Metabolism

Many flavonoids are rapidly broken down either in the intestine before absorption is completed or in the liver and other nietabolically active organs. Most of these reactions are not well characterized because no metabolic products have yet been identified. The picture is complicated by bacterial action, either prior to absorption or upon entero-hepatic cycling. Methylation by catee hoi-O-methy I transferase (COMT; EC2.1.1.6) is common. Alternative splicing of this enzyme, whose main physiological substrates are catecholamines, produces a soluble cytosolic (S-COM I > and a membrane-bound (MB-COMT) form. Glucuronide and sulfate groups are added as well as removed while the flavonoids and their breakdown products move through different organs and target tissues. The late and biological activity of particular compounds and intermediates is too diverse to predict without concrete experimental evidence. Isoflavones. Daidzcin is metabolized extensively, either to cquol or to O-desmethyl-angolensin. Only some people (about one in three) generate equol with some regularity. One pathway of daidzein metabolism proceeds via dihydtodaidzein and tetra-hydrodaidzein to equol. This pathway has raised considerable interest, since equol has

O-Desmelhylangolensin Equol

Figure 5.7 Only some people produce the estrogenic metabolite equol from da id inn

O-Desmelhylangolensin Equol

Figure 5.7 Only some people produce the estrogenic metabolite equol from da id inn higher estrogenic potency than its precursor daidzein. A different pathway generates 2-dehydro-O-desmethylangolensin and then O-desmethylangolensin (Joannou et al.. 1995). Only some individuals excrete significant amounts of equol (Setehell el al., 1984: Hutchins el al., 1995). Bacterial en/ymes are likely to play at least some part in these poorly understood conversions. The genetic basis for this difference is not well understood. since the enzymes responsible for the various steps are still unknown. Surprisingly, equol was found to be highest in plasma from infants fed cow milk-based formula,but low in plasma from infants fed spy-based formula (Setehell et al., 1998).

Gcnislein ealabolism occurs via dihydrogenistein to 6'-hydroxy-O-desmethy 1-angolensin (Joannou et at., 1995), p-Ethylphcnol is another possible product (Adlercreutz et at., 1995). bin questions remain aboul ihis pathway. Unabsorbed gen istein and daidzein are completely lost to degradation in the lower intestinal tract (Xu et al, 1994).

OH 0 Oihydfogeriisiein

Figure 5.8 (Jacatxilism irreversibly degradesgenistein

OH 0 Oihydfogeriisiein

6 - Hydroxy -O-des me thy la ngolen si n p-Elhytphenol

Figure 5.8 (Jacatxilism irreversibly degradesgenistein

Just as iili estrogen conjugates, sulfatases in tissues release tlie isoflavone aglycones from sulfate conjugates I Pasquaiini etal., 19X9). It is not clear whether isollavones are released in tissues from their glucuronides lor even transported into cells) and thus exert activity.

Flavones: Metabolism to4'-methoxyapigenin (acacetine) appears to be minimal, ¡fit occurs at all (Nielsen et «/., 1999).

Flavonoh: Quercctin is methylated extensively by eatechol-O-methy [transferase (EC2.1.I.6: DuPont etal.. 2002). This reaction is easily saturated at higher than minimal intakes. The main metabolite is 3'-0-methylquercelin (isorhamnetin). Some indiv iduals also generate the 4'-0-methylqucrcetin derivative Itamartxetin), Degradation of quencetin through unknown pathways in the kidney or other sites may affect 95% or more of the absorbed flavonoid (Hollman et at.. 1995).

Flavanones: A significant fraction of absorbed naringenin is broken down to p-hydroxy-pheny (propionic acid (p-HPPA), p-coumaric acid, and p-hydroxy benzoic acid in rats (Felgines etal.. 2000). The extent of naringenin catabolism in man and the underlying mechanisms remain to be investigated.

Catechms- Catechms are metabolized and excreted mainly as the glucuronides and gjucuronidc sulfate conjugates of 3'-O-methylcatechin. less as the analogous conjugates of catcchin (Donovan et a!., 1999).

Storage

Retention of flavonoids in specific tissues and later release does not account for significant amounts available to tissues.

OH 0 Quercetin

S-Adenosyl-methionine

S-Adenosyl-methionine

OH 0 Quercetin

S-Adenosy! homocysteine

S-Adenosyl-methionine

S-Adenosyl-methionine

S-Adenosy! homocysteine

OH OH O 4-O-mettiylquercetin (tamarixetin)

Figure 5.9 Quercetin is extensively methylated

OH OH O 4-O-mettiylquercetin (tamarixetin)

Catechoi-O-methyl S-Adenosyl-

transferase \ homocysteine (magnesium) N.

