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Review The effects of green tea polyphenols on drug metabolism Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Lib of Chinese Aca of Med Sciences on 08/06/13 For personal use only. Chung S Yang† & Eva Pan † 1. Introduction 2. The composition, consumption and chemical properties of tea polyphenols 3. Drug metabolizing-enzymes, drug transporters and their roles in the biotransformation of tea catechins 4. The effects of tea catechins on drug absorption, biotransformation and elimination 5. Expert opinion The State University of New Jersey, Ernest Mario School of Pharmacy, Department of Chemical Biology, NJ, USA Introduction: Tea, made from the dried leaves of the plant Camellia sinensis Theaceae, is a very popular beverage consumed worldwide. Recently, green tea extract-based dietary supplements have also been widely consumed for the acclaimed beneficial health effects, such as weight reduction. Although tea consumption is considered to be innocuous, the potential interactions between tea polyphenols and drugs have been demonstrated in studies in vitro and in vivo. Areas covered: This article reviews the current literature on the chemistry and biotransformation of tea constituents, mainly catechins from green tea. The article also provides a review of their effects on the absorption, efflux, metabolism and elimination of different drugs. Expert opinion: Tea catechins may bind to certain drugs to affect their absorption and bioactivities. Tea catechins may inhibit the activities of drug-metabolizing enzymes and drug transporters or affect the expression of these proteins, either upregulation or downregulation. Although these effects have been demonstrated in studies in vitro and in animal models, such effects have only been observed in limited cases in humans at common doses of human tea consumption. The ingestion of tea catechins from dietary supplements, which could be in large bullet doses, may produce more profound effects on drug metabolism, and such effects with drugs need to be further investigated. Keywords: absorption, bioavailability, catechins, drug metabolism, efflux, elimination, tea polyphenols, transporters Expert Opin. Drug Metab. Toxicol. (2012) 8(6):677-689 1. Introduction Tea, made from the leaves of the plant Camellia sinensis Thaecae, has been used by humans for thousands of years. Tea was first used as a medicinal herb in ancient China and now tea is a widely consumed beverage. It is the second most popular beverage worldwide, next to water. The possible preventive activities of green tea against cancer and cardiovascular diseases have been studied extensively during the past 25 years. Most recently, green tea extracts have also been used as major ingredients in many food supplements, for example, those that are marketed for weight reduction. The possible beneficial and adverse health effects of tea consumption have been discussed in several review articles [1-5] as well as special volumes of journals, for example, in the August 2011 issue of Pharmacological Research and in the June 2011 issue of Molecular Nutrition and Food Research. The characteristic constituents in green tea are tea polyphenols (known as catechins), caffeine and a unique amino acid (theanine). These chemicals are absorbed, metabolized and eliminated similar to many drugs. Therefore, possible interactions between tea constituents and drugs as competitive substrates or inhibitors are expected. Tea catechins may directly bind to drugs and decrease their absorption, bioavailability and their biological activities. Tea catechins may also increase or decrease the expression (or activities) 10.1517/17425255.2012.681375 © 2012 Informa UK, Ltd. ISSN 1742-5255 All rights reserved: reproduction in whole or in part not permitted 677 C. S. Yang & E. Pan Article highlights. . Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Lib of Chinese Aca of Med Sciences on 08/06/13 For personal use only. . . . . Green tea is a commonly consumed beverage and tea extracts have been used in many dietary supplements. Green tea polyphenols may affect the absorption and metabolism of drugs by directly binding to drugs and/or affecting the expression or activities of drug-metabolizing enzymes and drug transporters. Many laboratory studies have demonstrated that green tea polyphenols can affect the expression or activities of drug-metabolizing enzymes and drug transporters. Such effects, however, may not be produced by the consumption of one or two cups of tea per day in humans. When green tea and drugs are taken concomitantly, direct binding may occur. There is a report on the effect of tea drinking on the clinical effects of a therapeutic drug. More laboratory and clinic studies on such interactions are needed. Green tea-based dietary supplements may be taken at rather high doses (as recommended by the manufacturer), for example, for the purpose of weight reduction by some individuals. Such high doses of tea polyphenols may have a significant effect on drug metabolism. This topic remains to be studied further. Black tea polyphenols have low or no systemic bioavailability, but they may interact and affect the absorption and metabolism of drugs in the intestine. Because black tea is widely consumed worldwide, more studies on the effects of black tea consumption on drug metabolism are needed. This box summarizes key points contained in the article. of drug-metabolizing enzymes and drug transporters. This article will first review the chemistry of tea constituents as well as their absorption and biotransformation, and then discuss the possible mechanisms by which tea polyphenols affect drug metabolism. It will assess