The Effects of Green Tea Polyphenols on Drug Metabolism

Review The effects of green tea polyphenols on drug metabolism

† Chung S Yang & Eva Pan † 1. Introduction The State University of New Jersey, Ernest Mario School of Pharmacy, Department of Chemical Biology, NJ, USA 2. The composition, consumption and chemical properties of tea Introduction: Tea, made from the dried leaves of the plant Camellia sinensis polyphenols Theaceae, is a very popular beverage consumed worldwide. Recently, green 3. Drug metabolizing-enzymes, tea extract-based dietary supplements have also been widely consumed for drug transporters and their the acclaimed beneficial health effects, such as weight reduction. Although roles in the biotransformation tea consumption is considered to be innocuous, the potential interactions of tea catechins between tea polyphenols and drugs have been demonstrated in studies 4. The effects of tea catechins on in vitro and in vivo. drug absorption, Areas covered: This article reviews the current literature on the chemistry biotransformation and and biotransformation of tea constituents, mainly catechins from green tea. elimination The article also provides a review of their effects on the absorption, efflux, 5. Expert opinion 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

For personal use only. 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

Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Lib of Chinese Aca Med Sciences on 08/06/13 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)

When green tea is brewed in hot water, about a third of the Article highlights. solid material is extracted into water. Of the water-extractable . Green tea is a commonly consumed beverage and tea materials (the dried form is known as tea solids), about a third extracts have been used in many dietary supplements. are polyphenols, generally known as catechins. The major Green tea polyphenols may affect the absorption and tea polyphenols are (-)-epigallocatechin-3-gallate (EGCG), metabolism of drugs by directly binding to drugs and/or (-)-epigallocatechin (EGC), (-)-epicatechin-3-gallate (ECG) affecting the expression or activities of drug-metabolizing enzymes and drug transporters. and (-)-epicatechin (EC). The structures of these compounds . Many laboratory studies have demonstrated that green are shown in Figure 1. Black tea is the major form of tea con- tea polyphenols can affect the expression or activities of sumed worldwide and constitutes 78% of the world tea pro- drug-metabolizing enzymes and drug transporters. Such duction. It is produced by crushing the tea leaves to allow the effects, however, may not be produced by the enzyme polyphenol oxidase to be released. This enzyme cata- consumption of one or two cups of tea per day in humans. lyzes the oxidation of tea catechins and the oxidized catechins . When green tea and drugs are taken concomitantly, are subsequently polymerized. This process, generally known direct binding may occur. There is a report on the effect as ‘fermentation,’ converts most of the monomeric catechins of tea drinking on the clinical effects of a therapeutic into oligomeric polyphenols (theaflavins), which account for drug. More laboratory and clinic studies on such 2 -- 6% of the weight of black tea solids, and polymeric poly- interactions are needed. . Green tea-based dietary supplements may be taken at phenols (generally known as thearubigins), which account for rather high doses (as recommended by the more than 20% of tea solids and are poorly characterized manufacturer), for example, for the purpose of weight chemically. Caffeine accounts for 2 -- 5% of the dry weight of reduction by some individuals. Such high doses of tea the water-extractable materials in green and black tea. Oolong polyphenols may have a significant effect on drug tea is a specialized tea prepared in southeast China, Taiwan, metabolism. This topic remains to be studied further. . Black tea polyphenols have low or no systemic and Japan made by crushing only the rims of the tea leaves bioavailability, but they may interact and affect the and ‘fermented’ under tightly controlled conditions to generate absorption and metabolism of drugs in the intestine. special aromas that are enjoyed by consumers. Because black tea is widely consumed worldwide, more A typical cup of green tea, with 2.5 g of tea leaves studies on the effects of black tea consumption on drug brewed for 3 min in 250 ml hot water, usually contains metabolism are needed. 620 -- 880 mg of water-extractable materials, of which about -- This box summarizes key points contained in the article. a third are catechins. EGCG accounts for 50 75% of the total catechins, and the remainder is made up of EGC,

