265). i The rate drops at cell concentrations >107/ml because of II the reaction of peroxide with membrane lipids. R-S=0 The spontaneous inactivation of superoxide dismu- I tase with time in ejaculated sperm correlates with the R-S=0 loss of motility. The susceptibility to oxidative damage II of the highly unsaturated membranes of sperm is indi- 0 cated by the rates of malondialdehyde formation in Q - Disulfone sperm incubated at 37OC. In Tris phosphate buffer, the

rate averages 0.05 nmol l h-l. IO* cells-l for many hours (18). The number of inert spermatozoa increases lin- early with malondialdehyde production. Movement Taurine ceases completely at 0.05 nmol/lO* cells. Malondialde- hyde inhibits motility independent of lipid peroxidation FIG. 13. Hydroxyl radical trap in proposed route of enzymatic oxidation of hypotaurine. (19). Thus addition of malondialdehyde to nonoxidized sperm reduces motility. The loss of motility on storage also correlates with the loss of plasmalogen (l&346,494, 512) and degree of peroxidation (135). fone (+3) to taurine (+4). Hypotaurine is able to quench As superoxide is formed aerobically, the movement hydroxyl radicals generated by the xanthine oxidase of sperm from an anaerobic to an aerobic environment system (EC 1.1.3.22) (165) in keeping with the chemical on ejaculation represents a considerable biochemical studies (28). This suggests that the free radical mecha- stress (20,264). The oxygen tension in rabbit oviduct has nism of disulfone formation may be related to the high been measured as 60 Torr (500). concentration of hypotaurine found in male accessory A small fraction of hypotaurine is irreversibly sexual tissues. The disulfone has been detected in rat transaminated to acetaldehyde and sulfate (163, 164, testes, but more work on the enzymology of its forma- 166). The enzymology of the oxidation of the remainder tion is required. Although experimental support has to taurine was for many years one of the more profound been adduced for the radical oxidation of hypotaurine mysteries of taurine biosynthesis. Although, in vivo, hy- (163, 164, 166), it still requires verification. potaurine is readily converted to taurine, on attempts to The millimolar concentrations of hypotaurine in purify the responsible enzyme, activity would “softly ejaculate and oviductal fluid may serve to protect the and suddenly vanish away.” Evidence has now been ob- highly unsaturated membranes of sperm from the high tained, however, for a radical mechanism of oxidation ambient oxygen in the female genital tract (516). Hypo- (165, 293). The suggested pathway involves radical in- taurine inhibits the loss of sperm motility (19). This is a termediates formed from hypotaurine by an NADPH- protective effect that is shared by a number of other dependent process (Fig. 13). The oxidation involves the agents, possibly acting by different mechanisms. Thus novel intermediacy of a disulfone, an unexpected inter- substances as diverse as epinephrine, albumin, lactate, position of a dimeric intermediate in a monomeric path- and taurine also inhibit the loss of motility. The forma- way (Fig. 13). Hydrolysis of the disulfone releases 1 mol tion of malondialdehyde is reduced by hypotaurine in taurine and 1 mol hypotaurine. The monomeric oxida- keeping with the effect on motility. Hypotaurine re- tion of sulfur-containing metabolites (e.g., cysteine to duces superoxide formation in sperm, an observation at cysteine sulfinate to cysteate) involves oxidation states variance with the reported lack of scavenging of super- of 0, +2, and +4. However, the formation of a disulfone oxide by hypotaurine (28). However, hypotaurine also allows one electron oxidation of the sulfur. Thus hypo- reduces the inactivation of superoxide dismutase. As taurine, at oxidation state +2, is converted via a disul- this is the prime enzymatic defense against peroxida- January 1992 PHYSIOLOGICAL ACTIONS OF TAURINE 133 tion, this is probably an important biochemical activity decarboxylase activity in the brains of vitamin B,-defi- of hypotaurine in ejaculated sperm (20). cient animals are probably invalidated, or at least con- The protective effects of hypotaurine on peroxida- founded, by the high substrate levels used. Under such tion and sperm motility show markedly different poten- conditions, the bulk of cysteine sulfinate decarboxyl- cies. Protection from peroxidation is seen at concentra- ation is, in fact, being performed by glutamate decarbox- tions of 20.5 mM, while an effect on motility is seen in ylase, as discussed in a recent review (297). the low micromolar range (450). Taurine has similar ac- The regenerating liver is another system in which tions on both motility and viability. At 20 PM, it main- relatively enormous amounts of hypotaurine are found tains motility without providing protection from perox- (734). From undetectable concentrations in normal idation (529). Hypotaurine, along with taurine, has been livers, up to 3 pmol/g wet wt may be found within 4 h of considered to be a sperm motility factor in hamsters and partial hepatectomy. The functional significance of this mice (49,449,516,529) but not in boars (234). Epineph- is unknown. rine and hypotaurine independently capacitate hamster Myeloperoxidase (EC 1.11.1.7) oxidizes the sulfur in sperm, but prior exposure of the sperm to hypotaurine is N-acetylcysteine and N-acetylcystine to sulfonate (149). a prerequisite for the action of epinephrine (19,60,450). The cysteic acid formed can be decarboxylated to tau- Capacitation is the sequence of metabolic and cellular rine. The oxidant is Cl- and H,02 or HOC1 directly. Such changes whereby the sperm is prepared for fusion with a reaction serves to remove oxidizing intermediates, as the ovum. Conversely, the greatest effect of hypotaurine discussed in section VIA. and taurine on motility and fertilization is obtained in the presence of the ,&adrenergic agonist isoproterenol (449). This may be related to adrenergic stimulation of I. Conclusions on antioxidation by taurine precursurs transport of these ,&amino acids into the sperm, as has been found for the &adrenergic systems present in the 1) Cysteamine and hypotaurine are readily oxi- heart and pineal (103, 810, 811). dized, both enzymatically and chemically, to taurine. Sperm, once unmanned and wandering like the 2) Hypotaurine may be oxidized enzymatically to 2Marie Celeste, also encounter hypotaurine in the oviduc- taurine via the intermediacy of a disulfone. The oxida- tal secretions (370). Mammalian oviductal fluids typi- tion process may serve as a radical trap of hydroxy radi- cally contain between 0.5 and 2 mM taurine plus hypo- cals. taurine (516). 3) Hypotaurine reduces malondialdehyde forma- Flavins catalyze the oxidation of sulfinate groups to tion, an index of peroxidation, from lipids. sulfonates under irradiation at 365 nm (650). Such pho- 4) Hypotaurine concentrations are high in the male tooxidation of hypotaurine has been proposed to be of reproductive tract where it may function as an antioxi- physiological significance in the retina, a flavin-rich dant, protecting the highly unsaturated membranes of tissue. spermatozoa. In summary, the protective effect of hypotaurine (and taurine) on male sexual function is complex. Hypo- taurine in some of its actions is an antioxidant. Other B. Radioprotection actions it has in common with taurine, and these are presumably mediated by separate mechanisms. Possi- Antioxidative and radioprotective mechanisms are bly these mechanisms involve sperm cell osmoregula- related inasmuch as both involve interruption of free tion. Oxidative damage results in osmoregulatory dis- radical propagation reactions and detoxification of par- turbances, loss of cell constituents, and cell death. Tau- tially reduced oxygen intermediates. However, whereas rine and hypotaurine are present in seminal fluid and a relatively small number of investigations have exam- sperm in millimolar quantities and share the same ined the physiological actions of hypotaurine as an an- transport system. tioxidant, a large body of work has been devoted to the In the brain, the process of taurine biosynthesis pharmacology of cysteamine as a radioprotective agent. may be part of an antioxidant mechanism protecting Cysteamine and its simple derivatives comprise the neuronal membranes, while the product of biosynthesis most potent radioprotectors yet found. may fulfill specific neuromodulatory and membrane- As discussed in section VA, mammals readily oxi- stabilizing functions. An otherwise “wasted” oxidation dize cysteamine to hypotaurine, and on to taurine, by of cysteine (to P-sulfinylpyruvate and sulfate) is di- means of the enzyme cysteamine dioxygenase (EC verted to a biologically functional oxidation (the trap- 1.13.11.19) (8889). However, little cysteamine is formed ping of free radicals during the oxidation of hypotau- endogenously. The study of the protective actions of cys- rine). The conservation of central biosynthesis, even in teamine and related thiols against ionizing radiation species lacking the overall ability to synthesize suffi- began with the nuclear age. From the 1950s onward, an cient taurine for their needs, and the greater immunity immense amount of research was conducted in the of cysteine sulfinate decarboxylase compared with glu- United States, Europe, and the Soviet Union. tamate decarboxylase to vitamin B, deficiency (647), Water is the most abundant constituent of cells. suggest this remnant biosynthesis is physiologically sig- The initial changes caused by ionizing radiation involve nificant. Earlv reports on the loss of cvsteine sulfinate the radiolvsis of water (793). The initial step in radioly- 134 R. J. HUXTABLE Volume 72