the possible relevance of these mechanisms in humans who consume tea as a beverage or through dietary supplements. Green tea catechins, which have been studied extensively, will be the focus of this article. The possible interactions between the oligomeric and polymeric polyphenols in black tea will also be discussed, because of the wide consumption of black tea worldwide. The composition, consumption and chemical properties of tea polyphenols 2. Depending on the manufacturing process, tea is divided into three major types: green tea, black tea and oolong tea [6]. Green tea, which constitutes about 20% of the world tea production, is mainly consumed in Asian countries such as China and Japan. Its consumption has significantly increased in the Western countries during the past 30 years, mainly due to its publicized potential beneficial health effects. Green tea is produced by steaming or panfrying tea leaves. This process inactivates the enzymes and preserves the product by stabilizing the tea constituents and preventing the growth of microorganisms. 678 When green tea is brewed in hot water, about a third of the solid material is extracted into water. Of the water-extractable materials (the dried form is known as tea solids), about a third are polyphenols, generally known as catechins. The major tea polyphenols are (-)-epigallocatechin-3-gallate (EGCG), (-)-epigallocatechin (EGC), (-)-epicatechin-3-gallate (ECG) and (-)-epicatechin (EC). The structures of these compounds are shown in Figure 1. Black tea is the major form of tea consumed worldwide and constitutes 78% of the world tea production. It is produced by crushing the tea leaves to allow the enzyme polyphenol oxidase to be released. This enzyme catalyzes the oxidation of tea catechins and the oxidized catechins are subsequently polymerized. This process, generally known as ‘fermentation,’ converts most of the monomeric catechins into oligomeric polyphenols (theaflavins), which account for 2 -- 6% of the weight of black tea solids, and polymeric polyphenols (generally known as thearubigins), which account for more than 20% of tea solids and are poorly characterized chemically. Caffeine accounts for 2 -- 5% of the dry weight of the water-extractable materials in green and black tea. Oolong tea is a specialized tea prepared in southeast China, Taiwan, and Japan made by crushing only the rims of the tea leaves and ‘fermented’ under tightly controlled conditions to generate special aromas that are enjoyed by consumers. A typical cup of green tea, with 2.5 g of tea leaves brewed for 3 min in 250 ml hot water, usually contains 620 -- 880 mg of water-extractable materials, of which about a third are catechins. EGCG accounts for 50 -- 75% of the total catechins, and the remainder is made up of EGC, ECG, EC and other minor catechins. Thus, a freshly brewed cup of green tea may contain 130 -- 180 mg of EGCG. Readyto-drink teas in bottles and cans are becoming popular. Their catechin contents may vary extensively depending on the manufacturing conditions and the stability of catechins during storage. Green tea extracts are also used now as ingredients in many dietary supplements, such as vitamins and weight reduction pills [7]; the following are some examples. The Whole Health Multivitamin, Super Multi Plus pill contains 10 mg of EGCG, whereas the Anselmo Super Multis pill has 16.7 mg EGCG; both are to be taken three times daily. Dexatrim Max Slim Packs Powder Mix, advertised to help boost metabolism and burn fat, contains 45 mg of EGCG and 25 mg of caffeine per pack and should not be taken more than six times a day. Similarly, the Schiff Natural Green Tea Diet, which contains 90 mg of EGCG and 50 mg of caffeine per tablet, is recommended to be taken three times a day. Green tea extracts are also manufactured into supplement pills as sources of catechins. For example, one serving size of two capsules of Nature’s Bounty Green Tea Extract provides 630 mg of EGCG to be taken twice daily, and NOW Foods’ EGCG Green Tea Extract tablet consists of 200 mg EGCG to be taken once a day [5]. Source Naturals EGCG, with 350 mg of EGCG per tablet, can be taken up to twice a day and Whole Health Green Tea Extract Expert Opin. Drug Metab. Toxicol. (2012) 8(6) The effects of green tea polyphenols on drug metabolism OH 3′ O HO 7 A OH 4′ B 2 3′ 5′ OH C 3 5 HO O OH D O 7 3″ OH O Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Lib of Chinese Aca of Med Sciences on 08/06/13 For personal use only. OH OH 5′ OH C 3 5 OH 4″ 5” A B 2 OH 4′ OH OH (–)–Epigallocatechin-3-gallate (EGCG) (–)–Epigallocatechin (EGC) OH O HO 7 A 4′ B 2 OH 5′ OH C 5 HO 3 O O 7 OH A 5 D 4″ 5” 5′ OH C 3″ OH O B 2 4′ OH OH OH OH (–)–Epicatechin-3-gallate (ECG) (–)–Epicatechin (EC) Figure 1. The structures of tea catechins. 500 mg contains 1000 mg of EGCG per recommended serving of two capsules. In general, many of the green tea extract supplements manufactured to have high concentrations of catechins for proclaimed beneficial health effects provide more catechins than the daily intake from a typical green tea beverage. Thus, the consumption of green tea extract supplements could be major concerns in regard to interactions with other drugs. Tea catechins possess multiple phenolic groups, which make them chemically reactive. For example, EGCG possesses eight phenolic groups, all of which are potential donors for hydrogen bonding. Through hydrogen bonding and other interactions, EGCG and other catechins can bind to a variety of proteins and other biological molecules [1]. As will be discussed later, they could also bind to certain drugs. These phenolic groups also make tea catechins potent antioxidants. In addition to the quenching of reactive