Pantethine: a Review of Its Biochemistry and Therapeutic Applications

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Pantethine: A Review of its Biochemistry and Therapeutic Applications

Gregory S. Kelly, N.D.

Abstract Pantethine is the stable disulfate form of pantetheine, the metabolic substrate which constitutes the active part of coenzyme A (CoA) molecules and acyl carrier proteins. Because pantethine is located nearer to CoA than is pantothenic acid in the biosynthetic pathway of CoA, it has been suggested it will have clinical benefits in conditions where pantothenic acid is not effective, and clinical trials with pantethine appear to prove this argument. Oral administration of pantethine has consistently shown an ability to favorably impact a variety of lipid risk factors in persons with hypercholesterolemia, arteriosclerosis, and diabetes. Pantethine administration positively affects parameters associated with platelet lipid composition and cell membrane fluidity. In several animal models, preliminary studies have indicated pantethine can inhibit cataract formation. Pantethine is capable of lipotropic activity, and in experimental models exerts hepato-protective action and impacts adrenal cortex function. The intravenous administration of pantethine has been shown to impact several central nervous system neurotransmitters and hormones; however, oral doses of pantethine have not demonstrated a similar action, suggesting cysteamine, a metabolite of pantethine, is responsible for these actions. (Alt Med Rev 1997;2(5):365-377)

Introduction As the stable disulfate form of pantetheine, pantethine is the metabolic substrate which constitutes the active part of coenzyme A (CoA) molecules and acyl carrier proteins (ACP). The reactive component of both CoA and ACP is not the pantothenic acid molecule but rather it is the sulfhydryl (SH) group donated from cysteine. Although pantothenic acid is commonly

known as Vitamin B5,, pantethine, or its reduced-SH form pantetheine, contain the SH molecule required for enzyme activity. Pantethine, as opposed to pantothenic acid, bypasses the cysteine reactions required to form pantetheine from pantothenic acid, providing a more metabolically active form of the vitamin. See Figure 1 for the chemical composition of CoA, pantethine, pantetheine, and pantothenic acid. The metabolic activity of Vitamin B5 is due to its role in the synthesis of CoA and ACP. CoA is a cofactor in over 70 enzymatic pathways, including fatty acid oxidation, carbohydrate metabolism, pyruvate degradation, amino acid catabolism, heme synthesis, acetylcholine

Gregory S. Kelly, N.D.—Associate Editor, Alternative Medicine Review; Private Practice, San Diego, CA. Correspondence address: 937 South Coast Highway 101, Suite 205. Encinitas, CA 92024. [email protected]

Alternative Medicine Review ◆ Volume 2, Number 5 ◆ 1997 Page 365 Copyright©1997 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission Figure 1. Chemical composition of CoA and its constituents: pantetheine and pantothenic acid. acid with b-alanine. Mammals lack the enzyme for this synthetic step, so are unable to syn- NH2 thesize pantothenic acid. N Although foods contain CoA, ACP, N pantetheine, and pantethine, as well as pan- O tothenic acid, endogenous synthesis of both N N CoA and ACP can begin with pantothenic acid HO P O CH in humans. After pantothenic acid is absorbed 2 O and transported into cells, it can be converted O to either CoA or ACP by a synthetic process HH H requiring several enzymatic steps. Described HO P O H below is the most common biosynthetic path- O O OH way; however, the initial phosphorylation reaction can also occur after pantetheine, the re- CH2 O P OH duced form of pantethine, is formed or provided exogenously. H3CCHC 3 OH The first step is a phosphorylation re- H C OH action catalyzed by pantothenate kinase, a magnesium-dependent enzyme, resulting in C O the formation of 4'-phosphopantothenic acid (4'-PPA). High levels of CoA can inhibit this

antothenic acid NH

P enzymatic step; however, carnitine has been CH2 shown to reverse the inhibitory action under

antetheine 1

P experimental conditions in rat hearts. CH2 The next step in CoA or ACP biosyn-

C thesis is a condensation reaction with cysteine, producing 4'-phosphopantothenoyl cysteine. NH The enzyme needed for this synthetic step is also magnesium dependent. In the absence of CH2 cysteine, 4'-PPA will accumulate, suggesting, in biological systems, an absence of cysteine CH2 Cysteamine beta-Alanine acid Pantoic as a substrate is the limiting factor in biosyn- SH thesis of pantothenic acid’s down-line metabolites. 4'-phosphopantetheine (4'-PP) is then synthesis, and phase II detoxification formed by a decarboxylation reaction. The acetylations. ACP is an essential component reaction rate of this enzymatic step is increased of the fatty acid synthase complex required for by the availability of protein-SH compounds, fatty acid elongation. such as cysteine, suggesting the importance of these compounds for the activity of this de- Biosynthesis of Pantetheine and carboxylase enzyme.2 The final two steps in the synthesis of Related Compounds CoA involve the addition of an adenosyl group Biosynthesis of pantothenic acid can derived from ATP and the phosphorylation of be accomplished by most plants and microor- this molecule. Both of these enzymatic ganisms by enzymatically combining pantoic