Catechoi-O-methyl S-Adenosyl-

transferase \ homocysteine (magnesium) N.

OH O 3-0- metn yl quercet i n (tsorhamnetin)

Figure 5.9 Quercetin is extensively methylated

Excretion

The xenobiotic transporters at the ba so lateral membrane (MDR5 ABCB4) and the brush border membrane (MDRl/A BCB1. and MRP I ABCC1) transport many conjugates of flavonoids. This means that active tubtiiar secretion occurs in addition to glomerular filtration. What is not known, yet. is the extent of net secretion into urine. Isoflavones: Genistein and daidzein arc excreted mostly with urine (Xu et al., 1994) as glucuronides and sulfate conjugates (ianti el al., 1999). Clearance is very rapid once the compounds appear in biood.

Effects

The numerous biological actions of flavonoids reflect the diversity of these compounds and their origin it should be remembered that many of the classical plant-deriv ed medications are flavonoids. The heart medication digitalis vividly illustrates this point. A renewed interest in such botanicals has identified many candidate compounds that might help to light cancer, arthritis, and other common ailments. The many ways in which flavonoids in herbs or foods affect human ecll biology (including the slowing of oxidation, proliferation, bacterial and viral infection, and inflammation) cannot be enumerated in detail here and only a few examples will be given. Sex-hormone like actions: Their structural similarity w ith estrogen and gestagen enables many flavonoids to bind to human sex-hormone receptors (Tang and Adams, 1980) and activate estrogen-regulated genes (Ratna and Simonelli, 2002). Typically, it is the diphenolic compounds ihat have such phytoestrogen activity. Observed responses may differ due to differences in approaches for the assessment (human studies, anima! models, and m-vitro experiments), Genistein and biochanin A tend to have relatively high estrogenic poiency, only two orders of magnitude below that of estrogen, which is present at a much lower concentration de novo (Zand et al.. 2000). Flic estrogenic potency of luteolin and nanngenin is about three orders of magnitude below that of estrogen. Apigenia has considerable gestagen-like activity.

Phase I enzymes: The potent inhibition of cytochrome P450 3A4 (CYP3A4) by nanngenin slows the elimination of medications such as statins and contraceptive hormones (Hodek et al.. 2002).

Phase II enzymes: The llavonc chrysin and the flavonol quercetin potently induce UDP-glucuronosyltransferase (EC2.4.U7) UGT1 At (Galijatovic et al.. 2001). On the Other hand, quercetin inhibits phenol sulfotransferase AI (SULT1A1: EC2.8.2.1) in liver (De Sami et al., 2002).

Drug absorption: Sincc many ilavonoids bind to transporters that pump many drugs back into the intestinal lumen, they have the potential to increase drug bioavailability. Moderate doses of orange juice and other citrus products contain enough tangeretm and other polymethoxylaied phytochemicals to inhibit the reverse transport of digoxin and other drugs and increase their effectiveness as well as risk of side effects (Takanaga et at., 2000).

Antioxidant action: Many Ilavonoids are redox active and their consumption with a varied diet rich in fruits and vegetables contributes significantly to free radical defense and possibly reduction of disease (Kris-Etherton and Keen. 2002). Quercetin and other common dietary Ilavonoids have been shown to be very effective scavengers of peroxynitrite and other potent oxidants (Terao et a/., 2001).

References

Adlercreutz II. Fotsis T, kurzer MS, Wahala k. Make I a T, llase T, Isotope dilution gas chromalographic-mass spectrometnc method for the determination of unconjugated lignans and isofiavonoids in human feces, with preliminary results in omnivorous and vegetarian women. .-Imil Biochem 1995:225:10] K Adlercreutz 11. Yamada T. Wahala k. Watanabc S. Maternal and neonatal phytoestrogens in

Japanese women during birth. Am J Ohst Gynecol 1999; 1 NO:737 43 Blekas G, Vassilakis (.'. Harizanis C.Tsimidou M, Boskou DG. Biophenols in table olives.

JAgric Food Chem 2002;50:3688-92 C'omtcG. Daskiewicz JB. Bayet C. tonscil G, Viornery-VanierA, Dumontet C, Di Pictro A, Barron D. C-lsoprenylation of Ilavonoids enhances binding affinity toward P-glycopro-tein and modulation of cancer cell chen tores i stance. J Medicinal ( hem 2001:44:763 8 Day AJ, DuPoni MS. Ridley S. Rhodes M. Rhodes MJ, Morgan MR. Williamson G. Deglycosy lation of flavonoid and isoflavonoid glycosides by human small intestine and liver beta-glucosidase activity. FEBS Lett 1998;436:7I 5 Day AJ, Canada FJ, Diaz JC, Kroon PA. Melauehlan R. Faulds C'B. Plumb GW. Morgan MR, Williamson G, Dietary llavonoid and isoflavone glycosides are hydrolysed by the lactase site of lactase phlorizin hydrolase. FEBSLett 2000:468:166 70