oxygen species, tea catechins can chelate trace elements, such as iron and copper, and this action prevents the formation of reactive oxygen species. On the other hand, tea catechins can be auto-oxidized, possibly catalyzed by trace amounts of copper and iron, at slightly alkaline or even neutral conditions. This property makes tea catechins preoxidants in generating superoxide radical and hydrogen peroxide [8]. The presence of vicinal phenolic groups also allows catechins to be easily oxidized to form quinones, which can generate oxidative stress by redox cycling. To prevent such reactions from happening in vivo, mammalian cells possess the enzyme catechol-O-methyltransferase (COMT), which methylates EGCG, for example, at the 4’ and 4’’ positions to form 4’’-O-methyl-(-)-EGCG and 4’,4’’-O-dimethyl-(-)EGCG [9]. This eliminates the vicinal phenolic structure and prevents possible toxicity through redox cycling. Drug metabolizing-enzymes, drug transporters and their roles in the biotransformation of tea catechins 3. Most drugs undergo an initial Phase I metabolism, generally catalyzed by cytochrome P450 (CYP) enzymes, to form more water-soluble metabolites. The metabolites are then catalyzed by Phase II enzymes, such as UDP-glucuronosyl transferases (UGT) and sulfotransferases (SULT), to form glucuronides and sulfates as metabolites, which are then eliminated from the body (Figure 2). Because of the polyphenolic structure, catechins are rather water soluble and are not likely to undergo Phase I metabolism by CYP enzymes. In addition to the methylation reaction catalyzed by COMT, tea catechins are conjugated by UGT and SULT to glucuronides and sulfates [6]. Studies of EGCG and EGC glucuronidation reveal that EGCG-4"-O-glucuronide is the major metabolite formed by human, mouse and rat microsomes [10]. Mouse small intestinal microsomes have the highest catalytic efficiency (Vmax/Km) for glucuronidation followed, in decreasing order, by mouse Expert Opin. Drug Metab. Toxicol. (2012) 8(6) 679 C. S. Yang & E. Pan Systemic circulation Xenobiotic X X Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Lib of Chinese Aca of Med Sciences on 08/06/13 For personal use only. Phase I X X CYP enzymes CYP enzymes XOH XOH Phase II X-conj X MRP2 Phase I UGT ST UGT ST X-conj X X-conj MRP1 X MRP1 Phase II X-conj MRP2 X-conj Bile Enterocyte Hepatocyte Systemic circulation Fecal excretion Urine excretion Fecal excretion Figure 2. Drug absorption, biotransformation and excretion. X-conj: X-conjugate. liver, human liver, rat liver and rat small intestine. Of the 12 human UGT isoforms studied, the intestinal-specific UGT1A8 having the highest catalytic efficiency, UGT1A1 and 1A9 also had high glucuronidation activity toward EGCG. With EGC, EGC-3’-O-glucuronide is the major product formed by microsomes from mice, rats and humans with the liver microsomes having a higher efficiency than intestinal microsomes. EGCG is also time- and concentrationdependently sulfated by human, mouse and rat liver cytosol [11]. The rat has the greatest activity followed by the mouse and the human. It has been reported that EC also undergoes sulfation catalyzed by human and rat intestinal and liver enzymes in cytosol, with the human liver enzyme being the most efficient [12]. Further studies have revealed that SULT1A1 is largely responsible for this activity in the liver, whereas both SULT1A1 and SULT1A3 are active in the human intestine. The results from Sang et al. [13] from data-dependent tandem mass spectrometric analysis of mouse urine samples after intraperitoneal or intragastic administration of EGCG have shown that methylated EGCG (or glucuronidated or sulfated EGCG) can be further glucuronided and/or sulfated (or methylated) to form mixed (methylated and conjugated) EGCG metabolites. Tea catechins are known to undergo metabolic degradation by 680 microorganisms in the intestine. Three metabolites, 5-(3’,4’,5’trihydroxyphenyl)-g-valerolactone, 5-(3’, 4’-dihydroxyphenyl)g-valerolactone and 5-(3’,5’-dihydroxyphenyl)-g-valerolactone, have been identified [6]. At high doses, EGCG can form cysteine adducts in vivo, EGCG-2"-cysteine and EGCG-2’-cysteine [14]. These metabolites can be detected in the urine following administration of EGCG at doses of 200 -- 400 mg/kg, i.p. or 1500 mg/kg, i.g. These metabolites are probably formed as a result of oxidation of EGCG to a quinone or semiquinone, which then reacts with the sulfhydryl groups in vivo. The extensive depletion of sulfhydryl groups could lead to toxicity, and indeed hepatotoxicity has been observed with these EGCG doses [14]. Active efflux has been shown to limit the bioavailability and cellular accumulation of many compounds. The multidrug resistance-associated proteins (MRP) are ATP-dependent efflux transporters that are expressed in many tissues. MRP1 is located on the basolateral side of cells, and is present in nearly all tissues, and serves to transport compounds from the interior of the cells into the interstitial space [15]. By contrast, MRP2 is located on the apical surface of the intestine, kidney and liver, where it transports compounds from the Expert Opin. Drug Metab. Toxicol. (2012) 8(6) Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Lib of Chinese Aca of Med Sciences on 08/06/13 For personal use only. The effects of green tea polyphenols on drug metabolism bloodstream into the lumen, urine and bile, respectively (Figure 2). Studies on EGCG uptake showed that indomethacin (an MRP inhibitor) increased the intracellular accumulation of EGCG, EGCG 4"-O-methyl-EGCG and 4’,4"-di-O-methyl-EGCG by 10-, 11- and 3-fold in Madin--Darby canine kidney (MDCKII) cells with overexpressing of MRP-1 [16]. Similarly, treatment