Tangeretin /603

SUPPLEMENT MONOGRAPHS TANGERETIN /603

carbon dioxide and methane; and lactate, pyruvate, succinate LITERATURE and formate. Acetate, propionate and butyrate that are not Collins MO, Gibson GR. Probiotics, prebiotics, and synbiotics: metabolized in colonocytes are absorbed from the colon and approaches for modulating the microbial ecology of the gut. Am transported via the portal circulation to the liver. These J Clin Nutr. 1999; 69(suppl): 10525-10575. short-chain fatty acids are extensively metabolized in hepato- Macfarlane GT, Cummings JH. Probiotics and prebiotics: can cytes. Acetate, propionate and butyrate that are not metabo- regulating the activities of intestinal bacteria benefit health? lized in hepatocytes are transported by the circulation to West J Med. 1999; 17:187-191. various tissues where they undergo further metabolism. Roberfroid MB. Prebiotics and synbiotics: concepts and Butyrate is an important respiratory fuel for colonocytes. nutritional properties. Br J Nutr. 1998; 80:5197-5202.

INDICATIONS AND USAGE For additional Literature, see Prebiotics and Probiotics. Synbiotics are useful for the same indications as prebiotics and probiotics. Some may protect against intestinal patho- gens and ameliorate the severity of some inflammatory bowel diseases. Some may be helpful in antibiotic associated Tangeretin diarrhea, as well as some infectious and viral diarrheas. They may have some immune-enhancing, anticarcinogenic, anti- DESCRIPTION osteoporotic, glucose-modulating and lipid-modulating Tangeretin is a member of the polymethoxylated flavone, or effects. polymethoxyflavone, family of flavones. Flavones them- selves comprise a subclass of the large class of plant RESEARCH SUMMARY substances, the flavonoids. Polymethoxylated flavones See Probiotics and Prebiotics. (PMFs) exist almost exclusively in the Citrus genus, particularly in the peels and tissues of sweet oranges (Citrus CONTRAINDICATIONS, PRECAUTIONS, ADVERSE REACTIONS sinensis), the peels and tissues of bitter oranges (Citrus CONTRAINDICA TIONS Synbiotics are contraindicated in those who are hypersensi- aurantium L.) and, especially, in the peels and tissues of tive to any component of a synbiotic-containing supplement. tangerines (Citrus reticulata Blanco), including Dancy and Cleopatra tangerines and clementines. The two most com- PRECAUTIONS mon PMFs found in citrus peels and tissues are nobiletin (see Pregnant women and nursing mothers should only use Nobiletin) and tangeretin. Sinensetin is the third most synbiotic supplementation if prescribed by their physicians. common PMF found in the peels and tissues of citrus fruits. Only trace amounts of tangeretin, at best, are found in ADVERSE REACTIONS lemons (Citrus limon) and grapefruits (Citrus paradisi). The most common adverse reaction to synbiotics is flatulence. Tangeretin, like other flavonoids, is a plant secondary metabolite. Plant secondary metabolites comprise the de- INTERACTIONS fense system of plants against fungi, predators and pests, NUTRITIONAL SUPPLEMENTS among other things. Tangeretin possesses activity against Minerals (calcium, magnesium): Concomitant intake of certain fungal diseases, such as mal seco, an often fatal calcium or magnesium supplements and synbiotics may disease of horses in Argentina. However, tangere tin is not enhance the colonic absorption of these minerals. nearly as potent in this regard as is nobiletin (see Nobiletin). FOODS Tangeretin has been studied for its possible lipid-lowering Synbiotics, via their prebiotic oligosaccharides, may enhance activity, as well as for its possible anticancer activity. the colonic absorption of calcium and magnesium in foods. Tangeretin is chemically described as 5,6,7,8-tetramethoxy- DOSAGE AND ADMINISTRATION Synbiotic supplements that are currently available include 2-(4-methoxyphenyl)-4H-I-benzopyran-4-one. It is also combinations of bifidobacteria and fructo-oligosaccharides known as 