reactions require magnesium as a cofactor. See Ono et al have suggested pantethine is Figure 2 for the synthetic pathway for CoA. more readily absorbed than calcium Although degradative enzymes exist pantothenate, a commonly-used form of for the breakdown of CoA, the scattered loca- Vitamin B5 supplementation, when given tion of these enzymes within the cell appear to indicate the cell is geared to minimize degradation of CoA once it has been formed.3 While CoA accounts for a large pro- Figure 2. Coenzyme A biosynthesis. portion of cellular pantothenic acid, ACP also contains the pantothenic acid molecule. The synthesis of ACP is not completely elaborated; Pantothenic acid however, as in CoA, 4'-PP has been identified ATP as the prosthetic group.3 Evidence suggests mg2+ ACP, in addition to its role in fatty acid syn- ADP thase, might be associated with a number of protein complexes. Observations also indicate ACP levels are maintained at the expense of 4'-Phosphopantothenic acid 3 CoA in bacteria; however, it is unclear CTP whether this is also the case in mammals. mg2+ Several hormones might impact the CDP+Pi synthesis of pantothenic acid-dependent enzymes. In experimental models, glucagon increases, while insulin decreases, the incorpo- 4'-Phosphopantothenylcysteine ration of pantothenic acid into CoA. Gluco- corticoids appear to potentiate the effects of glucagon.3 Hyperthyroidism is also reported to CO2 increase CoA synthesis.4 4'-Phosphopantetheine Metabolism of Pantethine The metabolic fate of an oral dose of ATP pantethine in humans has not been clearly de- mg2+ scribed. However, because pantethine is closer PPi to CoA than is pantothenic acid in the biosynthetic pathway of CoA, it has been suggested Dephosphocoenzyme A that pantethine will have clinical benefits in conditions where pantothenic acid is not ef- ATP fective. Based on clinical trials with mg2+ pantethine, this theoretical argument appears ADP to be true. It is generally accepted that a portion Coenzyme A of pantethine is hydrolyzed to pantetheine and a portion is degraded to pantothenic acid prior to intestinal absorption. The pantetheine can then be phosphorylated to provide the active orally to rats. In these animals, pantethine was 4'-PP moiety of CoA and ACP.5 hydrolyzed to pantetheine and pantothenic acid prior to absorption.6 Shigeta et al have also

Alternative Medicine Review ◆ Volume 2, Number 5 ◆ 1997 Page 367 Copyright©1997 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission Figure 3. CoA and ACP dependent pathways

ACP Directly or indirectly, Carbohydrates Tr iglycerides Doliquol Bile Salts Amino Acids Phospholipids CoQ-10 Vitamin D CoA is involved in the (Glucogenic) Prostaglandins Squalene Pantethine Fatty Acids Steroid Hormone breakdown of the carbon skeleton of most amino Pyrurate Acetyl-CoA 34mg-CoA Cholesterol acids. Alanine, cystine,

CoA cysteine, glycine, serine, threonine, and hydrox- Lipids Ketones Amino Acids yproline are metabolized (Ketogenic) TCA Acetylation of Amino Sugars to pyruvate and then en- CYCLE ter the TCA cycle with Acetylcholine Succinyl the help of CoA. CoA is CoA Acetylation of Xenobiotics directly involved with the

CoA breakdown of leucine, lysine, and tryptophan. α - Keto Acids CoA Porphyrin The degradation of the pyrimidine bases, cy- Branched Chain Adapted from: Smith CA, Song WO. Comparative Nutrition of Pantothenic Acid. Amino Acids Nutr. Bioch. 1996; 7:312-321 tosine, uracil, and thym- ine, is also dependent on CoA. CoA can direct acetyl suggested pantethine, following intramuscular groups into the formation injection in healthy subjects, is retained longer of all the polyisoprenoid-containing in the blood and has more tissue affinity than compounds, which include dolichol, pantothenic acid.5 ubiquinone (CoQ10), squalene, and cholesterol. Dolichol is a sugar carrier used in Biochemical Functions of the synthesis of glycoproteins. In addition to this indirect role in the formation of Pantethine and CoA glycoproteins, CoA is also used in the The biological functions of pantethine formation of N-acetylated derivatives of amino as an enzyme component is dependent on its sugars, including N-acetylglucosamine, N- degradation to pantetheine and its subsequent acetylgalactosamine, N-acetylmannosamine, incorporation into CoA or ACP. Both CoA and and N-acetylneuraminic acid. Because of the ACP function as acyl or acetyl carriers. CoA involvement of CoA in the initial steps of performs this function by forming thioester cholesterol synthesis, all down-stream linkages between its sulfhydryl group and metabolites of cholesterol, including steroids, available acyl or acetyl groups. In this man- Vitamin D, and bile acids, are indirectly ner, CoA facilitates the transfer of acetyl impacted by CoA. groups from pyruvate to oxaloacetate in order CoA is required for the acetylation of to initiate the tricarboxylic acid (TCA) cycle. choline to form the neurotransmitter acetyl- Before pyruvate can be used in the TCA cycle, choline. It is also used for acetylation conju- it must be converted to acetyl-CoA by oxida- gations of phenol amines, sulfur amino, ali- tive carboxylation. Coenzyme A, as well as phatic amines, and hydrazines. The biosyn- thiamine, lipoic acid, riboflavin, niacin, and thetic pathway of melatonin also requires an magnesium are all required. acetylation reaction.