of MRP-2 overexpressed MDCKII cells with MK-571 (an MRP-2 inhibitor) resulted in more than a 10-fold increase in the intracellular levels of EGCG and its methylated metabolites. Treatment of HT-29 human colon cancer cells with indomethacin also resulted in increased intracellular accumulation of EGCG and its methylated and glucuronidated metabolites [17]. P-glycoprotein (P-gp) is another important drug efflux protein. Treatment of P-gp-overexpressing MDCKII cells with a variety of P-gp inhibitors, however, resulted in no significant effects on the intracellular levels of EGCG or its metabolites. These data suggest a role for MRPs, but not P-gp, in affecting the bioavailability of EGCG. The involvement of drug transporters and metabolizing enzymes in the uptake, biotransformation and elimination of EGCG has been discussed previously [18]. The apical location of MRP2 suggests that it acts to limit the bioavailability of EGCG by actively exporting EGCG in the enterocyte back into the intestinal lumen either before or after EGCG is methylated by COMT or glucuronidated by UGT. The remaining fraction of EGCG would then be absorbed into the portal circulation, enter the liver and be methylated or conjugated, and then could subsequently be effluxed by MRP2 located on the canalicular membrane of the hepatocytes. MRP1, located on the basolateral membrane of enterocytes and hepatocytes, is expected to increase the bioavailability of EGCG; however, this point remains to be demonstrated. The influence of MRP1 and MRP2 on the bioavailability of EGCG in vivo is likely to depend on the tissue distribution of each efflux protein. It was reported that the transcript level of MRP2 was more than 10-fold higher than that of MRP1 in the human jejunum [19]; therefore, efflux of EGCG by MRP2 may be predominant in the intestine, resulting in a decrease in bioavailability. The pharmacokinetics of tea catechins have been studied in rats, mice and humans [20-26]. For example, human studies showed that after oral administration of 20 mg green tea solids/kg body weight, it took 1.3 -- 1.6 h for the catechins to reach maximum levels in the blood (Tmax) [24]. The maximum plasma concentrations (Cmax) for EGCG, EGC and EC were 0.17, 0.73 and 0.43 µM, respectively. The halflives (t½) were 3.4, 1.7 and 2.0 h for EGCG, EGC and EC, respectively. Since green tea solids contain higher amounts of EGCG than EGC and EC, these data suggest that the bioavailability of EGCG is comparatively lower. In humans, approximately 70% of the EGCG existed in the free (unconjugated) form, whereas EC and EGC were present mainly in the conjugated forms [24]. Methylated forms of EGCG and other catechins were also observed [24]. The bioavailability and metabolic pattern of tea catechins in mice were similar to those in humans; however, the bioavailability of tea catechins in rats was much lower and the metabolic pattern was less similar to humans [20-24]. Chow et al. [26] studied the pharmacokinetics of EGCG in humans after ingesting 200 -- 800 mg of EGCG as Polyphenon E (a standardized tea catechin preparation containing 65% EGCG). The authors found that the Cmax of free (unconjugated) EGCG ranged from 73.7 to 438 mg/l (0.16 -- 0.96 µM), depending on the dose administered. The black tea polyphenols, because of their larger molecular weights and greater number of phenolic groups, have extremely low or no systemic bioavailability. Mulder et al. [27] reported that the Cmax of theaflavins in human plasma and urine was only 1 and 4.2 ng/ml, respectively, following consumption of 700 mg of pure theaflavins mixture, equivalent to about 30 cups of black tea. Neither theaflavins mono- nor di-gallates were detectable in this study. The effects of tea catechins on drug absorption, biotransformation and elimination 4. The effects of tea catechins on drug metabolism have been studied by many investigators, and this topic has been reviewed [5,18,28]. Tea catechins may affect the biological fate of drugs at different levels. They may physically bind to drugs and reduce their absorption and biological activities. Tea catechins may affect the activities or expression levels of drug transporters and drug-metabolizing enzymes. The results of some studies during the past decade are summarized in two tables and reviewed in this section. Table 1 summarizes the effect of tea catechins on drug transporters and drug-metabolizing enzymes in vitro and Table 2 summarizes the effect of green tea catechins on drug metabolism in animal models and in humans. Direct interaction between tea catechins and drugs There are two well-studied examples that illustrate the impact of direct binding of tea catechins to drugs. The interaction between EGCG and sunitinib was first observed in clinic by Ge et al. [29] that tea drinking disturbed the symptom control of sunitinib in a clinical case of metastatic renal cell carcinoma. Subsequent studies found that EGCG directly binds with sunitinib to form a precipitate in solution and to form sticky semisolid contents in the mouse stomach. As a consequence, the plasma concentrations of sunitinib are markedly lower. A second example is the interaction between EGCG and bortezomib that green tea catechins effectively block the therapeutic effect of bortezomib in cell lines and in an animal model reported by Golden et al. [30]. Bortezomib, a proteasome inhibitor, is a drug used for the treatment of multiple myeloma and mantle cell lymphoma. It was shown that such an interaction occurred only with boronic acidbased proteasome inhibitors, such as MG-262 or PS-IX, but not with non-boronic acid proteasome inhibitors, such as 4.1 Expert Opin. Drug Metab. Toxicol. (2012) 8(6) 681 C. S. Yang & E. Pan Table 1. The effects of tea catechins on drug metabolizing enzymes/transporters activity -- studies in vitro. Enzyme/Transporter CYP1A CYP1A1 Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Lib of Chinese Aca of Med Sciences on 08/06/13 For personal use only. CYP1A2 CYP2A6 CYP2C CYP2C9 CYP2D6 CYP2E1 CYP3A CYP3A4 NADPH-CYP reductase UGT UGT1A1 UGT1A4 SULT Phenol SULT GSTP1 NQO1 COMT P-glycoprotein MRP2 BCRP b-glucuronidase Study results Suppressed expression by tea catechins Induced expression by Aquila green tea + lemon Inhibition of activity by catechins Induced expression by green tea extract, EGCG, Aquila green tea + lemon, Aquila red tea + pear Inhibition of activity by catechins, green tea extract Induced expression by green tea extract Inhibition of activity by EGCG Induced expression by green tea extract Inhibition of activity by EGCG Induced expression by green tea extract Inhibition of activity by EGCG Induced expression by green tea extract Inhibition of activity by green tea extract Inhibition of activity by green tea catechins, green tea extract, EGCG No effect on activity by catechins Induced expression by Nestea white tea + apricot, Nestea lemon, Nestea green tea + lemon, Nestea red tea + pear, Nestea peach, Aquila black tea + lemon Inhibition of activity by EGCG Inhibition of activity by epicatechin Inhibition of activity by EGCG No effect on activity by catechins Inhibition of activity by EGCG Inhibition of activity by epicatechin Inhibition of activity by EGCG Induced expression by green tea extract Induced expression by green tea extract Inhibition of L-DOPA methylation by EGCG Inhibition of activity by tea polyphenols, EGCG Suppressed expression by tea polyphenols Inhibition of activity by green tea extract Inhibition of activity by EGCG Inhibition of activity by EGCG Ref. [76] [36] [33] [37,34,36] [33,34] [37,34] [33] [37] [33] [37] [33] [37] [66] [33-35,77] [78] [36] [33] [38] [40] [78] [39] [38] [79] [44] [44] [32] [48,46,47,45] [50] [51] [45] [80] BCRP:Breast cancer resistance protein. MG-132, PS-1 or nelfinavir (Viracept). The structure basis for the binding is that the 1,2-diol groups in catechins are able to form covalent cyclic boronate moieties with boronic acid, resulting in strong single-pair reversible functional group interactions [30]. These examples are of clinical relevance because many cancer patients consume substantial amounts of dietary supplements that contain tea catechins and other herbal extracts. More studies in this area are needed. Kim and Hong [31] studied the interactions between EGCG and commonly consumed over-the-counter drugs and found that EGCG did not affect the stability of the drugs studied. It would be interesting to study the possible binding between EGCG and drugs. Effects of catechins on drug-metabolizing enzymes and transporters in vitro 4.2 It has been shown that tea catechins inhibit the COMTmediated methylation of 3,4-dihydroxy-L-phenylalanine (L-DOPA) in human liver cytosol [32]. EGCG was the most 682 potent inhibitor with IC50 values of 0.07 -- 0.2 nM. These concentrations are within the range of concentrations found in the plasma following consumption of normal doses of green tea, suggesting that these effects may be observable in vivo. Whether green tea consumption would inhibit the methylation of L-DOPA, and thus enhance its efficiency in, for example, patients with Parkinson’s disease taking L-DOPA therapy, remains to be studied. On the other hand, consumption of large quantities of green tea-based supplements by individuals taking COMT inhibitors, such as Parkinson’s disease patients, may produce oxidative stressrelated side effects. Molecular modeling studies have shown that the strong binding of EGCG to COMT was due to the formation of a hexa-coordination complex with the active site Mg2+ of COMT and interaction between the 4¢¢-OH of EGCG and Lys144-NH2. The binding of EGCG to COMT was stabilized by hydrophobic interactions between the D-ring of EGCG and Trp38, Leu198, Pro174 and Trp143 of COMT [32]. EGCG may also inhibit COMT, Expert Opin. Drug Metab. Toxicol. (2012) 8(6) The effects of green tea polyphenols on drug metabolism Table 2. The effects of green tea catechins on drug metabolism -- studies in vivo. Enzyme/transporter/drug Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Lib of Chinese Aca of Med Sciences on 08/06/13 For personal use only. Animal studies Cytochrome P450s Cytochrome b5 and reductase Nrf2 and heme oxygenase-1 GST, UGT GCL g-Glutamyltransferase I P-glycoprotein Midazolam Clozapine Bortezomib Irinotecan, Diltiazem, Verapamil, Nicardipine, Tamoxifen, Doxorubicin, 5-Fluorouracil Human Studies Cytochrome P450s GST Sunitinib Study results Ref. Induction of CYP1A1 by Japanese green tea in Wistar rats Induced expression of CYP1A2 by green tea extract in Sprague-Dawley rats Induction of CYP2B by green tea extract in Sprague-Dawley rats Inhibition of AHH (CYP1A1) activity by green tea catechins in Wistar rats Inhibition of CYP3A, CYP3A4 by green tea extract, EGCG Suppressed expression of CYP1A2, CYP2E1 by green tea catechins in Kunming mice Suppressed expression of CYP3A by green tea extract in Sprague-Dawley rats No effect on CYP1A2, CYP3A by Japanese green tea in Wistar rats Inhibition by green tea catechins [53] [52] Induction by EGCG in Wistar rats Induction of GST by Sunphenon green tea extract, green tea catechins Induction of UGT by green tea catechins in Wistar rats No effect on UGT by green tea in Fischer rats Induced expression by EGCG in mice Induced expression by EGCG in mice Inhibition by EGCG, ECG [57] [58,56] [56] [81] [61] [61] [72,69,70] (?), [68,67] (?), [71,82] [66] [52] [30] [72,69,70,68,67,71,83] Increased