4',5,6,7,8-pentamethoxyflavone, and ponkanetin (FOS), Lactobacillus GG and inulins and bifidobacteria and (ponkan is the conventional name for Citrus reticulata). Its lactobacilli and FOS or inulins. New combinations are CAS number is 48 I-53-8. Its empirical formula is C2oH2007 currently being developed. and its molecular weight is 372.37. The major chemical difference between tangeretin and nobiletin is the absence of Probiotic intake typically ranges from one to ten billion a 3'-methoxy group on the flavone skeleton in tangeretin and colony-forming units a few times a week. Doses of the presence of a 3'- methoxy group on the flavone skeleton prebiotics, in the form of synbiotics, are variable. in nobiletin. 604/TANGERETIN PDR FOR NUTRITIONAL SUPPLEMENTS

The following chemical structures are described within this Antifungal: The antifungal mechanism of action of tangeretin monograph. is not entirely clear. Hypolipidemic: Apolipoprotein B (apoB) is the primary MeO apolipoprotein of low-density lipoprotein (LDL), which is responsible for carrying cholesterol to tissues. The role of tangeretin on the regulation of apoB and lipid metabolism MeO was studied in the human hepatoma cell line HepG2. It was OMeO found that tangeretin significantly lowered apoB secretion and decreased intracellular synthesis of cholesteryl esters, Tangeretin free cholesterol and triacylglycerol (TAG). The suppression of TAG synthesis went along with lowered activity of diacylglycerol (DAG) acyltransferase (DGAT) and micro- somal triglyceride transfer protein (MTP). Tangeretin was also found to activate the peroxisome proliferator-activated receptor (PPAR). PPAR is a transcription factor that has a o positive regulatory impact on fatty acid oxidation and TAG availability. Flavone Skeleton Citrus polymethoxylated flavones (PMFs), especially tanger- 4' etin, were found to significantly lower total cholesterol, very 7 3' low-density lipoprotein (VLDL) and LDL-cholesterol in hamsters with diet-induced hypercholesterolemia. The PMFs 6 reduced or tended to reduce serum triglyceride levels, as well. High-density lipoprotein cholesterol (HDL) was not affected. The mechanism of this lipid-lowering effect is Flavonoid Skeleton unclear.

ACTIONS AND PHARMACOLOGY The hypolipidemic effect of tangeretin in human HepG2 ACTIONS cells along with its hypocholesterolemic effect in hamsters Tangeretin has antifungal activity against some citrus warrants further study as well as human trials to determine if pathogenic fungi. Tangeretin has possible anticancer and tangeretin might have a role in the management of hypolipidemic activities. hyperlipidemia.

MECHANISM OF ACTION PHARMACOKINETICS Anticancer activity: Tangeretin was found to induce cell- The pharmacokinetics (PK) of tangeretin IS incomplete. cycle G I arrest in human colorectal carcinoma COLa 205 Almost all of the PK studies of tangeretin have been cells, inhibiting the growth of these cells. The polymethoxy- performed in animals. Tangeretin is absorbed across the lated flavone was demonstrated to inhibit the activities of small intestine to some degree. Tangeretin has very low cyclin-dependent kinases 2 (Cdk2) and 4 (Cdk4). In addition, solubility in water, but its permeability is quite high, which the Cdk inhibitors p21 and p27 were also shown to be ultimately contributes to fair bioavailability for this citrus elevated with the tangeretin treatment. Tangeretin possibly flavone. Tangeretin, following absorption, most likely enters exerted its growth inhibitory effect either via modulation of first into the lymphatics and is transported to the systemic the activities of several key G I regulatory proteins (Cdk2, circulation, which transports it to various tissues and organs, Cdk4) or via mediating the increase of Cdk inhibitors (p21, including the liver. It has been reported that tangeretin p27). More research is needed to understand this growth crosses the blood-brain barrier and, in a rat study, it was inhibitory