Pantetheine has a wide array of func- rapid heart beat on exertion, epigastric distress, tions which interact with fat metabolism, in- anorexia, constipation, numbness and tingling cluding synthesis, degradation, and transpor- of the hands and feet, parethesis (“burning feet tation of fatty acids. The formation of fatty syndrome”), hyperactive deep tendon reflexes, acids from excess amounts of glycogen in- and weakness of finger extensor muscles have volves CoA. In the first step in the synthesis also been reported. More severe deficiency in of fatty acids, malonyl-CoA is formed by the some animals results in impaired carboxylation of acetyl-CoA. Fatty acid chain glucocorticoid production and adrenal cortex elongation is also dependent on CoA. The cy- failure.8 In animals, other deficiency toplasmic fatty acid synthesizing system uses symptoms include dermatitis, graying hair, loss ACP, a protein analog of CoA derived from of hair, hemorrhage, neurological lesions, pantetheine to bind intermediates in the syn- inflammation of nasal mucosa, corneal thesis of long-chain fatty acids. CoA is also vascularization, and sexual dysfunction. needed for the transport of long chain fatty acids into the mitochondria, a critical compo- Clinical Applications of Pantethine nent of beta-oxidation, the process of convert- Hyperlipidemia ing fats to energy. The majority of human research on Before fatty acids can be attached to a pantethine has focused on its role as a thera- glyceride backbone (e.g., triglycerides) they peutic agent in the treatment of dyslipidemia. must first be converted to a CoA thioester. The Oral administration of pantethine has consis- acyl groups can then bond with the hydroxy tently shown an ability to favorably impact a group of glycerol. Additionally, the biosynthe- variety of risk factors in persons with hyperc- sis of phospholipids (phosphatidylcholine, holesterolemia, arteriosclerosis, and diabetes. ethanolamine, serine, inositol, cardiolipin), as Arsenio et al concluded that oral well as plasmalogen, sphingenin, and supplementation with pantethine results in a ceramide, require CoA. Figure 3 provides a “clear tendency towards normalization of the schematic diagram of several of the physi- lipidic values.” They administered 600 mg/day ological functions of pantethine.7 of pantethine to 37 hypercholesterolemic and/ or hypertriglyceridemic patients for a three- Pantothenic Acid Deficiency month period. Twenty-one of these patients Because pantothenic acid and its were also diabetic. Administration of derivatives are so widespread in foods, it is pantethine resulted in a quick and progressive generally considered a dietary deficiency in decrease in total cholesterol, triglycerides, low humans is unlikely; however, symptoms of density lipoprotein (LDL) cholesterol and deficiency have been produced in both animals apolipoprotein B (Apo-B), and an increase in and humans using a pantothenic acid agonist. high density lipoprotein (HDL) cholesterol and Pantothenic acid deficiency has also been apolipoprotein A (Apo-A) in all groups. After produced in persons fed a semisynthetic diet suspending the treatment, a reversal of the virtually free of pantothenic acid. Subjects improvement of these parameters was ob- typically complain of headache, listlessness or served.9 Arsenio et al subsequently conducted fatigue, and a sensation of weakness. Other a one-year clinical trial with pantethine in 24 symptoms can include personality changes, patients with established dyslipidemia of depression, sleep disturbances, and impaired Fredrickson’s types IIa, IIb, and IV, alone or motor coordination.3 Sleep disturbances, associated with diabetes mellitus. Blood lipid frequent infections, postural hypotension, assays revealed consistent reductions in total