bioavailability by green tea extract in Sprague-Dawley rats Decreased bioavailability by green tea extract in Sprague-Dawley rats Decreased bioavailability by green tea catechins Increased bioavailability by EGCG No effect on CYP1A2, CYP2D6, CYP2C9, CYP3A4 by Polyphenon E, green tea extract Reduction of CYP3A4 activity by 20% by Polyphenon E (a mixture of 65% EGCG and other catechins), green tea catechins Induction by Polyphenon E Reduced activity by Polyphenon E Decreased bioavailability by EGCG [54] [56] [66,69,68,67] [55] (?) [54] [53] [56,55] [73,74] [73] [75] [75] [29] AHH: Aryl hydrocarbon hydroxylase; GCL: Glutamate--cysteine ligase. and other methyltransferase activities, indirectly by depleting S-adenosyl-L-methionine (SAM). It was observed that treatment of mice with EGCG (200 -- 2000 mg/kg, i.g.) dose dependently decreased levels of SAM and S-adenosyl-Lhomocysteine (SAH) in the liver and small intestine. The maximal decreases in SAM and SAH were 83.8 and 33.8%, respectively, in the liver. In the small intestine, the magnitude of decrease was 17.8 and 12.1% for SAM and SAH, respectively [18]. Since CYP enzymes are a key family of enzymes in catalyzing Phase I metabolism of drugs, their modulation by green tea catechins has received much attention. Whereas the inhibition of the activities of CYP1A1, 1A2, 2A6, 2C9, 2E1 and 3A4 has been reported in studies in vitro [33-35], induction of the expression of CYP1A1, 1A2, 2D6, 2E1, 3A4 in cell lines has also been reported [34,36,37]. These results are in agreement with our general understanding that many inhibitors of CYP enzymes can serve as their inducers. EGCG has been shown to inhibit UGT activities, such as UGT1A1 and 1A4, and SULT as well [38-40]. Mohammed et al. [40] used the formation of estradiol-3-O-glucuronide (E-3-G) as an assay of UGT1A1 activity and found the activity was inhibited to 50% by an EGCG concentration (IC50) of 7.8 µg/ml, a concentration achievable in vivo. Another study found that EGCG inhibited UGT1A4 at an IC50 value of 33.8 µg/ml [39]. A study by Fong et al. [38] observed that epicatechin exhibited a slightly stronger inhibitory effect on sulfation than on glucuronidation in the Phase II metabolism of baicalein. Glutathione-S-transferase (GST) plays a key role in the detoxification of electrophilic species by catalyzing the conjugation of these compounds to glutathione [41]. GST exists as 17 isoforms divided into four classes (a, µ, p and q), which are important for Phase II metabolism. One possible mechanism for the induction of Phase II metabolism by dietary polyphenols is Expert Opin. Drug Metab. Toxicol. (2012) 8(6) 683 Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Lib of Chinese Aca of Med Sciences on 08/06/13 For personal use only. C. S. Yang & E. Pan through the antioxidant response element (ARE) and nuclear factor-erythroid 2-related factor 2 (Nrf2)-mediated signaling. This signaling cascade responds to electrophiles, oxidants and dietary antioxidants resulting in increased transcription of genes encoding GSTs, UGTs, NAD(P)H quinone oxidoreductase1 (NQO1), hemeoxygenase-1 (HO-1) and others [42]. Chen et al. reported that treatment of HepG2 cells with 25 -- 250 µM EGCG for 24 h resulted in a 2- to 11-fold increase in ARE promoter activity [43]. Induction of GSTP1 and NQO1 expression by green tea extracts has also been reported in human lung cell lines [44]. The increase in NQO1 mRNA levels was more pronounced than that of GSTP1. Several studies have indicated the inhibition of P-gp and breast cancer resistance protein (BCRP) activity by EGCG [45-48]. The accumulation of rhodamine-123, a P-gp substrate, in the multidrug-resistant cell line CHRC5 increased 3-fold in the presence of tea catechins, suggesting an inhibition of the efflux of drugs by P-gp [46]. Treatment of P-gp-overexpressing KB-C2 human epidermal carcinoma cells with 100 µM EGCG decreased the P-gp-mediated efflux of Rhodamine-123 by approximately twofold [49]. A study by Qian et al. [47] measured the intracellular accumulation of doxorubicin in drug-resistant KB-A1 cells and noted that it increased upon administration with EGCG in a concentration-dependent manner, thus indicating that EGCG modulated P-gp activity. Mei et al. [50] observed that EGCG and other catechins modulated P-gp activity by inhibiting the ATPase activity of P-gp in KB-A1 cells. The study also found that 40 µg/ml of tea catechins and 10 µg/ml of EGCG downregulated the expression of P-gp [50]. Green tea extract has also been reported to inhibit the activity of MRP2 at 1 mg/ml, but not at 0.01 or 0.1 mg/ml [51]. It should be pointed out that because of the strong binding of tea catechins to purified proteins or microsomes, some of the reported inhibition of activity could be due to nonspecific binding. In this sense, the studies in vivo are more relevant. Effects of green tea catechins on drug-metabolizing enzymes and drug transporters in vivo 4.3 In animal studies, several studies have indicated the induction of CYP1A1, 1A2, 2B and 3A by green tea extracts, but the results are inconsistent, possibly due to the different experimental conditions used [52-55]. The induction of CYP1A2 expression (by twofold) by green tea extract was observed by Jang et al. [52]. These authors noted, however, that green tea extracts were unlikely to affect the pharmacokinetics of clozapine, an antipsychotic medication, because the rate of elimination of the drug in green tea extract-treated and control groups was similar [52]. Niwattisaiwong et al. [53] found that Japanese green tea extracts had no significant effect on CYP3A or CYP1A2 activity, but it increased CYP1A1 activity in rats. However, a reduction of CYP3A expression and an increase in CYP2B expression were found with repeated treatments of green tea extracts in Sprague-Dawley rats [54]. 