R’ +SH- A The earlier literature on cysteamine can be ac- eaq RS-+H’ B cessed through the review of Bacq (42). Quenching, or “repair,” of target radicals (T . ) formed by radiolysis is _/-- probably a major mechanism whereby cysteamine ex- RSH ‘OH . RS’ + Hz0 C erts its radioprotective effects

H’ To +RSH+TH+-RS (7) RS’+H2 D To +O,-,TO, (8) c R’ + H2S E Equations 6 and 7 are competing reactions. How- FIG. 14. Radical trapping by thiols of products of radiolysis of water. Reaction A is preferred reaction for most thiols with hydrated ever, this is not the sole action of cysteamine. It binds electron. Reaction D is preferred for reaction of hydrogen radical with tightly to DNA through electrostatic interactions of the primary . amine group with phosphate residues (72, 462). Radia- tion-induced breaks are reduced as a result of such bind- ing (423). Some spatial specificity is involved, since sis can involve either ionization or electronic excitation. higher homologues of cysteamine, such as aminobutane The latter process involves the transfer of insufficient thiol, have much less radioprotective capability in ani- energy to a water molecule to remove an electron com- mals (72, 137, 222, 626). Bacteria, however, are not so pletely. Instead, the electron is raised to a normally un- discriminating with regard to chain length (119). occupied outer orbital. Thiols may also protect from radiation by reoxidiz- The solvolysis of water yields three radicals: hy- ing disulfide bridges of cell macromolecules inactivated droxyl, hydrogen, and the solvated electron. Hydroxyl by radiation. However, a significant involvement of and hydrogen are scavenged by organic substrates such a mechanism does not explain the selectivity of within the cell, initiating the biological damage that is a cysteamine compared with other thiols. Thiols also consequence of exposure to ionizing radiation. Hydroxyl react avidly with oxygen, reducing the rate of formation is a strongly oxidizing species. Because the O-H bond is of peroxyl radicals. Cysteamine lowers indirect radia- stronger than the typical C-H bond, carbon-bound hy- tion effects by scavenging hydroxyl(400). For this to be drogen is abstracted indiscriminately. significant, high concentrations of thiols are needed. Both the solvated electron (e;J and the hydrogen The amino group of cysteamine is involved in its atom independently react with oxygen to form peroxyl radioprotective activity inasmuch as acylation mark- radicals (superoxide) edly reduces potency (137). The amino group may serve to stabilize the initially formed thiyl radical via cyclic e&+0,+0,’ (3) resonance forms (Fig. 15). He +O,+HO,e A transient inhibition of DNA synthesis has been (4) reported for cysteamine in mouse liver (522). It has been The formation of superoxide by reaction of the pri- suggested that this also results in a radioprotective ef- mary radiolytic products of water with oxygen is a ma- fect. jor reason why ionizing radiation is biologically less damaging under anoxic or hypoxic conditions. It also 1. Conclusion on radioprotection by taurine precursors suggests the close relationship between antioxidants and radioprotectants. Cysteamine is a powerful radioprotectant due to its A number of endogenous radioprotectants are radical scavenging abilities. found in the cell. The main ones are a-tocopherol in lipid phases and GSH and ascorbate in aqueous phases. Mech- C. Cysteine Detoxijcation anisms by which radioprotection is mediated include energy transfer (providing a sink to absorb radiation Free cysteine is neurotoxic, particularly to the de- energy), quenching of organic free radicals, and enzyme veloping animal (573,574). The toxicity is similar to that repair. Water radicals are so reactive that radioprotec- tants are inefficient scavengers. However, thiols react readily with all three of the primary radicals formed by radiolysis of water (Fig. 14). The thiyl radical (RS) is probably then oxidized further

RS +O,-,RSO,e (5)