Alternative Medicine Review ◆ Volume 2, Number 5 ◆ 1997 Page 369 Copyright©1997 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission cholesterol, LDL-cholesterol, and Apo-B, (900 mg daily (children and young boys) and along with an increase of HDL-cholesterol and 1200 mg daily (adults)) for 3Ð6 months. In the Apo-A in individuals with types IIa and IIb pediatric group they reported a 20% reduction dyslipidemia. The results were equally good of total cholesterol and a 27% decrease in in patients with uncomplicated dyslipidemia LDL-cholesterol. In adult patients with type and in those with associated diabetes melli- IIa hyperlipoproteinemia, a 25% decrease in tus. A marked reduction in triglycerides was total cholesterol, a 39% decrease in LDL-cho- observed in the patients with Fredrickson’s lesterol, a 34% decrease in Apo-B, and a mod- type IV dyslipidemia.10 Seghieri et al similarly est increase in HDL-cholesterol were ob- reported a decrease in triglycerides in uremic served. In adult patients with type IIb patients on hemodialysis with type IV hyperlipoproteinemia, total cholesterol was dyslipidemia.11 reduced by 19.8%, LDL-cholesterol by 37%, Maggi et al investigated the effect of triglycerides by 31%, and Apo-B by 6%. In 900 mg per day of pantethine on 30 patients this subgroup, a 23% increase of HDL-cho- with dyslipidemia. The six patients in the sub- lesterol and a 15% increase in apolipoprotein group of type IIa dyslipidemia decreased total A-I were also observed.14 cholesterol by 26%, triglycerides by 28%, Donati et al tested the effectiveness and LDL-cholesterol by 38%, very low density li- tolerability of pantethine in the treatment of poprotein (VLDL) cholesterol by 28%, and 31 patients with dyslipidemia undergoing Apo-B by 16%. HDL-cholesterol increased by chronic hemodialysis. The mean duration of 34%. The nine patients with type IIb treatment was nine months, with an oral dose dyslipidemia experienced decreases of 25% of between 600Ð1200 mg of pantethine daily. for total cholesterol, 49% for triglycerides, A significant improvement in total blood cho- 33% for LDL-cholesterol, 44% for VLDL- lesterol was noted in the patients with basal cholesterol, and 11% for Apo-B. An increase hypercholesterolemia, and a highly significant in HDL-cholesterol of 43% was observed. The reduction of serum triglycerides was observed 15 individuals with type IV dyslipidemia de- for the entire group. Significant variations of creased total cholesterol by 13%, triglycerides HDL-cholesterol or total Apo-A were not de- by 68%, VLDL-cholesterol by 53%, and Apo- tected.15 B by 18%. HDL cholesterol increased by Murai et al administered 1000 mg of 25%.12 pantethine orally daily for three months to 12 Gaddi et al gave pantethine (900 mg/ male survivors of cerebral infarction. A ten- day) to 11 patients with type IIb and 15 pa- dency toward a decrease in plasma concentra- tients with type IV dyslipidemia. The patients tions of total cholesterol, triglyceride, phos- with type IIb dyslipidemia experienced reduc- pholipid, and VLDL- and LDL-cholesterol tions in total cholesterol, LDL-cholesterol, and was observed. HDL-cholesterol concentration, triglycerides, and an increase in HDL-choles- especially HDL2, and the HDL:LDL ratio terol. In type IV patients, a clear decline in improved significantly.16 triglycerides was demonstrated. The variation Binaghi et al treated 24 hypercholes- in total, LDL-, and HDL-cholesterol in these terolemic perimenopausal women with 900 individuals was not significant.13 mg/day of pantethine. After 16 weeks of treat- Bertolini et al treated a series of seven ment they reported an efficacy rate of about children and 65 adults suffering from hyperc- 80% with significant reductions in total cho- holesterolemia alone or associated with lesterol, LDL-cholesterol, and LDL/HDL ra- hypertriglyceridemia (types IIa and IIb of tios.17 Fredrickson’s classification) with pantethine

Table 1. Pantethine’s reported impact on lipid parameters in patients with Fredrickson’s type IIa, IIb, and IV dyslipidemia

Type Clinical Definition Pantethine’s Impact

IIa total cholesterol elevated decrease total cholesterol LDL elevated decrease LDL-cholesterol triglyceride normal decrease VLDL-cholesterol decrease triglyceride decrease Apo-A increase HDL-cholesterol increase Apo-A

IIb total cholesterol elevated decrease total cholesterol LDL elevated decrease LDL-cholesterol VLDL elevated decrease VLDL-cholesterol triglyceride elevated decrease triglyceride decrease Apo-B increase HDL-cholesterol increase Apo-A

IV total cholesterol normal mixed results with total cholesterol VLDL elevated mixed results with LDL-cholesterol triglyceride elevated decrease VLDL-cholesterol decrease triglyceride decrease Apo-B mixed results with HDL-cholesterol