684 Whereas Jang et al. [52] reported an increase in CYP1A2 expression by green tea extracts, Chen et al. [55] reported a reduction of both CYP1A2 and CYP2E1 mRNA and protein levels by tea catechins. The expressions of cytochrome b5 and b5 reductase have also been shown to be decreased by treatments with tea catechins [55,56]. Because these enzymes are involved in some of the CYP-catalyzed reactions, this effect may decrease related drug metabolism. In a study on the effects of EGCG on the Nrf2 and HO-1 signaling pathway, EGCG was found to partially alleviate cisplatin nephrotoxicity by inducing Nrf2 and HO-1 [57]. Supplementation of tea catechins caused an increase in activity of both UGT and GST, while supplementation with Sunphenon (containing 76.6% catechins) resulted in enhanced activity of GST in the intestine [56,58]. A number of studies have shown that dietary catechins can increase the expression of GST isoforms in the liver, GI tract and other tissues, but the results were not consistent [59,60]. Shen et al. showed that treatment of mice with EGCG (200 mg/kg, i.g.) resulted in a number of Nrf2-dependent gene expression changes in the small intestine and liver [61]. These included a 2- to 2.7-fold increase in the expression of glutamate-cysteine ligase (GCL) and a 6-fold increase in the expression of g-glutamyltransferase I in the liver. This study demonstrates modulation of ARE-mediated gene expression by EGCG in vivo [61]. Catterall et al. found that intragastric treatment of rats with theaflavins (20 mg/kg) for 4 weeks reduced CYP1A1 activity in the intestine, but not in the liver [62]. Because of the lack of systemic bioavailability of theaflavins, they may not reach the liver. Theaflavins also decreased the protein levels of CYP2E1 in intestinal microsomes from rats in the same study. Because of the wide consumption of black tea polyphenols, their effects on drug-metabolizing enzymes and drug transporters deserve further studies. Multidrug resistance efflux pumps, including MRPs and P-gp, are responsible for limiting the bioavailability and efficacy of a number of pharmaceutical agents, including cancer chemotherapeutics, antibiotics and others [63,64]. A number of studies showed that dietary catechins inhibited the activity of these efflux pumps. Qian et al. [47] showed that EGCG could modulate P-gp in vivo. The authors found that cotreatment of nude mice bearing P-gp-overexpressing tumors with EGCG and doxorubicin showed a 10-fold increase in tumor growth inhibition compared with mice treated with EGCG or doxorubicin as single agents [47]. This increased growth inhibition was correlated with a 51% increase in tumorassociated doxorubicin. Similar results have been observed with kaempferol, which dose dependently increased the accumulation of Rhodamine-123 in KB-C2 cells [65]. Effects of catechins on the bioavailability and metabolism of drugs 4.4 Through interactions at different stages of the drug metabolism process, green tea catechins can affect the bioavailability of drugs. In addition to the direct binding of catechins to Expert Opin. Drug Metab. Toxicol. (2012) 8(6) Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Lib of Chinese Aca of Med Sciences on 08/06/13 For personal use only. The effects of green tea polyphenols on drug metabolism sunitinib, as previously described, there are examples for other mechanisms of action. For example, treatment of male Sprague-Dawley rats with green tea extracts (400mg/kg b.w./ day) for 1 week resulted in a significant increase in the Cmax and AUC values of midazolam (Versed), a benzodiazepine used for preanesthetic sedation. It is possible that green tea constituents inhibit CYP3A enzymes in the intestine, thereby enhancing the plasma levels of midazolam in the blood [66]. The inhibitory activity of EGCG on the CYP3A enzyme subfamily as well as P-gp leading to increased drug bioavailabilities has also been reported in several other studies. Shin et al. showed that the bioavailability of tamoxifen, an estrogen receptor antagonist in treating breast cancer, was increased two to threefold by 3 and 10 mg/kg of EGCG in male Sprague-Dawley rats [67]. Likewise, male Sprague-Dawley rats treated with 0.05, 3 and 10 mg/kg EGCG showed greater total AUC values than the control rats for nicardipine, a calcium channel blocker for hypertension and angina [68]. The AUC value of diltiazem, another drug used to treat hypertension and angina, was also increased after treatment with 4 and 12 mg/kg of EGCG in rats [69]. A study on the oral pharmacokinetics of verapamil, a drug for hypertension and angina, in male Sprague-Dawley rats concluded that the enhanced bioavailability of verapamil was mainly due to the inhibition of P-gp since the AUC values of both verapamil and its active metabolite, norverapamil, were increased by the oral treatment of 2 or 10 mg/kg of EGCG [70]. Inhibition of CYP3A was also suggested from the decreased clearance of verapamil. Another study by Liang et al. reported that green tea catechins, particularly EGCG at 40, 80 and 160 mg/kg, enhanced the bioavailability of doxorubicin, a drug used to treat different types of cancers, in BABL/c nu/nu mice by inhibiting P-gp efflux activity [71]. Lin et al. observed that irinotecan, a topoisomerase I inhibitor for treatment of colon or rectal cancer, had a diminished bile to blood distribution ratio (AUCbile/AUCblood) after coadministration with 20 mg/kg of EGCG in male Sprague-Dawley rats, indicating that EGCG probably reduced bile efflux by inhibiting P-gp [72]. The doses of EGCG at 10 or 20 mg/kg