l l l RSO, + RSH + RSOzH + RS (6) H H Much of the chemistry of thiyl radicals is obscure, FIG. 15. Stabilization of thiyl radical formed from cysteamine via due to the high rates of reaction and the instability of cyclic resonance forms. Such stabilization favors radical trapping by the intermediates. reactions C and D of Fin. 14. January 19% PHYSIOLOGICAL ACTIONS OF TAURINE 135 seen with the excitotoxins, i.e., acidic, excitatory amino vitro, at least, one of the most reactive amines is taurine acids such as aspartate and glutamate. Damage to the (757,802). Endogenously, this is one of the amines pres- developing brain from cysteine is more widespread than ent in greatest concentration. Human leukocytes are re- that resulting from the excitatory amino acids. Gluta- ported to contain 26 mM taurine (726), and human neu- mate and aspartate are toxic to those areas having a trophils contain 22 mM (223). Extracellular concentra- fenestrated endothelium in their vascular beds (i.e., tions are normally lower, averaging 50 PM in human having a poorly developed blood-brain barrier). These plasma (24, 769, 789). Researchers appear undecided as regions, the circumventricular regions of the brain, in- to whether the N-chlorotaurine generated should wear clude the hypothalamus, a neuroendocrine regulatory a white or black hat, i.e., whether it is protective or toxic center (571, 574, 575). It has been suggested that cys- (223, 224, 688, 758, 803). teine, a nonacidic, rather lipophilic, amino acid, pene- On the one hand, the formation of mono- and di- trates other areas of the brain more readily that the chloro derivatives of taurine has been suggested to be a charged lipophobic excitotoxins. Once in the brain, cys- protective mechanism removing the highly toxic hypo- teine appears to be excitotoxic partially due to N-carba- chlorite. N-chlorotaurine is transported into erythro- mate formation (575) and partially due to oxidation to cytes by the anion transport system where it is reduced the acidic cysteine sulfinate (574). by . The released taurine is thereby Cysteine is also toxic to the retina (609). Levels in “trapped” within the cell. The glutathione consumed is excess of 1 g/kg body wt given subcutaneously to 4-day- regenerated by glutathione reductase old rats produce permanent retinal dystrophy. Ganglion cells in the retina are reduced to one-half of normal. RNHCl + 2GSH --) RNH; + Cl- + GSSG (10) Metabolism of cysteine sulfinate to taurine, jthere- fore, could be considered a detoxification function. How- GSSG + NADPH + H+ --) 2GSH + NADP+ (11) ever, carnivores, with a high dietary intake of cysteine and methionine, in general are poor metabolizers to tau- where GSSG is oxidized glutathione. When Equation IO rine. Furthermore, in mice, as dietary cysteine load is is the rate-limiting step, there is no depletion of cell increased, the conversion to taurine decreases (801). glutathione. At high chloramine concentrations, Equa- Thus detoxification of sulfur amino acids is an ancillary tion II becomes rate limiting, and the glutathione pool is rather than a major function of taurine biosynthesis. depleted. Under these conditions, other cell components react, including hemoglobin, sulfhydryl groups, and in- VI. METABOLIC ACTIONS: TAURINE AS PRECURSOR termediates involved in energy metabolism (758). Cell lysis and death can result. Normally, however, the pro- cess serves as a removal mechanism for hypochlorite A. Antioxidation: Chloramine Story and is postulated to be a defensive strategy against oxi- Taurine has often been suggested to have a function dative damage to circulating components. The bacterio- in protecting biological systems from oxygen, despite its tidal action of N-chlorotaurine may also serve a biologi- lack of ready oxidizability (688, 758, 823). The free en- cal function (756). ergy difference between a sulfonate group at oxidation On the other hand, in view of the toxicity of N- state +4 and a sulfate group at an oxidation state of +6 chlorotaurine and other chloramines, it is difficult to is ~260 kJ/mol (294). Although the sulfonate group of conceive of their formation as conferring a benefit on taurine could, therefore, theoretically serve as a reduc- the cell. In effect, a highly reactive extracellular oxidant ing agent by undergoing oxidation to sulfate, mammals with a short half-life has been transformed into a less lack the enzymatic machinery to facilitate such an oxi- reactive intracellular oxidant with a half-life of 18 h dation. Chemically, taurine reacts poorly with superox- (690). It rather appears as if the cell must accept the ide, peroxide, and the hydroxyl radical (28). However, burden of removing these adventitiously formed metab- some intriguing observations suggest a potential func- olites to avoid the expression of their toxicity. Their tion for taurine as an antioxidant by virtue of its amino toxic actions include dismutation to the more reactive group. dichloroamines (Eq. I@, reaction with ammonium ion to Neutrophilic polymorphonuclear leukocytes, or neu- generate chloramine (NH&l), oxidation of iodide ion to trophils, are circulating defensive cells having antimi- iodine with resulting iodination of cell components, and crobial, cytotoxic, and cytolytic activities. They release oxidation of cell thiols and disulfides the whole armamentarium of reactive oxygen interme- diates in the course of these activities (803). They gener- RNHCl + RNHCl + RNH, + RNCI, (I@ ate H,Os and secrete the enzyme myeloperoxidase (EC 1.11.1.10). Substrate and enzyme react with Cl- to pro- N-chlorotaurine impairs the barrier functions of duce the highly reactive hypochlorite cell membranes. Cultured endothelial cells from various sources exposed to N-chlorotaurine show increased al- H,Oz + Cl- + H+ -+ HOC1 + H,O (9) bumin flux, increased hydraulic conductivity, and de- creased electrical resistance (704). Hypochlorite reacts with primary amines to form Other mechanisms are also involved in the expres- chloroamines, RNHCl, in the extracellular medium. In sion of antioxidant activities by taurine. Taurine has 136 R. J. HUXTABLE Volume 72 protective actions on the functions of retinal rod outer protective effect in hypoxia. Indirect evidence includes segments. Membranes of rod outer segments are rich in the finding that taurine given intracerebroventricularly unsaturated fatty acids and are vulnerable to peroxida- protects mice from learning impairments induced by tive damage (66, 128, 351, 809). Between 40 and 50% of hypoxia. Taurine also protected mice from hypoxia-in- the fatty acids in rod outer segments are tetra unsatu- duced convulsions (483, 689). rated or greater (128). These high levels permit the de- gree of membrane fluidity required for phototransduc- I. Conclusions on antioxidation by taurine tion. Exposure to light increases the rate of membrane peroxidation by -50%. Both taurine and hypotaurine 1) Taurine reacts with hypochlorite biologically at the relatively high concentration of 25 mM reduce generated from peroxide and Cl- to form N-chlorotau- malondialdehyde formation (592). Taurine does not, rine, which is reduced intracellularly to Cl- and taurine. however, reduce peroxidation induced by Fe2+ (590). 2) Although this process removes a powerful oxi- Similarly, taurine decreases the degree of carbon dant, the toxicity of N-chlorotaurine renders it unclear tetrachloride-induced malondialdehyde formation in as to whether on balance the operation of this process is liver and liver microsomes (535) and scavenges superox- beneficial or damaging to the cell. ide radicals in rabbit spermatozoa (19). 3) Taurine protects against oxidative damage under The pneumotoxic herbicide, paraquat, stimulates many conditions, decreasing rates of malondialdehyde lipid peroxidation secondary to superoxide formation. formation from unsaturated membrane lipids. Taurine, continuously infused, protected dogs from the acute effects of paraquat poisoning, preventing oliguria B. Radioprotection by Taurine and reducing paraquat accumulation by the lung (336). Another pneumotoxic agent is the antineoplastic com- Taurine has radioprotective abilities in both micro- pound bleomycin. This produces pulmonary fibrosis, lim- organisms and higher animals (138,141,376,831). In the iting its clinical use. Taurine inhibited the inflamma- yeast Saccharomyces ellipsoides, it increases surviv- tion and the increase in lung collagen induced by bleo- ability following irradiation without influencing the im- mycin (800). Bleomycin forms an intracellular complex mediate radiation damage (52). In liver mitochondria, with Fe2+, and it has been proposed that taurine scav- respiratory control and oxidative phosphorylation are enges oxygen free radicals generated by the complex. A maintained in the presence of taurine following gamma possible mechanism is the depletion of GSH caused by radiation (141). Taurine prolongs the life of %o-irra- N-chlorotaurine preventing reduction