Atherosclerotic manifestations are not (900 mg/day) resulted in improved lipid only common in individuals with diabetes but metabolism in patients with and without also result in significant long-term diabetes.20 Miccoli et al observed a decrease complications. Correspondingly, lipoprotein in total cholesterol, LDL-cholesterol, and Apo- disorders must be managed in diabetics. B in diabetics following administration of Tonutti et al reported that pantethine was pantethine. No variations were observed in effective in lowering triglyceride levels in other lipid parameters.21 diabetic patients with dyslipidemia.18 Pantethine administration has been Hiramatsu et al reported oral administration shown to favorably affect parameters associ- of pantethine to 31 diabetic patients with ated with platelet lipid composition and cell hyperlipidemia decreased cholesterol from a membrane fluidity. Prisco et al observed a mean value of 236 mg/dl to 217 mg/dl, and significant decrease of total cholesterol and increased HDL-cholesterol from a mean value total phospholipids in plasma and in platelets of 40 mg/dl to 43 mg/dl.19 Donati et al following pantethine supplementation. A rela- conducted a clinical study on 1045 tive increase of omega-3-polyunsaturated fatty hyperlipidemic individuals; 57 with insulin- acids both in plasma and in platelet phospho- dependent and 241 with non insulin-dependent lipids, and a decrease of arachidonic acid in diabetes. Oral administration of pantethine plasma phospholipids was also observed.22

Alternative Medicine Review ◆ Volume 2, Number 5 ◆ 1997 Page 371 Copyright©1997 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission Gensini et al studied the effect of oral treat- squalene) occurs.26 In vitro and cell culture ment with pantethine on platelet lipid compo- experiments suggest pantethine can inhibit the sition in 20 patients with dyslipidemia. In ad- activity of HMG-CoA reductase.27 Adminis- dition to a reduced phospholipid and choles- tration of pantethine has been shown to in- terol content, treatment resulted in a reduction crease lipoprotein lipase activity in adipose of saturated and mono-unsaturated, and a rela- tissue of rats.28 Pantethine is also capable of tive increase of polyunsaturated fatty acid con- inhibiting total fatty acid synthesis.25 tent of platelet phospholipids. An increased Although the efficacy of pantethine in content of eicosapentaenoic and normalizing parameters of dyslipidemia has docosahexaenoic acid, and a concomitant de- been attributed to its ability to increase CoA crease of arachidonic acid content was also levels, this relationship has never been dem- noted.23 onstrated. Theoretically, if pantethine enhances In diabetic patients, composition of the formation of CoA, the additional CoA platelets is characterized by a derangement in might then combine with free acetyl groups to a wide variety of lipid concentrations and a form acetyl-CoA. The acetyl-CoA could then higher microviscosity than in healthy plate- be directed into the TCA cycle or beta-oxida- lets. Administration of pantethine is reported tion of fats at the expense of cholesterol for- to normalize these values of fatty acids to con- mation. Enhanced formation of CoA could also trol levels, and result in a concomitant reduc- impact cholesterol levels since the CoA mol- tion in experimentally induced ecule is important in the formation of bile salts. hyperaggregation. The volume of platelets and Wittwer et al have proposed the action the microviscosity were also lower following of pantethine might be a result of its hydroly- oral administration of pantethine.19 Oral ad- sis product, cysteamine. In vitro experiments ministration of 1200 mg/day of pantethine is have shown modulation of cholesterol and very effective in lowering elevated levels of methyl sterol synthesis by pantethine, cys- beta-thromboglobulin, a marker associated teamine, or cystamine (the disulfide of cys- with increased platelet activation and release teamine), while pantothenic acid had no ef- in diabetes.24 fect. In vivo experiments have also shown oral While the exact mechanism of action pantethine or equimolar cystamine can lower of pantethine in normalizing parameters asso- plasma cholesterol, while pantothenic acid ciated with dyslipidemia is unknown, several does not.29 explanations have been proposed. Some au- thors have suggested pantethine might be ca- Cataract Protection pable of directly modulating the action of sev- In several animal models, preliminary eral enzymes. The addition of pantethine to studies have indicated pantethine can inhibit cultured cells has been shown to cause an 80% cataract formation. Administration of inhibition in cholesterol synthesis.25 Experi- pantethine (820 mg/kg) inhibits selenite-in- mental evidence suggests pantethine is effec- duced opacification in rats. The effect of tive at inhibiting cholesterol synthesis when pantethine was most significant when it was levels of the cholesterol precursor mevalonate administered within six hours following se- are elevated. Under this circumstance, an in- lenite injection. Administration of pantethine creased incorporation of the substrate into cho- 10Ð17 hours after selenite injection was not lesterol is progressively reduced and an in- protective.30 Other experimental results sug- creased incorporation of the substrate into pre- gest protein aggregation and lens opacifica- cursors of cholesterol (methyl sterols and tion associated with a variety of physiological