effect of tangeretin. found in the hypothalamus, the striatum and the hippocam- pus. In contrast to polyphenolic flavonoids, tangeretin itself Tangeretin was demonstrated to inhibit the growth of human is not glucuronidated by UDP-glucuronosyltransferase to a mammary cells. In estradiol-primed human T47D mammary glucuronide. Nor does it get sulfated by sulfotransferases to a cancer cells, it was observed that tangeretin inhibited sulfate. This is because the hydroxyl groups are methylated. extracellular signal-regulated kinases 1/2 (ERK 1/2) phosphorylation. It was thought that this kinase inhibitory action However, when the methoxy groups get demethylated, accounted, in part, for the inhibition of mammary cell phenolic hydroxyl groups open up, which can be glucuroni- growth. dated or sulfated. Metabolites of tangeretin that have been SUPPLEMENT MONOGRAPHS TANGERETIN /605 found in rat urine include monohydroxytetramethoxy fla- One group has reported that formulations containing citrus vone, dihydroxytrimethoxy flavone and glucuronide conju- PMFs, primarily tangeretin, show some promise as cholester- gates of the flavones. ol- and triacylglycerol-Iowering agents. These conclusions were based upon both in vitro and animal studies. One of the INDICATIONS AND USAGE same researchers, in collaboration with others, has also Clinical evidence in support of the claim that the citrus reported that PMFs ameliorate fructose-induced hyperglycer- flavonoid tangeretin is therapeutic in breast and some other idemia and other metabolic abnormalities associated with cancers is lacking. There is very preliminary nonclinical data insulin resistance in hamsters. More research is needed and suggesting that tangere tin might have beneficial lipid-Iower- warranted to determine whether tangeretin and related ing effects, antidiabetic effects and neuroprotective effects. substances can be of benefit in lipid and glucose metabolism and thus, possibly, in heart disease and diabetes. RESEARCH SUMMARY There was hope that tangere tin might be an effective Finally, there is one report in which tangeretin was found to anticancer treatment because, in numerous in vitro studies, it exert a neuroprotective effect in a rat model of Parkinson's inhibited proliferation of cancer cells without inducing cell disease. After 28 days of oral administration of tangeretin, death (apoptosis), leaving open the possibility that it would significant levels of tangeretin were found in the brains of thus spare normal cells, in contrast with so many other these animals, producing the first evidence that it can cross highly toxic cancer therapies. Most notably in these in vitro the brain-blood barrier. Study data showing that the supple- studies, tangere tin proved cytostatic in both human breast ment has protective effects on dopaminergic neurons suggest and colon cancer cells lines. Other in vitro research showed that tangeretin should be investigated to confirm and further positive results in human lung carcinoma cells. explain its possible beneficial activity in this context.

CONTRAINDICATIONS, PRECAUTIONS, ADVERSE REACTIONS In a study using the hamster, cheek pouch model, however, CONTRA INDICA TIONS tangeretin and three other flavonoids (hesperetin, neohesperi- Tangeretin is contraindicated in those who are hypersensitive din and nobiletin) all failed to inhibit chemically induced to any component of a tangeretin-containing product. cancer. (Two flavonoids derived from grapefruit-naringin and naringenin-did, however, exert significant anticancer PRECAUTIONS effects in this study.) Women who are under tamoxifen treatment should avoid excessive consumption of ta!1geretin-containing citrus prod- Several researchers have reported finding that tangeretin is ucts and supplements while under treatment. not effectiv~. in inhibiting ~reast; cancer in vivo, and that, in fact, it neutralizes the effects of the selective estrogen Those who wish to try tangeretin for the support