of the bleomycin- diated mice, perhaps because of its insulin-like actions iron complex, which in turn blocks further formation of (140). It also promotes leukocyte recovery in radiation- reactive oxygen intermediates. Taurine also prevents exposed mice (2). Likewise, survivability of cardiomyo- the acute inflammation and morphological alterations cytes from cynomolgus monkeys is increased by taurine, produced in hamster lungs by dioxide (218). while radiation-induced hemolysis of erythrocytes is The release of prostaglandin I, from aorta and decreased (376). These actions of taurine, however, are myometrium is increased by taurine both in vivo and in probably secondary to a membrane-stabilizing effect vitro (154). This has been suggested to be due to the rather than being a direct radioprotective action. How- protection of prostaglandin I, synthetase from the ac- ever, the radioprotectant activity of cysteamine is possi- tion of lipid peroxides. bly due both to its own activity and to the protection Retinoids have a detergent action on biological offered by the taurine to which it is converted (302). membranes, leading to impairment of function or even Twelve days after exposure of rats to 700 rads, insu- disruption. Taurine protects human lymphoblastoid lin-like activity in the circulation drops. Taurine re- cells in culture from retinol-induced injury (605, 606). stores the insulin-secreting capacity of the pancreas and However, taurine affords no protection from the em- normalizes carbohydrate metabolism (139). bryotoxicity of isoretinoin in rats (5). The urinary excretion of taurine increases after ra- Taurine lowers blood pressure and increases the diation exposure (e.g., see Ref. 2). This may be an in- force of cardiac contraction (increasing the change in stance of the general increase in taurine excretion fol- pressure over time) in rabbits made atherosclerotic by lowing cell damage. A similar response is seen following being fed cholesterol (617). These effects of taurine are X-irradiation, surgery, and myocardial infarction. achieved without alteration in serum lipids or Ca2’. It has been suggested that taurine is acting to reduce lipid I. Conclusion on radioprotection by taurine oxidation and resulting foam cell formation. Increased cholesterol intake has been shown to raise susceptibility The radioprotective actions of taurine are probably to lipid peroxidation in red blood cells. secondary to its membrane stabilizing actions, i.e., it It has been suggested that in the CNS taurine pro- reduces the consequence of membrane damage. tects from hypoxia by attenuating the Ca2’ overload that normally results in cells in which energy produc- C. Energy Storage (Phosphagen) tion has been impaired (688). However, although there is a wealth of information concerning the effect of tau- Although ATP is the proximate source of chemical rine on Ca2’ movements, there is no direct evidence for a energv in the cell, its levels in mammals are maintained January 1992 PHYSIOLOGICAL ACTIONS OF TAURINE 137 by replenishment from a secondary energy source, may be replaced with guanidinopropionate or other phosphorylcreatine, by the enzyme kinase (EC guanidino compounds with no apparent ill effects (176, 2.7.3.2) 707, 822). However, synthesis of creatine from guanidi- noacetate consumes -80% of methyl group neogenesis ADP + phosphorylcreatine ~1 ATP + creatine (13) (295). Huxtable (295) has suggested that the use of cre- atine is a biochemical adaptation, “inefficiently but ef- The equilibrium constant for this reaction is close to fectively cobbled together,” whereby enough methyl unity, so the reaction is freely reversible. In muscle groups could be removed from methionine to produce cells, adenine nucleotides are concentrated in two pools, the concentrations of required for trans- one in the mitochondria and one adjacent to the myofi- sulfuration to cysteine. However, Huxtable is no expert brils. The reverse reaction (Eq. 13) proceeds in the mito- in this field and may well be wrong. chondria, since ATP freshly generated by oxidative Asterubin, or dimethylguanidinoethane sulfonate, phosphorylation replenishes the phosphorylcreatine is found in the starfish, Asterias. In dogs, asterubin pool. The forward reaction occurs at the myofibrils to causes an increase in the blood glucose level, whereas replace the ATP pool depleted by contraction. Creatine taurine causes a decreased glucose level and guanidino- serves as a molecular Mercury, shuttling “high energy” ethane sulfonate causes an initial increase followed by a phosphate groups from power house to fireplace. fall (4). Creatine phosphokinase is fairly tolerant of sub- In invertebrates, guanidinoethane sulfonate is strate. Many guanidino compounds are accepted with formed by transamidation of hypotaurine by , greater or less affinity. This tolerance preserves the followed by oxidation. In mammals, guanidinoethane evolutionary diversity of secondary energy sources, or sulfonate is formed directly from taurine by transami- phosphagens, part of which is still represented in lower dation (309, 526). The physiological function of guani- phyla where various amidino derivatives of taurine are dinoethane sulfonate in mammals is unknown. It has, used. A substance tends to assume as many identities as however, become an important pharmacological tool in it has names. The compound known variously as guani- the study of taurine (307). Two of the normal pharmaco- dinotaurine, amidinotaurine, taurocyamine, and guani- logical weapons for probing the function of an endoge- dinoethane sulfonate lives its schizoid existence in the nous substance have been in short supply for taurine. literature and is no exception to this unfortunate rule Substances that would lower taurine concentrations (Fig. 16). The first name is inaccurate, as the compound, and pharmacological antagonists to its actions have although a , is the amidino derivative of tau- been lacking. Guanidinoethane sulfonate provides a rine. Guanidinoethane sulfonate was originally found in partial and interim solution to both these problems. It is a competitive antagonist of taurine transport in brain a marine polychaete worm, Arenicola marina (755). It was subsequently found in other marine worms, synaptosomes and perfused heart, it is convulsant under conditions where taurine is anticonvulsant, and it pro- sponges, and sea anemones (1554,482) and in mamma- duces retinal degeneration of the same type as is seen in lian brain and other tissues (58,230,525,817). Following taurine-deficient cats (299, 602, 637). its use by Huxtable et al. (308), it has been widely em- When guanidinoethane sulfonate is given to intact ployed as a transport antagonist for taurine and as a rats, taurine concentrations are lowered in both the taurine-depleting agent (e.g., see Refs. 65, 107, 132, 332, CNS and peripheral tissues (307). The urinary excretion 387,427,444,589). In various marine organisms, guani- of [3H]taurine is much accelerated (289). In its taurine- dinoethane sulfonate is a phosphagen, acting precisely lowering action, guanidinoethane sulfonate discrimi- analogously to phosphorylcreatine in mammals (98,157) nates between dietary and biosynthetic taurine, de- pressing the contribution of the latter more than the ADP + phosphorylguanidinoethane sulfonate H ATP former. In a tissue unable to synthesize taurine and that + guanidinoethane sulfonate (14) obtains it by transport, guanidinoethane sulfonate, if it is acting purely by inhibition of transport, should not affect the proportion of taurine in that tissue that is The enzyme catalyzing the interchange is taurocya- obtained from the diet. In a tissue, such as the liver, that mine kinase (EC 2.7.3.4) (356, 742). Other guanidino can synthesize taurine, inhibition of transport should compounds phosphorylated as phosphagens include argi- result in a lower percentage of taurine being derived nine, guanidinoacetate, lombricine, opheline, guanidin- from the diet. The findings suggest that guanidinoeth- oethane sulfinate (the amidino analogue of hypotau- ane sulfonate is having some effect on biosynthesis as rine), and thalassemine (653). Bacteria and most inver- well as inhibiting transport. Guanidinoethane sulfonate tebrates use phosphoarginine as phosphagen (653). cannot be used as a taurine-depleting agent in cats, as Marine polychaetes are virtuosos when it comes to this species efficiently metabolizes it to taurine via the phosphagens, all the known ones being present in this action of a transamidinase (309). phylum. In fact, the puzzle is why mammals use the metabolically expensive creatine when a cheaper com- I. Conclusions on energy storage bjy taurine pound would appear to be equally as effective. The methyl group in creatine is apparently functionless. 1) Phosphorylated guanidino derivatives of taurine Even in mammals, a high percentage of muscle creatine serve as phosphagens in invertebrates. 138 R. J. HUXTABLE Volume 72