Je Kleijn MJJ, van tier Schonw YT, Wilson PWF. Grobbee IJE, Jacques PF. Intake of dietary phytoestrogens in postmenopausal women: The Framingham Heart Study. J Nutr 2000; 130:705S De Santi C, Pietrabissa A. Mosca F. Rane A. Pacific i GM. Inhibition of phenol sulfotrans-t"erase (SUL'I 1 A! I by quercetin in human adu!t and foetal livers.Xenobiotica 2U(i2; 32:363 8

Donovan JL. Bell JR. kasim-Karakas S. German JB. Walgern RL, Hansen RJ. Watcrhouse AL. Catechin is present as metabolites in human plasma after consumption of red win c.JNutr 1999;129:1662-8 DuPonl MS. Bennett RN. Mellon FA. Williamson G. Polyphenols from alcoholic apple cider arc absorbed metabolized and excreted by humans. J Nutr 2002:132:172-5 Fand P. Sawaya BP. Custer I J. Franke AA. Levels and metabolic clearance of the isoflavones genistein and daid/ein in hemodialysis patients. J Ant Soc Nephrol 1999; 10:864 71 Felgines C.TexierO. Morand C, ManachC, Scalbcrt A. Regerat F. Reniesy C. Bioavailability of the flava none naringenin and its glycosides in rats. Am J Physio! Gastwint Liver Physiol 2000:279^31148-G1 i 54 Franke AA. Custer I J, Cema CM. Narala K. Rapid HPLC analysis of dietary phytocstro-gens from legumes and from human urine. Prnc Soc Exp Biol Med 1995:208:18 26 Galijatovic A, Otake Y. Walle UK, Walle T. Induction of UDP-glucuronosy1transfera.se UGT1AI by the flavonoid chrysin in Caco-2 cells potential role in carcinogen hio-inactivation. Pharm Res 2001; IN:374 <i I lakkinen SH. Karenlampi SO, I leinonen IM. Mykkanen HM.Torronen AR. Content of the Savonols quercetin. myricetin, and kaempferol in 25 edible berries. J. it*y Food Cheni I999;47:2274- 9

Nertog MG. Ilollman PC, katan MB. kromhout D. Intake of potentially ant ¡carcinogenic llavonoids and their determinants in adults in i he Netherlands. Nutr Cancer 1993: 20:21-9

Hodck P.Tretil P. Stiborova M. Flavonoids potent and versatile biologically active compounds interacting with cytochromes P450. Chem Biol interact 2002:139:1-21 Hollman PCI I. de Vries JHM. van Lccuwcn SD. Mengelers MJB. katan MB. Absorption of" dietary quercetin glycosides and quercetin in healthy ileostomy volunteers. Am J Clin Nutr 1995;62:1276-82 Hutehins AM, Slavin JL. Lampe JW. Urinary isoilavonoid phytoestrogen and lignan excretion after consumption of fermented and im fermented sov products. J Am Diet Assoc 1995:95:545 51

Joannou GF. Kelly GE. Reeder A1!'. Waring M. Nelson C. A urinary profile study of dietary phytoestrogens. The identification and mode of metabolism of new isotlavonoids. J Steroid Biochem Molec Biol 1995:54; 167 84 King RA, Broadbcnt JL. Head R.I. Absorption and excretion of the soy isoflavone genistein in ms.JNutr 1996:126:176 82 Knekt P. Kumpulaincn J. Järvinen R, Rissanen H. Heliövaara M. Reunanen A. HakulinenT, Aromaa A. Flavonoid intake and risk of chronic diseases. Im J Clin Nutr 2002; 76:560-8

Kohlmeier M, Muldrow W. Swiuer B. Supplemental beta-galactosidase cleaves soy milk isoflavone beta-7-glucosides. J Bone Miner Res 2000:15:S311

Kris-Etherton I'M, Keen CL. Evidence that the antioxidant flavonoids in tea and cocoa are beneficial for cardiovascular health. Curr Opin Lipidal2002; 13:41 L> Liu M, Li XQ, Weber C. Lee (_'Y. Brown J. Liu RH. Antioxidant and antiproliferative activities of raspberries. JAgric Food Cheat 2002:50:2926 30 Lu L.IW, Anderson KL. Sex and long-term soy diets affect (he metabolism and excretion of soy isoflavones in humans, Am J Clin Nutr 1998;68:1500S I504S Merken HM. Beecher CiR. Liquid chromatographic method for the separation and quantification of prominent tlavonoid aglyeoncs../ ChmmatogrA 2000:897:177-84 Nielsen SL. Young JF. Daneshvar B. Lauridsen ST. Knuthsen P. Snndstrom B. Dragstcd LO. Effect of parsley {Petmselinum crispuni) intake on urinary apigenin excretion, blood antioxidant enzymes and biomarkers for oxidative stress in human suhjects. Br J Nutr 1999;81:447-55