of any receptor modulator (SERM) tamoxifen, often used to reduce health condition should first discuss its use with his or her the risk of breast cancer. In a study of mice with mammary physician. cancer, one group of mice was given water with tamoxifen, ADVERSE REACTIONS another group water with tangeretin added, another both c, None known. tamoxifen and tangeretin and a fourth group water alone (control group). The group receiving only tamoxifen had INTERACTIONS significantly enhanced survival time. The tangeretin group DRUGS did not; neither did the combination tangeretinltamoxifen Midazolam: Midazolam is a member of the benzodiazepine group, indicating that the flavonoid had neutralized the family of drugs and has anxiolytic and sedative activities. dI1Jg's beneficial effect. Another group of researchers has Midazolam is metabolized by the cytochrome P450-3A4 reported that tangeretin reduces the number of natural killer (CYP3A4) enzyme. Naringin, a flavonoid found in grapefruit cells in vivo and that this may explain why its positive in and grapefruitjuice, is a potent inhibitorof CYP3A4 and can vitro effects are abolished in vivo. One group cautions that cause a number of interactions with drugs and dietary those using tamoxifen should avoid tangeretin supplements supplements, some that are not at all desirable. Naringin is or any tangeretin-fortified products. Fruit juices that do not an inhibitor of the metabolism of CYP3A4. On the other include pulped peel are thought to be safe for those taking hand, tangeretin has been found to stimulate the catalytic tamoxifen. activity of CYP3A4. Studies have found that besides slightly , delaying the absorption of midazolam in fasting volunteers, Given that there are other flavonoids that show more promise ingestion of tangerine juice along with an oral;dose of as potential cancer therapies, an indication for further midazolam had no influence on the pharmacokinetics of research on tangeretin in this context is debatable. midazolam, including its metabolism. It was concluded from 606/TANGERETIN PDR FOR NUTRITIONAL SUPPLEMENTS these studies that neither tangeretin nor tangerine juice was Bracke ME, Vyncke BM, Van Larebeke NA, et at. The likely to have much of an effect on CYP3A4-mediated drug flavonoid tangeretin inhibits invasion of M04 mouse cells into metabolism in humans, very unlike the situation with the embryonic chick heart in vitro. Clin Exp Metastasis. citrus flavonoid, naringin. 1989;7(3):283-300. Canivenc-Lavier MC, Brunold C, Siess MH, et at. Evidence for Tamoxifen: When tangeretin was added to the drinking water tangeretin O-demethylation by rat and human liver microsomes. of a tumor-bearing mouse line (MCF 7/6), it was found to Xenobiotica. March 1993;23(3):259-66. Erratum in: Xenobiotica neutralize the tumor-suppressing effect of the drug tamoxi- 1993 ;23(6): 717. fen. Tamoxifen is a selective estrogen receptor modulator Chaumontet C, Bex V, Gaillard-Sanchez I, et at. Apigenin and (SERM) used to reduce the risk of breast cancer. Tangeretin tangeretin enhance gap junctional intercellular communication in has also been found to downregulate lymphokine activation rat liver epithelial cells. Carcinogenesis. 1994;15(10):2325-2330. of natural killer (NK) cells. NK cells are cytotoxic-type Chaumontet C, Droumaguet C, Bex V, et at. Flavonoids lymphocytes that playa major role in innate immunity. (apigenin, tangeretin) counteract tumor promoter-induced inhibition of intercellular communication of rat liver epithelial NUTRITIONAL SUPPLEMENTS, FOODS, HERBS cells. Cancer Left. 1997;114(1-2):207-210. None known. Chen KH, Weng MS, Un lK. Tangeretin suppresses IL-I beta- OVERDOSAGE induced cyclooxygenase (COX)-2 expression through inhibition There are no reports of overdosage. of p38 MAPK, lNK, and AKT activation in human lung carcinoma cells. Biochern Pharmacol. 