HN, 0 O,C-NHCH,CH,SO; H,NCHCH,S$ w &H,OH

A Taurine B Guanidinoethane sulfonate C 2-Amino-3-hydroxy-1 -propane sulfonate

0 HzNCH,CH,SOF I GH, 0 CH, CH;CH*NH,CH,CH,SO,O 6~0~ I h I i;~,0H CH3*(CH,),CO*NCH,CO*NHCH,CH,SO~ CO,H

D N-(2,3-Dihydroxy-n-propyl)taurine E Decanoylsarcosyltaurine F N-( 1 -Carboxyethyl)taurine

R,CHCOzCHCH,CO*NH*CHCO*NHCH,CH,SOF &H A, (&H,),&,

G Cerilipin

FIG. 16. Some naturally occurring structural analogues of taurine (A). B is widespread in marine invertebrates and mammals. Cis found in various green and red marine algae (159,325, 816), and D and F are found in red algae (420,815). E is surface tension-lowering substance in alimentary canal of crab Cancer pagerus. G, taurine- and -containing lipid, is found in cell wall of bacterium Gluconobacter cerinus (746).

Z) Guanidino derivatives of taurine can pharmaco- with aerobic/anaerobic bacterial overgrowth, plasma logically replace creatine as a substrate for creatine taurine concentrations are reported to fall from 153 to phosphokinase. 80 PM (706). These values indicate, however, that a de- gree of cell lysis has occurred in the course of sample preparation, as true plasma concentrations of taurine in D. Metabolism and Energy Production humans average -45 PM (24, 789). In both rats with experimentally induced bacterial overgrowth and in hu- Mammals are unable to oxidize the sulfur in taurine mans, electroretinogram and pigment epithelium abnor- or to cleave the C-S bond or to recycle the carbon of malities were noted (706). taurine into the general metabolic pool. To complete the Although taurine does not serve an osmoregulatory natural sulfur cycle and to prevent the biological carbon function in bacteria (513), taurine can be detected in pool from slowly accumulating in taurine, the metabolic various species. Thus taurine concentrations in Bacillus abilities of bacteria are utilized. In soil samples, 50% of subtiZis increase during growth and fall during sporula- taurine is oxidized to sulfate within 1 wk (189; quoted in tion (536). It appears that taurine is obtained by trans- Ref. 728). Taurine is metabolized by mycelia of Aspergil- port from the medium. All Staphylococcus species exam- lus niger, supposedly to isethionate (71). Certain Strep- ined have an Na+- and energy-dependent transport sys- tomyces and Pseudomonas can utilize taurine as the sole tem for taurine (57, 209, 717). In S. aureus, the K, for source of energy, nitrogen, sulfur, and carbon (209,728), transport is 42 PM (57). Sodium-independent transport as can an unidentified bacterium isolated from sewage occurs in Pseudomonas aeruginosa (209). (378). Agrobacterium grown on taurine decomposes it to The major route of taurine metabolism involves ammonia -and sulfate (320). There is considerable older transamination as the initial step. This yields the unsta- literature on the use of taurine as a sulfur source for ble sulfoacetaldehyde, which decomposes to acetalde- microorganisms, which may be accessed through the hyde and sulfate (71, 378, 685, 710, 711). Two transami- paper of Stapley and Starkey (728). Staphylococcus au- nases have been characterized to date: a taurine:cw- reus is unable to cleave the C-S bond and hence cannot ketoglutarate transaminase (EC 2.6.1.55) (Eq. 15) and a use taurine as a sulfur source (209). Fungi are able to use taurine: pyruvate transaminase (Eq. 16) taurine as sole sulfur source, although not as sole carbon source. taurine + 2-oxoglutarate e Bacterial overgrowth in humans and rats can lead to a loss of availability of dietary taurine. In patients HO&S. CH,CHO + glutamate (15) January 1992 PHYSIOLOGICAL ACTIONS OF TAURINE 139

taurine + CH, l CO l COzH ~1 E. Surfactant and Detergent Actions

HO,S l CH,CHO + alanine (16) Yellow bile and black bile were two of the four hu- mors thought until comparatively recently to be respon- Taurine:cu-ketoglutarate transaminase is found in sible for the health and disposition of a person. There numerous bacteria (765) and has been obtained in a are numerous linguistic remnants of this outmoded con- stable crystalline form from Achrmobacter super&& cept. A melancholic person suffers from an excess of alis (764,835). It has a molecular weight of -156,000 and black bile. Bile is stored in the gall bladder, and we find is activated by pyridoxal phosphate. The reaction is re- an outpouring of bile galling if directed at us. Bile acids versible (767). cr-Ketoglutarate is the sole acceptor for are detergents that serve to solubilize or emulsify fats to amino transfer, but a number of donors are accepted by make them more accessible for digestion. With an insuf- the enzyme. The relative activities and Michaelis con- ficiency of bile, undigested fats are passed in the feces, stants of various substrates are, respectively, hypotau- an unpleasant condition known as steatorrhea (250). rine, 601,16 mM; ,&aminoisobutyrate, 20811 mM; ,&ala- Normally, emulsified long-chain triglycerides are di- nine, 184, 17 mM; and taurine, 100, 12 mM (765, 835). gested to Z-monoglycerides by pancreatic lipase. In a With hypotaurine, the reaction products are glutamate, sense, our forebears were correct; only the language has acetaldehyde, and sulfite (750). altered. However, whether considered as a humor or a Taurine:pyruvate transaminase (Eq. 16) has been secretion, a proper flow of bile is required for good isolated from Pseudomonas aeruginosa (709, 766). The health. sulfoacetaldehyde resulting from the action of these Bile salts are detergents because they contain both transaminases is further metabolized to acetate and lipophilic and hydrophilic regions, the latter being hy- sulfite by a sulfolyase (710). Sulfolyase activity is in- droxy, sulfate, sulfonate, or carboxylate. Bile salts are duced by taurine but is unaffected by sulfoacetate, ace- derivatives of cholesterol. Their characteristics include tate, glyoxalate, P-alanine, alanine, cysteine, or pyru- free solubility in water, surface activity (lowering of vate. Mutants lacking the enzyme are unable to grow on surface tension), and micelle formation. taurine. Two paths are available for the further metabo- In all vertebrates except for mammals, taurine is lism of acetate, one assumed and the other demon- the sole amino acid conjugated with cholesterol deriva- strated. Entry into the tricarboxylic acid cycle will gen- tives to form bile salts (Table 5). Taurine conjugates are erate energy. Entry into the glyoxalate cycle can be used quantitatively the major metabolites of taurine formed both to generate energy and to make carbon available in vertebrates. Indeed, for a considerable period, their for anaplerotic reactions (481, 711). Mutants lacking formation was considered “the” physiological function malate synthase, an enzyme in the glyoxalate cycle, are of taurine. Mammals use glycine in addition to taurine. unable to grow on taurine (711). All vertebrates have bile (242-244, 262). Inverte- The other product of the sulfolyase, sulfite, can be brates have neither bile nor a true liver. Arthropods, in oxidized to sulfate directly via sulfite oxidase (EC addition, are unable to synthesize sterols. However, the 1.8.3.1) or, potentially, via the two enzymes adenylylsul- alimentary canal contains surface tension-lowering fate reductase (EC 1.8.99.2) and sulfate adenylyltrans- substances that serve a similar function to bile. Thus ferase (EC 2.7.7.4) (292). This is an ATP-generating the crab, Cancer pagerus, secretes decanoylsarcosyl- pathway that utilizes the free energy of oxidation of taurine (Fig. 16). sulfite to sulfate. Whether it exists in microorganisms The teleologically oldest organisms use sulfate con- deriving their energy from the catabolism of taurine has jugates of sterols as digestants, with this evolving in not been demonstrated. higher organisms to the more efficient taurine conju- Another route of taurine metabolism in bacteria gates of steroid acids (Table 5). The insolubility of cer- involves the enzyme taurine dehydrogenase (EC tain sulfate salts is presumably a disadvantage atten- 1.4.99.2). The enzyme catalyzes the reduction of an ac- dent on the use of sulfates. In other ways, also, evolution ceptor by taurine with the production of sulfoacetalde- has improved the efficiency of fat digestion. The bile hyde and ammonia. The enzyme is selective for taurine, acids of the lower vertebrates are sulfonated in the ste- hypotaurine only being slowly oxidized (379, 380). The roid side chain rather than the nucleus, for example. K, for taurine is 20 mM. The natural acceptor is un- The hagfish, perhaps the most primitive of the ver- known. tebrates, secretes large quantities of a poor amphiphile, myxinol disulfate. The other group of primitive fishes, the lampreys, secrete in the larval stage a rather more I. Conclusion on taurine as energy source efficient amphiphile, Sa-petromyzonol sulfate. The gall bladder is not present in the adult form. The cartilagen- ous fishes, the holocephalans and selachians (sharks), Mammals are unable to oxidize taurine. Bacteria also use sulfates, as do the most primitive of the bony can utilize taurine as a source of energy, sulfur, nitro- fishes, the coelacanths. Latimeria, also a primitive bony gen, and carbon. The first step is transamination, yield- fish, produces latimerol sulfate, a bile salt sulfated in ing sulfoacetaldehyde or oxidation to ammonia and sul- the side chain. Higher fishes produce taurocholate. foacetaldehyde. Amphibians ambidextrously use both sulfate and 140 R. J. HUXTABLE Volume 72