and biochemical mechanisms, including radia- lactin concentrations.36 tion, selenite, galactose, and streptozotocin can The effects of pantethine on central be delayed or inhibited by the systemic ad- neurotransmissions was investigated in rats. ministration of pantethine.31 The pattern of pro- Pantethine administered in low doses (0.48- teins in animal lenses protected from selenite- 0.96 mM/kg SC) induced a decrease of the induced protein aggregation and opacification hypothalamic noradrenaline level without in- by administration of pantethine is reported to fluencing the concentrations of dopamine and resemble the pattern for proteins from trans- dihydroxyphenyl acetic acid (DOPAC). When parent lenses of normal untreated animals.32 pantethine was injected in higher doses (1.95- While it appears pantethine might be active in 3.90 mM/kg SC), a marked depression of no- preventing cataract formation in these animal radrenaline and an increased concentration of models, reversal of existing opacities has not dopamine and DOPAC was observed in the been observed with the use of pantethine. hypothalamus. This effect was attenuated 12 hours following administration of pantethine, Central Nervous System Impact of and disappeared after 24 hours.35 While Pantethine pantethine consistently reduces the noradrenaline and increases the dopamine and DOPAC Cysteamine, a cysteine derivative concentrations in the hypothalamus,37,38 pan- formed from the degradation of pantethine, is tothenic acid does not appear to influence hy- known to cause depletion of somatostatin, pro- pothalamic catecholamine concentrations.38 lactin, and noradrenaline in the brain and pe- Detoxification and Liver Protection ripheral tissues. Similarly, pantethine has been Acetylation reactions are an important com- shown to deplete somatostatin, prolactin, and ponent of the hepatic phase II detoxification noradrenaline, although with lower efficacy system. Although species variation in acety- compared to cysteamine.33 The actual clinical lation reactions appear to occur, in all relevance of pantethine’s impact on the cen- acetyltransferase reactions the donor of the tral nervous system in humans has not been acetyl group is acetyl-CoA. Acetylation reac- explored. In animals, the effect on somatosta- tions primarily metabolize NH groups. Acety- tin, prolactin, and noradrenaline has been dem- 2 lation reactions of OH and SH groups are onstrated following intraperitoneal and intra- known but uncommon. The compounds typi- venous administration of pantethine; however, cally metabolized by acetylation reactions in- the effect does not appear to occur after an clude aliphatic amines (such as histamine and oral dose. mescaline), aromatic amines (such as sulfona- Ong et al reported intraperitoneal in- mide), hydrazine and hydrazide, and certain jection of pantethine depleted somatostatin and amino acids (such as phenylcysteine). Because prolactin levels in experimental animals.34 of its biochemical position as the most stable Vecsei et al also observed decreased concen- supplemental form of an immediate precursor trations of striatal somatostatin following ad- to CoA, pantethine might be able to play an ministration of high doses (1.95-3.90 mM/kg important role in the metabolism of some SC) of pantethine. This effect was attenuated xenobiotic compounds. 24 hours after treatment.35 Both intraperitoneal Ligas et al have reported lipotropic and intravenous administration of pantethine activity of a preparation combining pantethine can deplete prolactin from plasma; however, and a calcium salt of phosphorylcholine oral administration of pantethine does not chloride.39 Pantethine should also be useful in seem to be capable of influencing plasma pro- the treatment of hepatitis A. Calcium

Alternative Medicine Review ◆ Volume 2, Number 5 ◆ 1997 Page 373 Copyright©1997 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission pantothenate (300 mg and 600 mg daily) and exposure to autoxidized linoleate.45 In a pantetheine (90 mg and 180 mg daily) were subsequent report, they suggest this activity administered orally for 3-4 weeks as combined might be due to decreased lipid peroxidation therapy in 156 patients with hepatitis A. A resulting from the reducing property inherent favorable clinical effect, as well as an in pantethine’s SH group.46 enhanced immunomodulatory action, a Pantethine’s ability to decrease lipid beneficial effect on the level of blood serum peroxidation is likely to provide clinical ben- immunoglobulins, and an increased efits in other tissues as well. Kobayashi et al phagocytic activity of peripheral blood note pantethine, glutathione, and ascorbic acid neutrophils were reported. Pantetheine are effective in controlling chronic urticaria. provided the most pronounced therapeutic They suggest a relationship exists between effect.40 peroxidation of serum lipids and fatty acids, Pantethine, as well as other derivatives and the pathogenesis of chronic urticaria.47 of pantothenic acid, can decrease acute toxicity of acetaldehyde in mice. The duration of Impact on Adrenal Function the narcotic action of ethanol in mice and rats The administration of pantethine ap- is also decreased by administration of pears to exert an influence on some indicators pantethine. The anti-toxic effect of pantethine of adrenal function. Several animal experi- and other pantothenic acid derivatives did not ments have indicated a deficiency of pan- appear to be mediated by CoA-dependent tothenic acid adversely affects adrenal cortex acetylation reactions of detoxification,41 so the function.48-50 The pantothenate derivatives protective effect is probably related to (pantethine, 4'-PPA, and CoA in particular) pantethine’s capability to decrease the rate of injected into animals have a marked ethanol oxidation.42 steroidogenous effect.51 Administration of Daily intraperitoneal administration of pantethine to 20 humans with a variety of clini- pantethine (500 mg/kg) has been shown to cal conditions was reported to buffer the in- offer significant protection against carbon crease in 24-hour urinary 17- tetrachloride-induced liver damage in a rat hydroxycorticosteroids and plasma 11- model. Hepatotoxicity and peroxidative hydroxycorticosteroids stimulated by a load- damage were prevented, and increases in ing dose of adrenocorticotropic hormone.52 serum ALT were lessened. Pantethine also While these reports are interesting, the clini- prevented the development of hepatic steatosis cal relevance of pantethine supplementation caused by the halocarbon.43 Pantethine and on adrenal function remains largely unex- other pantothenic acid-related compounds plored. have been shown to protect cell membranes against damage by oxygen free radicals. Toxicology and Dosage Slyshenkov et al suggest pantethine’s ability Animal studies have documented the to increase cellular levels of CoA is probably low toxicity and safety of pantethine.53,54 Al- responsible for the observed protection. It is though digestive disturbances have occasion- presumed CoA can diminish propagation of ally been reported in the literature, the major- lipid peroxidation and promote repair ity of researchers have commented on the com- mechanisms by enhancing phospholipid plete freedom from side-effects and subjective synthesis .64 Hiramatsu et al have reported a complaints experienced by individuals taking diet with an excess of pantethine protects the pantethine. drug-metabolizing system of the rat liver, and The most common oral dosage used increases the survival rate of animals against