2007;73(2):215-227. DOSAGE AND ADMINISTRATION Depypere HT, Bracke ME, Boterberg T, et al. Inhibition of The optimal dose of tangeretin for health benefits IS not tamoxifen's therapeutic benefit by tangeretin in mammary known. cancer. Eur J Cancer. 2000;36 Suppl 4:S73. Tangeretin is found in high concentrations in some tangerine Hirano T, Abe K, Gotoh M, et at. Citrus flavone tangeretin juices (approximately 3.7 mg per liter) and in some tangerine inhibits leukaemic HL-60 cell growth partially through induction peel oils (approximately 1.86 grams per liter). The highest of apoptosis with less cytotoxicity on normal lymphocytes. Br J concentrations of tangeretin are found in the tangerines Cancer. 1995;72(6): 1380-1388. Citrus kinokuni or kishu (27.9 mg per gram of dry weight) Kurowska EM, Manthey lA. Hypolipidemic effects and and Citrus depressa or shiikuwasha (26.7 mg per gram of absorption of citrus polymethoxylated flavones in hamsters with dry weight). Shiikuwasha is a cross between a tangerine and diet-induced hypercholesterolemia. J Agric Food Chern. a lime and found mainly in Okinawa, Japan. Clementines 2004;52( I0):2879-2886. (Citrus clementina) contain about 2.6 mg per gram of dry Kurowska EM, Manthey lA, Casaschi A, et at. Modulation of weight. Only trace amounts of tangeretin, at best, are found HepG2 cell net apolipoprotein B secretion by the citrus in lemons (Citrus limon) and grapefruits (Citrus paradisi). polymethoxyflavone, tangeretin. Lipids. 2004;39(2): 143-151. Tangerines (mandarins) are the richest source of tangeretin. MartInez Conesa C, Vicente Ortega V, Yanez Gasc6n Ml, et al. Treatment of metastatic melanoma B 16FIO by the flavonoids At present, only one dietary supplement containing a mixture tangeretin, rutin, and diosmin. J Agric Food Chern. of polymethoxylated flavones (PMFs), including tangeretin, 2005;53(17):6791-6797. is being marketed in the U.S. In addition, the supplement Morley KL, Ferguson Pl, Koropatnick 1. Tangeretin and contains tocotrienols and ascorbyl palmitate. The PMF/ nobiletin induce G I cell cycle arrest but not apoptosis in tocotrienol mixture contains a total of 150 mg per capsule human breast and colon cancer cells. Cancer Left. and those using this supplement take about two capsules per 2007;251 (I): 168-178. day. Nielsen SE, BreinhoIt V, Cornett C, et at. Biotransformation of It is expected that other tangeretin dietary supplements will the citrus flavone tangeretin in rats. Identification of metabolites with intact flavane nucleus. Food Chern Toxicol. enter the dietary supplement marketplace. 2000;38(9):739-746. LITERATURE Nogata Y, Sakamoto K, Shiratsuchi H, et at. Flavonoid Backman JT, Maenpaa l, Belle OJ, et at. Lack of correlation composition of fruit tissues of citrus species. Biosci Biotechnol between in vitro and in vivo studies on the effects of tangeretin Biochern. 2006;70( I): 178-192. and tangerine juice on midazolam hydroxylation. CUn Pan MH, Chen Wl, Lin-Shiau SY, et at. Tangeretin induces Pharmacol Ther. 2000;67(4):382-390. cell-cycle G I arrest through inhibiting cyclin-dependent kinases Bracke ME, Depypere HT, Boterberg T, et at. Influence of 2 and 4 activities as well as elevating Cdk inhibitors p21 and tangeretin on tamoxifen's therapeutic benefit in mammary p27 in human colorectal carcinoma cells. Carcinogenesis. cancer. J Natl Cancer Inst. 1999;91(4):354-359. 2002;23( I0): 1677-1684. SUPPLEMENT MONOGRAPHS TAURINE/607

Van Siambrouck S, Parmar VS, Sharma SK, et al. Tangeretin Taurine is different from most. biological amino acids in a inhibits extracellular-signal-regulated kinase (ERK) few particulars. It is a sulfonic acid rather than a carboxylic phosphorylation. FEBS Lett, 2005;579(7): 1665-1669. acid; it is a beta-amino acid rather than an alpha-amino acid and it does not have a chiral center. Taurine is also known as Walle T. Methoxylated flavones, a superior cancer chemopreventive flavonoid subclass? Semin Cancer BioI. 2-aminoethane sulfonic acid. Its molecular formula IS 2007; 17(5):354-362. C2H7N03S, and its molecular weight is 215.15 daltons.