TABLE 5. Phylogenetic distribution of conjugating acid About 24 C, steroids are known that conjugate in bile salts with glycine and taurine (533). The major bile acids of humans are cholic and chenodeoxycholic acids. These Family Species Conjugate are synthesized within the liver. Hydroxylation of cho- lesterol at position 7 is the rate-limiting step in biosyn- Primitive Hagfish, shark, skate, lungfish, Sulfate fishes coelacanth (Latimeria), thesis. In the final two steps, the coenzyme A ester of sucker cholic acid is first formed (Eq. lr), thereby activating Fish Sturgeon, carp goldfish Taurine, sulfate the sterol for reaction with taurine (533) Catfish, herring, anchovy, pike, Taurine salmon, eel, conger, cod, mackerel, swordfish, mullet, RCO,H + CoA l SH + ATP + turbot, plaice Amphibians Xenopus, toad, frog, newt Sulfate RCO . S l CoA + AMP + pyrophosphate Some frogs, salamanders Taurine, sulfate Reptiles Taurine. Birds Taurine RCO l Se CoA + H,NCH,CH,SOi + Mammals Koala, kangaroo, anteater, Taurine ground squirrel, dog, wolf, R l R l CO l NHCH,CH,SO, + CoA . SH some bears, coatimundi, mustelids, mongoose, cat, sea Bacterial action in the gut converts these primary lion, walrus, ardvaark, kudu, racoon bile salts to deoxycholic acid and a trace of lithocholic Hare, hamster, rat fin whale, Taurine, glycine acid. some bears, seal, pig, Conjugation to form taurocholate is a major sink hippopotamus, ox, oribi, for taurine. There is a progressive dependence on di- gazelle, goat, sheep etary taurine in the series: guinea pigs, rats, Old World Rabbit, Proechimys, fox, polar Glycine bear, sloth bear monkeys, New World monkeys, humans, and cats. Primates Macaca irus, capuchin Taurine Guinea pigs are a herbivore and thus have a taurine- Macaca maurus, baboon, Taurine, glycine free diet. They synthesize considerable quantities of tau- orangutan, human, langur, rine, excreting it in the urine (309). For bile salt forma- Rhesus tion, guinea pigs conjugate glycine only (363, 727, 787). Data summarized from Refs. 243, 244. Rats use taurine for conjugation but have a high syn- thetic capacity for it. Monkeys are poor synthesizers of taurine. Old World monkeys, however, can conserve tau- rine by switching bile salt synthesis toward glycine con- taurine conjugates. Reptiles use taurine conjugates of jugates. Humans have very poor capacity for taurine Cu and Cn steroid acids, such as allocholic and copros- synthesis but can also switch to glycine conjugates to tanic acids. These are primitive bile steroids. Birds are conserve. Cats are unable to make sufficient taurine for exclusive taurine conjugators, using the same bile ste- their needs but must use it for conjugation (639). Thus roids as do mammals. under conditions of dietary deprivation, even after large In mammals, sulfated bile salts represent the off- falls in total body taurine, the absolute amount of tau- spring of a relict biochemical pathway that still has sig- rine conjugated in depleted cats is the same (although nificance under pathological conditions (204). Under the turnover of bile taurine is reduced, conserving it normal conditions, however, the most common bile salts somewhat). Surprisingly, although no conjugation of are either tau rocholate or glycocholate, the latter being glycine occurs in taurine-depleted cats, the isolated N- found only in placental mammals. Tau rocholate is the choloyltransferase (EC X3.1.65) readily accepts glycine more efficient bile salt, as the acidity of the sulfonate as a substrate (787). function means it remains ionized even under the highly Humans normally produce tauro- and glycocholate acid conditions that may episodically occur in the upper in an -3:l ratio, although this varies widely from indi- intestine (263). Ionization is necessary for detergent ac- vidual to individual. The ratio is a function of the avail- tion, and it also prevents precipitation and lowers ab- ability of taurine, with increases or decreases in this sorption, thereby maintaining high intraluminal con- producing corresponding changes in the conjugation ra- centrations. Carnivores tend to be exclusive taurine tio (208, 251, 771). The administration of taurine (40 conjugators of cholic acid (Table 5). Herbivores and om- pmol . kg-‘. day-l) to infants without taurine in the diet nivores tend to be both taurine and glycine conjugators for 8 days dropped the glycine-to-taurine ratio from 3.0 and to conjugate with both mono- and dihydroxy ste- to 2.2 (208). Glycine is without effect on the ratio. The roids. anion-exchange resin, cholestyramine, lowers this ratio Among the primates, New World monkeys such as by binding bile salts and preventing their resorption. Cehs conjugate only taurine, even under conditions of Both cholesterol and taurine are thereby drained from taurine depletion (730). Old World monkeys such as cyn- the body. The human fetus and neonate are exclusive omolgus (Macaca), on the other hand, conjugate both taurine conjugators, glycine conjugation being seen glycine and taurine. If the latter is depleted, the conjuga- after ~3 wk of life. Infants deprived of dietary taurine tion of glycine increases (249). switch to glycine conjugation sooner (73). January 19% PHYSIOLOGICAL ACTIONS OF TAURINE 141

I. Conclusions on taurine as surfactant 1. Conclusion on taurine and xenobiotic metabolism

1) In all vertebrates except for mammals, taurine is Numerous xenobiotics in a variety of species are the sole amino acid conjugated to form bile salts. metabolized in part by conjugation with taurine. 2) Among the mammals, carnivores tend to be sole conjugators of taurine, whereas other species tend to conjugate both taurine and glycine. G. Isethionic Acid and Anion Balance