Pasqualini JR. Gelly C, Nguyen BL. Vella C. Importance of estrogen sulfates in breast cancer../Steroid Biochem 1989:34:155 63 Pillow PC, Duphorne CM. Chang S, Contois JH. Strom SS. Spitz MR. Bursting SD. Development of a database for assessing dietary phytoestrogen intake. Nutr Cancer 1999;33:3-19

Ratna WN, Simonelli JA. The action of dietary phytochemicals quercetin, catechin, rcsver-atrol and naringenin on estrogen-mediated gene expression. Life Sci 2002;7Q:1577- x1? Rong H, BoterbergT, Maubach J. Stove C, Depypere H, Van Slambrouck S. Serreyn R, De Keukeleire D, Marcel M. Bra eke M. 8-Prenylttaringentn, the phytoestrogen in hops and beer, upregulatcs the function of the E-cadheriivcatenin complex in human mammary carcinoma cells. Eur J Cell Biol 2001;80:580-5 Setehell KD. Boriello SP. Hulme P. Kirk DN. Axelson M. Nonsteroidal estrogens of dietary origin: possible roles in hormone-de pen dent disease. Am J Clin Nutr 1984: 40:569-78

Setehell KDR, Zimmer-Nechemias L, Cai J. Heubt JE. Isollavone content of intant lor-mulas and the metabolic fate of these phytoestrogens in early life. Am J Clin Nutr 1998:68:1453S -1461S Setehell KD. Brown NM. Zimmer-Nechemias L, Brashear WT, Wolfe BE. Kirschner AS. I leubi JL. Evidence iitr lack of absorption of soy i so il a von e glycosides in humans, supporting the crucial role of intestinal metabolism for bioavailability. Am J Clin Xutr 2002:76:447-53

Slakianos J, Coward L. Kirk M, Barnes S. Intestinal uptake and biliary excretion of the isoflavone genislein in ms. JNutr 1997;127:1260-8 Stevens JF, Taylor AW, Nickerson GB. Ivancie M. llenning J, Haunold A, Dcinzer ML. Prenyl tlavonoid variation in Hamulus lupulus: distribution and taxonomic significance of xanthogalenol and 4'-0-methylxanthohumol. Phytochemistry 2000:53:759 75 Takanaga H, Ohnishi A.Yamada S, Matsuoll, Morimoto S. ShoyamaY. Ohtani 11, SawadaY. Polymethoxylatcd fiavones in orange juice are inhibitors of P-glycopmtein but not cytochrome P450 3A4. J Pharmacol Exp Ther 2000;293:230-6 Tang BY, Adams NR. The effect ofequol on oestrogen receptors and on synthesis of DN A

and protein in the immature rat uterus. J Endocrinol 1980:85:291 -7 Terao J, Yamaguehi S, Shirai M. Mivoshi M, Moon .111. Oshima S, InakumaT.TsushidaT, Kato Y. Protection by quercetin and quercetin 3-O-beta-D-glucuronide of peroxynitrite-induced antioxidant consumption in human plasma low-density lipoprotein. Free Rad Res 2001;35:925-31 Walgren RA. Lin J1, Kinne RK1L Walle T. Cellular uptake of dietary flavonoid qucrcetin 4'-/3-glucoside by sodium-dependent glucose transporter SGLTL J Pharmacol Exp Titer 2000;294:837-43 Walle LK, French KL. Walgren RA. Walle F. Transport ofgenistcin-7-glucoside by human intestinal CACO-2 cells: potential role lor MRP2. Res Comm Mol Palli Pharmacol 1999:103:45-56

Walle T, Otake V. Brubaker JA, Walle UK. Ilalushka PV. Disposition and metabolism of the flavonoid chrysin in normal volunteers. Br./ Clin Pharmacol 2001:51:143-6 Wo Iff ram S. Block M. Ader P. Quercetin-3-glucoside is transported by the glucose carrier SGLTI across the brush border membrane of rat small intestine. JNutr 2002;132:630-5 Xu X, Wang ll.l. Murphy PA. Cook L. Hendrich S. Daidzein is a more biciavailable soymilk isoflavonc than is genistein in adult women. JNutr 1994:124:825 32 Zand RS, Jenkins DJ. Diamandis LP. Steroid hormone activity of fiavonoids and related compounds. Breast Cancer Res Treat 2000:62:35 49

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