ACTIONS AND PHARMACOLOGY ACTIONS Taurine has antioxidant activity. It has putative hypocholest- Taurine erolemic, hypotensive, antiatherogenic and detoxifying activities. It may also have steatorrhea-reducing activity in those DESCRIPTION with cystic fibrosis and has putative antidiabetic, inotropic Taurine is a nonprotein amino acid. It is an end product of L- and antiseizure activities. cysteine ,metabolism and the principal free intracellular amino acid in many tissues of humans and other animal The major antioxidant activity of taurine derives from its species. Taurine is present in high amounts in the brain, ability to scavenge the reactive oxygen species hypochlorite, retina, myocardium, skeletal and smooth muscle, platelets which is generated in neutrophils during respiratory-burst and neutrophils. It is classified as a conditionally essential activity of these cells. Taurine reacts with excess hypochlor- amino acid because it is necessary to be supplied in,the diet ite produced in the process of phagocytosis to form the of infants for normal retinal and brain development. relatively harmless N-chlorotaurine. N-chlorotaurine is then reduced to taurine and chloride. This activity may protect Research of taurine was greatly stimulated by the finding against collateral tissue damage that can occur from the that it is an essential nutrient for cats. Taurine deficiency in respiratory burst of neutrophils. Taurine may also suppress cats can result in a variety of clinical abnormalities, peroxidation of membrane lipoproteins by other reactive including central retinal degeneration, dilated cardiomyopa- oxygen species. It is thought that this effect is not due to thy and platelet function abnormalities. Shortly after the taurine's scavenging of these reactive oxygen species, but discovery that dietary taurine deficiency leads to retinal rather to taurine's membrane-stabilizing activity, which degeneration in cats, it was observed that infants who were confers greater resistance to the membrane lipoproteins fed formulas lacking taurine had lower plasma levels of this against lipid peroxidation. amino acid than did infants fed human milk. Further, it was Taurine has been demonstrated to reduce cholesterol levels discovered that children receiving total parenteral nutrition in animals, but results in humans have been contradictory. not containing taurine had abnormal electroretinograms, as The hypocholesterolemic effect of taurine in animals is well as low plasma taurine levels. Taurine has been added to thought to be due, in large part, to the stimulation of bile acid most human infant formulas since the mid-1980s. synthesis and enhancement of cholesterol 7 alpha-hydroxyl- ase activity. Taurine has been found to have antiatherogenic Taurine is produced in the body from L-cysteine. The first activity in animals, but there is less evidence that it does in reaction in the pathway is the formation of cysteine sulfinic humans. The antiatherogenic activity of taurine in animals is acid. Cysteine sulfinic acid (CSA) is converted to hypotau- thought to be due, in large part, to its hypocholesterolemic rine via the enzyme CSA-decarboxylase, and taurine is activity. formed from hypotaurine. Cats have low activity of CSA- decarboxylase. Dietary taurine mainly comes from animal Taurine has been found to normalize blood pressure in food. Taurine is present in very low levels in plant foods. spontaneous hypertensive rats, and there is some evidence. Taurine is found in seaweeds. from human studies that it also has hypotensive activity in hypertensive, but not normotensive, individuals. It is specu- The most understood role of taurine in humans is its lated that the hypotensive effect of taurine may result from involvement in the formation of taurine bile acid conjugates the normalization of increased sympathetic activity .in in the liver, which are essential for micelle formation and fat hypertensive individuals. absorption. Taurine is involved in the pre-and post-natal development of the central nervous system and visual Taurine has been found to ameliorate bleomycin-induced system, although the details of its involvement in these lung fibrosis in hamsters and also to ameliorate the side processes are unclear. Taurine also has antioxidant and effects of some nitrogen mustards. It is thought that the membrane-stabilizing activities. Much remains to be learned possible antioxidant and membrane-stabilizing activities of about the role of taurine in human physiology. taurine may account for these detoxifying actions.