F. Xenobiotic Conjugation In marine arthropods, isethionic acid (2-hydroxy- ethane sulfonic acid) is the major axonal anion, with Taurine conjugates with various xenobiotics, the concentrations approaching 220 pmol/ml in squid giant degree of conjugation varying markedly with the spe- axons (374). Despite these impressive concentrations, cies (347,352). Thus in dogfish sharks, 90% of a dose of there have been surprisingly few investigations of the phenylacetic acid is conjugated compared with 1% in biochemistry of this intriguing substance, perhaps be- rats (342). A taurine conjugate of phenoxybenzoate is cause of analytical difficulties. A compound containing formed in mice but not in rats (281). A survey of the a sulfonate and an as the only functional groups latter compound revealed wide differences between 25 does not lend itself conveniently to automated analysis. species in taurine conjugation, ranging from 0% in Even its biosynthesis is uncertain. Despite initial pro- vampire bats to 30% in ferrets (343). Some species, such posals, taurine does not appear to be a precursor in the as sheep, cats, and gerbils, only form conjugates of 3- squid. phenoxybenzoic acid with glycine; mice only form con- Studies on isethionic acid in mammals have an un- jugates with taurine, whereas ferrets form conjugates happy and confused history. At one time isethionic acid with both acids (278). The carnivorous species, dogs, was thought to be a major taurine metabolite that was cats, and ferrets, conjugate the antihypercholesterole- responsible for many of the actions of taurine due to the mic agent, clofibric acid, with taurine, but rats, guinea supposed calcium-chelating abilities of this acidic sub- pigs, rabbits, and humans do not (81, 155). Dogs also stance. It is now known that only a little isethionic acid conjugate 2-(2,4-dichlorophenoxy)phenylacetate with occurs in mammals, with concentrations ranging be- taurine. tween 0.01 and 0.3 pmol/g tissue (167, 337, 674). It may, Numerous cases of the ability of taurine to conju- however, have as yet to be discovered functions. gate with a wide variety of chemical structures are now Is isethionic acid formed from taurine? Brain slices known. Examples include the prostaglandin E, analogue were reported to convert [?]taurine to [35S]isethionic trimoprostil (377), 2naphthylacetic acid (155, 256), all- acid (608), and intraperitoneal injections of tracer trans.retinoic acid (716), and the anti-inflammatory amounts of [14C]taurine to intact rats were shown to give agent, pirprofen, a 2-phenylpropionate derivative (152). rise to small quantities of isethionic acid in all tissues Other propionate derivatives also conjugate with tau- examined. Five days after injection, for example, 2% of rine (84). Again, there are marked species differences. the total radioactivity in the brain was in the form of Thus only rats and mice conjugate taurine with pirpro- isethionic acid (282). Urquhart et al. (776) found a radio- fen, but only in rats is it the sole conjugate formed. active substance in the brain eluting off an amino acid Chlorinated compounds, like the important herbici- analyzer in the same position as isethionic acid after da1 phenoxyacetate and phenylacetate derivatives, are parenteral administration of [?S]taurine to rats and also conjugated by species such as spiny lobsters (341). monkeys. However, the kinetics of elimination of ise- Unusual, however, is the observation in this case that thionic acid from the brain are quite different from the conjugation does not hasten excretion. kinetics of elimination of taurine, suggesting that in 2-(4-Chlorophenyl)thiazol-4-yl acetic acid (fenclo- quantitative terms most of the taurine leaving the brain zic acid) is excreted into rat bile as the taurine conjugate is not converted to isethionic acid first (470). The con- in a dose-dependent manner (70). At low drug concen- version of taurine via sulfoacetaldehyde to isethionic trations, the primary route of metabolism is hydroxyla- acid has been well established in bacteria. Fellman et al. tion and glucuronidation. At high drug concentrations, (167) have been unable to demonstrate conversion of tau- the taurine conjugate is the major metabolite. In effect, rine to isethionic acid in homogenates and slices of conjugation with taurine in this instance is a “backup” heart, brain, and liver. system, being switched on when other pathways of con- Further investigations on isethionic acid in mam- jugation are saturated. mals are needed. However, the current state of knowl- Taurine thus joins sulfate, glucuronate, and gluta- edge can be summarized as follows. Isethionic acid oc- thione as a conjugation substrate for xenobiotics, in- curs in rather small amounts in brain. It may or may not creasing polarity, aqueous solubility, and, in most cases, be formed from taurine, but if so this is not a quantita- clearance of the xenobiotic from the body. The relative tively important route for the metabolism of taurine. importance of taurine conjugation is a function of the Other routes by which isethionic acid may be formed not species, the chemical nature of the xenobiotic, and the involving the intermediacy of taurine have been pro- dose of the drug administered. posed and partially studied (162,670). Finally, the physi- 142 R. J. HUXTABLE Vdume 72

ological actions of taurine are not predicated on its con- taurine and its derivatives in marine invertebrates (15). version to isethionic acid. Mono-, di-, and trimethyltaurine (the latter also being known as taurobetaine) are found in sponges. Other compounds are listed on Table 6. H. Taurine-Containing Peptides Marine algae contain other taurine derivatives, in- cluding D-CySteindiC acid (2-amino-3-hydroxy-l-pro- Various taurine-containing peptides have been iso- pane sulfonic acid) (159, 325), N-carboxyethyltaurine lated from the brain. The percentage of the total taurine (420), and N-(2,3-dihydroxy-n-propyl)taurine (815, 816) in the brain that the peptides comprise is minute. How- (Fig. 16). ever, they may be functionally important. The first peptides were reported by Reichelt and VII. CONCLUSIONS co-workers (645, 646). One of particular interest is y- glutamyltaurine or litoralon (169). This is the predomi- From the myriad studies on taurine, does any pat- nant taurine-containing peptide in synaptosomes (425, tern emerge to organize the disparate mass of informa- 495,783). The dipeptide is a combination of an excitatory tion available? Perhaps some cautious conclusions can (glutamate) and an inhibitory (taurine) amino acid. It is be drawn. The most pervasive action of taurine, an ac- produced by the parathyroid gland, and it stimulates tion that is independent of molecular structure, is that growth of thymus cultures (172, 174, 175). Numerous of an osmolyte. Any soluble compound has the same other hormonal actions have been claimed for it (170, property. The osmotic action of a compound is a direct 171,173). Its positive inotropic effect in the locust heart function of its molar concentration; it is a colligative was stronger than that of taurine (171). y-Glutamyl- action. In considering such an action, one is discussing taurine inhibits the K+-evoked release of GABA from physical chemistry and is not yet in the realm of biology. cortical slices of mouse brain (782). The synthetic Consideration of the osmoregulatory action of a com- stereoisomer y-D-glutamyltaurine is a potent antago- pound, however, brings us into biology, where now mo- nist of the quisqualate and kainate subtypes of the excit- lecular structure becomes important. Taurine has spe- atory a.mino acid receptor and has been used in their cific chemical and biochemical attributes that are of ad- characterization (161). vantage to an osmoregulatory substance: its inertness, Various acylated peptides have also been reported, relative ionic neutrality at physiological pH, lack of met- such as N-acetylaspartylglutamyltaurine, N-acetylas- abolic function in most cells, poor diffusibility across partyltaurine, and N-acetylglutamyltaurine (496). cell membranes, and relatively high solubility. The study of taurine-containing peptides is still in Osmoregulation is not an action unique to taurine. the early stages. This is an area of future growth and In bacteria and certain marine invertebrates, taurine future discoveries. appears to be of secondary importance to other amino acids. In other marine organisms, taurine is primus inter pares: quantitatively the most significant sub- I. Other Taurine Metabolites stance but sharing the overall responsibility for the os- moregulatory adaptation of the cell with a range of Taurine is incorporated into cell surface polymers other substances. In higher organisms, alterations in in a variety of bacteria (360,454,455,547,548). In encap- the concentrations of inorganic ions become important. sulated strains of Staphylococcus aureus, taurine is in- In such organisms, for a properly modulated response to corporated into lipids and polysaccharides where it may an osmotic stress, a mechanism is needed to link the be involved in conferring resistance to phagocytosis changes in inorganic ions with the changes in low-mo- (717). Typically, staphylococci live in warm-blooded ani- lecular-weight osmolytes. This is achieved in a number mals where they are exposed to taurine. Incorporation of ways. The Na+ dependency of amino acid transport, into polysaccharides produces a negatively charged cap- the linkage of ion and amino acid movements via Na+- sule surface. Antigenic polysaccharides consist of tau- K’-ATPase, the dependence of active transport on ATP rine, D-fucosamine, and D-aminogalacturonate from availability, the alterations in membrane permeability which taurine can be released by mild hydrolysis (455). consequential on altered Ca2+ concentrations, and other In Gluconobacter cerinus, a taurine residue is incor- mechanisms all link amino acid movements and the porated into a lipid, cerilipin (746; Fig. 16). The function movements of inorganic ions. Inorganic ions, however, of the lipid is not established, and it is unknown if tau- can have profound effects on cells that are unrelated to rine is directly incorporated. their osmotic actions. These include alterations in mem- Derivatives of both taurine and GABA, possibly the brane potential and electrical activity, enzyme activi- amides, are abundant in the webs of orb-weaving ties, chelation of adenosine nucleotides, conformation of spiders (Argiopes and Araneus species) (23). The webs of cell macromolecules, including nucleic acids, and an un- these spiders consist of nonadhesive radial strands and told host of other effects. The admittance of ions into a an adhesive spiral. It is the latter that entraps prey. The cell, therefore, has to be handled as cautiously as Greeks taurine derivative is located only in the spiral, suggest- bearing gifts. ing some function in disrupting prey behavior. In view of the interrelationships between ion and A useful list has been prepared of the occurrence of amino acid movements, it is natural that modulation of January 1992 PHYSIOLOGICAL ACTIONS OF TAURINE 143