in the treatment of dyslipidemia has been 300 pantethine supplementation are impressive, mg three times per day. Higher dosages can and because the coenzymes which utilize be utilized; however, in the majority of indi- pantethine for their metabolic activity are uti- viduals this seems to be unnecessary. When lized in over 70 biochemical reactions affect- utilizing pantethine for other clinical condi- ing a wide variety of cellular functions, it is tions, although information on dosage is lim- very likely that only the tip of the iceberg of ited, a similar schedule is advised. the therapeutic potential of pantethine has been discovered. Conclusion Pantethine is a metabolically active References substrate for CoA and ACP. Because it by- 1. Fisher MN, Robishaw JD, Neely JR. The passes several of the enzymatic reactions re- properties and regulation of pantothenate quired for incorporation of pantothenic acid kinase from rat heart. J Biol Chem 1985;260:15745-15751. into these molecules, pantethine is capable of 2. Scandura R, Barboni E, Granata F, et al. exerting a therapeutic effect in conditions Pantothenoylcysteine-4'-phosphate decarboxy- where pantothenic acid is ineffective. lase from horse liver. Eur J Biochem Pantethine contains a sulfhydryl (SH) group 1974;49:1-9. from a cysteine derivative, while pantothenic 3. Tahiliani AG, Beinlich CJ. Pantothenic acid in acid must be supplied with this SH group prior health and disease. Vit Horm 1991;46:165-227. to having vitamin activity. In vivo, availabil- 4. Tabachanick IIA, Bonnycastle DD. The effect ity of cysteine and SH groups is probably the of thyroxine on the coenzyme A content of some tissues. J Biol Chem 1954;207:757-760. limiting factor preventing biosynthesis of co- 5. Shigeta Y, Shichiri M. Urinary excretion of enzymes from pantothenic acid. Pantethine pantothenic acid and pantethine in human offers a significant biochemical advantage by subjects. J Vitaminol 1966;12:186-191. avoiding the need for this endogenous supply 6. Ono S, Kameda K, Abiko Y. Metabolism of of cysteine. pantethine in the rat. J Nutr Sci Vitaminol Pantethine has consistently demon- 1974;20:203-213. strated an ability to favorably impact lipid pa- 7. Smith CM, Song WO. Comparative nutrition rameters in a wide variety of clinical situations. of pantothenic acid. Nutr Biochem 1996;7:312- 321. Pantethine administration has been shown to 8. Chevaux KA, Song WO. Adrenocortical favorably affect platelet lipid composition and function and cholesterol in pantothenic acid cell membrane fluidity. Although supplemen- deficiency. FASEB 1994;8:2588. tation with pantethine should not be expected 9. Arsenio L, Caronna S, Lateana M, et al. to reverse existing opacities, administration Hyperlipidemia, diabetes and atherosclerosis: has successfully prevented experimentally-in- efficacy of treatment with pantethine. Acta duced cataract formation. Evidence suggests Biomed Ateneo Parmense 1984;55:25-42. pantethine might be beneficial in the treatment 10. Arsenio L, Bodria P, Magnati G, et al. Effec- tiveness of long-term treatment with of hepatitis A. In addition to having lipotropic pantethine in patients with dyslipidemia. Clin activity, pantethine seems to be very effective Ther 1986;8:537-545. in reducing peroxidative damage and enhanc- 11. Seghieri G, Maffuci G, Toscano G, et al. Effect ing hepatic enzyme function. Pantethine might of therapy with pantethine in uremic patients be capable of enhancing the function of the on hemodialysis, affected by type IV hyperlipoproteinemia. G Clin Med adrenal cortex; however, more research is 1985;66:187-192. [Article in Italian] needed to ascertain the exact nature of its im- 12. Maggi GC, Donati C, Criscuoli G. Pantethine: pact on the adrenal gland and glucocorticoid production in humans. Clinical results of