correspond to approximately 75 or 150 mg of EGCG for a person with a body weight of 70 kg. This amount can be obtained from a cup of green tea. Although the inhibition of these enzymes by green tea polyphenols can increase the blood level of some drugs, for the same reason, higher doses of tea polyphenols may increase the toxicity of certain drugs. A thorough study on the effect of tea catechins on drug metabolism was studied by Chow et al. [73] in 42 healthy volunteers using probe drugs: caffeine for CYP1A2, dextromethorphan for CYP2D6, losartan for CYP2C9 and buspirone for CYP3A4. After a 4-week initial washout period, in which volunteers refrained from any tea products, the volunteers were subjected to 4 weeks of daily Polyphenon E administration (corresponding to 800 mg of EGCG). The drug metabolism phenotypic indices (the ratio of metabolite to parent compound) for CYP1A2, CYP2C9 and CYP2D6 were not affected. However, the AUC of the plasma buspirone was increased by 20%, suggesting a small reduction in CYP3A activity [73]. A contribution by the inhibition of efflux pumps, such as P-gp, is also possible. A study by Donovan et al. [74] showed that daily administration of decaffeinated green tea (211 ± 25 mg) for 14 days to healthy volunteers did not alter the activities of CYP3A4 and 2D6. Apparently, tea catechins do not significantly affect CYP enzyme activities in vivo. The same group of 42 subjects used by Chow et al. was also studied for the effect of EGCG treatment on GST [75]. The GST activity and GST-p level were found to increase slightly, and the increases were statistically significant only in individuals with baseline activity in the lowest tertile. 5. Expert opinion In this article, we described how tea catechins are handled by drug transporters and drug-metabolizing enzymes, as well as reviewed the possible mechanisms by which tea catechins may affect drug metabolism. Examples are provided to illustrate that tea catechins may bind to drugs directly, affect the activities and levels of drug transporters and modulate the activities and levels of drug-metabolizing enzymes. Whether these actions take place in vivo or not depends on the specific drugs involved and the levels of tea catechins ingested. There are only limited data from human studies. In the absence of human data, we can only extrapolate from results of animal studies, in which different doses of catechins have been used. The doses of EGCG at 10 -- 20 mg/kg in rodents correspond to approximately 75 -- 150 mg of EGCG for a person with a body weight of 70 kg. This dose is achievable from one cup of green tea. For studies with EGCG doses of 100 -- 400 mg/kg in rodents, corresponding to 750 -- 3000 mg for one person, the doses would require more than five cups of green tea per day for humans to achieve. However, they may be achievable in individuals who take supplements containing high levels of EGCG and other catechins. Even though there is a common advice of taking medications with water instead of tea, scientific reports on this subject have been lacking. The clinical observation by Ge et al. [29] on the clinical effect of tea drinking in a renal cell carcinoma patient who took sunitinib is very interesting. However, this is an observation from only one case. Future clinical observations on the interactions between tea consumption and drug efficacy are important. In laboratory studies, the direct interactions between tea polyphenols and different drugs deserve more attention; the interactions may be studied efficiently using modern screening approaches. Green tea should not be taken concomitantly with drugs known to interact with green tea polyphenols. For habitual tea drinkers, it is important to know that tea catechins, such as EGCG, have a Tmax of 1 -- 1.5 h and a t½ of about 3 -- 4 h. This information may help individuals select the time of tea consumption in relation to the time of taking medication whose interactions with green tea are not known. Because of the extensive black tea Expert Opin. Drug Metab. Toxicol. (2012) 8(6) 685 Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Lib of Chinese Aca of Med Sciences on 08/06/13 For personal use only. C. S. Yang & E. Pan consumption worldwide, the effects of black tea polyphenols on drug metabolism deserve more attention. There is only limited information on this topic. Even though these largemolecular-weight polyphenols have very low or no systemic bioavailability, they may bind to drugs directly and affect drug transporters and drug-metabolizing enzymes in the intestine and affect the bioavailability of drugs. From the studies by Chow et al. [73,75], daily consumption of 800 mg of EGCG, which is equivalent to five or more cups of tea, had little effect on the metabolism of the different types of CYP enzyme and drugs studied. We may suggest that the lower doses from one or two cups of tea per day may not have a significant effect on drug metabolism, unless the drug is coadministered together with tea. Many patients and healthy people are taking dietary supplements that contain high levels of catechins. As discussed, the manufacturer’s recommended dosages of EGCG and Bibliography Yang CS, Wang X, Lu G, Picinich SC. Cancer prevention by tea: animal studies, molecular mechanisms and human relevance. 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Affiliation Chung S Yang†1 PhD & Eva Pan2 PharmD † Author for correspondence 1 Professor, The State University of New Jersey, Ernest Mario School of Pharmacy, Department of Chemical Biology, Rutgers, 164 Frelinghuysen Road, Piscataway, NJ 08854-8020, USA Tel: +732 445 5360; Fax: +732 445 0687; E-mail: [email protected] 2 Rutgers University, Piscataway, USA 689