TABLE 6. Distribution of taurine and its derivatives in marine invertebrates

Phylum

Compound Porifera Coelenterata* Sipuncula Mullusca Annelida Crustaceat

Hypotaurine + + + + Taurine + + + + Guanidinoethane sulfinate + + Guanidinoethane sulfonate + + + + N-methyltaurine + Dimethyltaurine + Trimethyltaurine + + Isethionic acid +

* Also designated Cnidaria. t Crustacea is a class in the phylum Arthropoda. [Data summarized from Allen and Garrett (15).]

ion entry by taurine evolved. The passage of both ions function despite opposing chemistries of maintaining an and amino acids into and out of the cell is controlled by appropriately hospitable environment for proteins to the membrane. This is an obvious point at which taurine function in. Taurine provides a molecular link between evolved to modulate Ca2’ entry. these two phases. Osmoregulation means giving the cell the capacity Cells with rigid walls do not experience the same for osmotic adaptation: in other words, allowing the cell pressures to adapt their intracellular milieus to the ex- to respond to the stress of a changing environment. In tracellular environment. An insulated brick house does many of the other functions taurine has assumed, this is not need the flaps, guys, fly sheets, and mosquito the common thread, a permissive effect on the ability of screens required for a sometimes comfortable existence the cell to respond to an externally applied stress. In the in a tent. In multicellular organisms, the extracellular main, pharmacological effects of taurine are observed environment is in a continually changing biochemical only in stressed systems, whether it be the stress of and hormonal state, secondary to changes in the exter- altered Ca2+ concentrations perfusing the heart, an epi- nal environment. Cells, in turn, must respond to the leptogenic stress in the central nervous system, the oxy- changing conditions around them. In complex organ- gen paradox, cell isolation or proliferation, or an os- isms, taurine is highest in cells that respond continu- motic stress. Similarly, changes in taurine concentra- ously to the environment. These include electrically ex- tions typically occur only in stress states, including citable cells, such as photoreceptors, neurons and myo- osmotic changes, anoxia, prolonged illumination of pho- cytes, and secretory structures. Taurine antagonizes the toreceptors, or congestive heart failure. Even cell prolif- tendency to change produced by a changing environ- eration or brain development can be considered a type of ment; it is a membrane stabilizer, concentrations tend internally generated stress. Can any common deduc- to increase under stress, and the whole cellular tendency tions by made about taurine and stress states? of taurine is toward enantiostasis. Taurine protects the cell from the disrupting ef- Life is lived at the interface between organization fects of exterior changes transmitted into the cell via and chaos, between the ordered crystal and the random such means as alterations in inorganic ion concentra- fire. The process of evolution as much as the life of an tions. To that extent, taurine is a stabilizing influence in individual is a constant restructuring that delays the an unstable molecular world. All of the actions of tau- intrusion of chaos with the resulting dark night of ex- rine listed tend toward conservation of function, a prop- tinction of life or of a life. Taurine, perhaps, is one of erty that has been termed enantiostasis (493). Enan- those protean molecules, along with water and the inor- tiostasis differs from homeostasis in that the effect of a ganic salts, helping to produce an orderly cellular re- change in the chemical and physical properties of the sponse to the continuous random changes around the internal milieu of a cell is opposed by a further change. cell. Such a response tends to conserve function and de- Thus, although the milieu is unstable (i.e., there is no lay the inevitable dissolution of such an inherently un- homeostasis), the functioning is stable. Changes in tau- stable entity. rine concentrations during osmotic stress, or the other Edward Gibbon, author of The Decline and FaZZ of stresses discussed, can serve enantiostatic functions. the Roman Empire, wrote, “Let no man who builds a Enantiostasis by taurine occurs in conjunction with house or writes a book presume to say when he shall other regulatory mechanisms. One of the more signifi- have finished. When he imagines that he is drawing cant of these is provided by the cell membrane. Mem- near to his journey’s end, Alps rise on Alps, and he con- branes evolved to yield a private space in which the dis- tinually finds something to add and something to organization and lack of stasis of the external world correct.” If this sentiment holds for the study of history, could be excluded and controlled. The lipophobic cytosol it certainly holds for a rapidly evolving field of scientific and hydrophobic lipid membrane share the common study. Incomplete as it is, however, perfection in a re- 144 R. J. HUXTABLE VoZume 72 view is not to be achieved. If this review is useful to 18. ALVAREZ, J. G., AND B. T. STOREY. Spontaneous lipid peroxi- those working on taurine or stimulates them or others dation in rabbit epididymal spermatozoa: its effects on sperm to investigate further the interesting biology of this sim- motility. BioZ. Reprod. 27: 1102-1108, 1982. 19. ALVAREZ, J. G., AND B. T. STOREY. Taurine, hypotaurine, epi- ple but profound substance, it will have fulfilled its pur- nephrine and albumin inhibit lipid peroxidation in rabbit sper- pose, despite its imperfections. matozoa and protect against loss of motility. BioZ. Reprod. 29: 548-555,1983. I thank Anders Lehmann, Barry Lombardini, Simo Oja, 20. ALVAREZ, J. G., AND B. T. STOREY. 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