Alternative Medicine Review ◆ Volume 2, Number 5 ◆ 1997 Page 375 Copyright©1997 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission A physiological lipomodulating agent, in the 23. Gensini GF, Prisco D, Rogasi PG, et al. treatment of hyperlipidemias. Cur Ther Res Changes in fatty acid composition of the single 1982;32:380-386. platelet phospholipids induced by pantethine 13. Gaddi A, Descovich GC, Noseda G, et al. treatment. Int J Clin Pharmacol Res Controlled evaluation of pantethine, a natural 1985;5:309-318. hypolipidemic compound, in patients with 24. Eto M, Watanabe K, Chonan N. Lowering different forms of hyperlipoproteinemia. effect of pantethine on plasma B- Artherosclerosis 1984;50:73-83. thromboglobulin and lipids in diabetes 14. Bertolini S, Donati C, Elicio N, et al. Lipopro- mellitus. Artery 1987;15:1-12. tein changes induced by pantethine in 25. Ranganathan S, Jackson RL, Harmony JA. hyperlipoproteinemic patients: adults and Effect of pantethine on the biosynthesis of children. Int J Clin Pharmacol Ther Toxicol cholesterol in human skin fibroblasts. Athero- 1986;24:630-637. sclerosis 1982;44:261-273. 15. Donati C, Barbi G, Cairo G, et al. Pantethine 26. Cighetti G, Del Puppo M, Paroni R, et al. improves the lipid abnormalities of chronic Effects of pantethine on cholesterol synthesis hemodialysis patients: results of a multicenter from mevalonate in isolated rat hepatocytes. clinical trial. Clin Nephrol 1986;25:70-74. Atherosclerosis 1986;60:67-77. 16. Murai A, Miyahara T, Tanaka T, et al. The 27. Cighetti G, Del Puppo M, Paroni R, Galli effects of pantethine on lipid and lipoprotein Kienle M. Modulation of HMG-CoA reductase abnormalities in survivors of cerebral infarc- activity by pantetheine/pantethine. Biochim tion. Artery 1985;12:234-243. Biophys Acta 1988;963:389-393. 17. Binaghi P, Cellina G, Lo Cicero G, et al. 28. Noma A, Kita M, Okamiya T. Effect of Evaluation of the cholesterol-lowering pantethine on post-heparin plasma lipolytic effectiveness of pantethine in women in activities and adipose tissue lipoprotein lipase perimenopausal age. Minerva Med in rats. Horm Metab Res 1984;16:233-236. 1990;81:475-479. 29. Wittwer CT, Graves CP, Peterson MA, et al. 18. Tonutti L, Taboga C, Noacco C. Comparison Pantethine lipomodulation: evidence for of the efficacy of pantethine, acipimox, and cysteamine mediation in vitro and in vivo. bezafibrate on plasma lipids and index of Atherosclerosis 1987;68:41-49. cardiovascular risk in diabetics with 30. Hiraoka T, Clark JI. Inhibition of lens opacifi- dyslipidemia. Minerva Med 1991;82:657-663. cation during the early stages of cataract 19. Hiramatsu K, Nozaki H, Arimori S. Influence formation. Invest Ophthalmol Vis Sci of pantethine on platelet volume 1995;36:2550-2555. microviscosity, lipid composition and func- 31. Clark JI, Livesey JC, Steele JE. Delay or tions in diabetes mellitus with hyperlipidemia. inhibition of rat lens opacification using Tokai J Exp Clin Med 1981;6:49-57. pantethine and WR-77913. Exp Eye Res 20. Donati C, Bertieri RS, Barbi G. Pantethine, 1996;62:75-84. diabetes mellitus and atherosclerosis. Clinical 32. Matsushima H, David LL, Hiraoka T, Clark JI. study of 1045 patients. Clin Ter 1989;128:411- Loss of cytoskeletal proteins and lens cell 422. opacification in the selenite cataract model. 21. Miccoli R, Marchetti P, Sampietro T, et al. Exp Eye Res 1997;64:387-395. Effects of pantethine on lipids and 33. Vecsei L, Widerlov E. Preclinical and clinical apolipoproteins in hypercholesterolemic studies with cysteamine and pantethine related diabetic and non-diabetic patients. Cur Ther to the central nervous system. Prog Res 1984;36:545-549. Neuropsychopharmacol Biol Psychiatry 22. Prisco D, Rogasi PG, Matucci M, et al. Effect 1990;14:835-862. of oral treatment with pantethine on platelet 34. Ong GL, Miaskowski C, Haldar J. Changes in and plasma phospholipids in IIa oxytocin and vasopressin content in posterior hyperlipoproteinemia. Angiology 1987;38:241- pituitary and hypothalamus following 247. pantethine treatment. Life Sci 1990;47:503- 506.