For personal use only. ECG, EC and other minor catechins. Thus, a freshly brewed of drug-metabolizing enzymes and drug transporters. This cup of green tea may contain 130 -- 180 mg of EGCG. Ready- article will first review the chemistry of tea constituents as to-drink teas in bottles and cans are becoming popular. Their well as their absorption and biotransformation, and then catechin contents may vary extensively depending on the discuss the possible mechanisms by which tea polyphenols manufacturing conditions and the stability of catechins affect drug metabolism. It will assess the possible relevance of during storage. these mechanisms in humans who consume tea as a beverage Green tea extracts are also used now as ingredients in many or through dietary supplements. Green tea catechins, which dietary supplements, such as vitamins and weight reduction have been studied extensively, will be the focus of this article. pills [7]; the following are some examples. The Whole Health The possible interactions between the oligomeric and poly- Multivitamin, Super Multi Plus pill contains 10 mg of meric polyphenols in black tea will also be discussed, because EGCG, whereas the Anselmo Super Multis pill has of the wide consumption of black tea worldwide. 16.7 mg EGCG; both are to be taken three times daily. Dexatrim Max Slim Packs Powder Mix, advertised to help 2. The composition, consumption and boost metabolism and burn fat, contains 45 mg of EGCG chemical properties of tea polyphenols and 25 mg of caffeine per pack and should not be taken Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Lib of Chinese Aca Med Sciences on 08/06/13 more than six times a day. Similarly, the Schiff Natural Green Depending on the manufacturing process, tea is divided into Tea Diet, which contains 90 mg of EGCG and 50 mg of three major types: green tea, black tea and oolong tea [6].Green caffeine per tablet, is recommended to be taken three times tea, which constitutes about 20% of the world tea production, a day. Green tea extracts are also manufactured into supple- is mainly consumed in Asian countries such as China and ment pills as sources of catechins. For example, one serving Japan. Its consumption has significantly increased in the size of two capsules of Nature’s Bounty Green Tea Extract Western countries during the past 30 years, mainly due to its provides 630 mg of EGCG to be taken twice daily, and publicized potential beneficial health effects. Green tea is pro- NOW Foods’ EGCG Green Tea Extract tablet consists of duced by steaming or panfrying tea leaves. This process inacti- 200 mg EGCG to be taken once a day [5]. Source Naturals vates the enzymes and preserves the product by stabilizing the EGCG, with 350 mg of EGCG per tablet, can be taken tea constituents and preventing the growth of microorganisms. up to twice a day and Whole Health Green Tea Extract

678 Expert Opin. Drug Metab. Toxicol. (2012) 8(6) The effects of green tea polyphenols on drug metabolism

OH 3′ OH 4′ OH B 3′ HO O 2 OH 5′ OH 7 A 4′ C B HO 2 3 O O 5 5′ OH 7 A OH 3″ OH C O 3 OH D 4″ 5 OH 5” OH OH

(–)–Epigallocatechin-3-gallate (EGCG) (–)–Epigallocatechin (EGC) OH 4′ B OH HO O 2 5′ OH 4′ 7 A C B HO O 2 5′ OH 3 O 7 5 A C OH 3″ OH OH O 5 D 4″ OH 5” OH OH (–)–Epicatechin-3-gallate (ECG) (–)–Epicatechin (EC)

Figure 1. The structures of tea catechins.

500 mg contains 1000 mg of EGCG per recommended the enzyme catechol-O-methyltransferase (COMT), which

For personal use only. serving of two capsules. In general, many of the green tea methylates EGCG, for example, at the 4’ and 4’’ positions extract supplements manufactured to have high concentra- to form 4’’-O-methyl-(-)-EGCG and 4’,4’’-O-dimethyl-(-)- tions of catechins for proclaimed beneficial health effects pro- EGCG [9]. This eliminates the vicinal phenolic structure and vide more catechins than the daily intake from a typical green prevents possible toxicity through redox cycling. tea beverage. Thus, the consumption of green tea extract supplements could be major concerns in regard to interactions 3. Drug metabolizing-enzymes, drug with other drugs. transporters and their roles in the biotrans- Tea catechins possess multiple phenolic groups, which make formation of tea catechins them chemically reactive. For example, EGCG possesses eight phenolic groups, all of which are potential donors for hydro- Most drugs undergo an initial Phase I metabolism, generally gen bonding. Through hydrogen bonding and other interac- catalyzed by cytochrome P450 (CYP) enzymes, to form tions, EGCG and other catechins can bind to a variety of more water-soluble metabolites. The metabolites are then proteins and other biological molecules [1]. As will be discussed catalyzed by Phase II enzymes, such as UDP-glucuronosyl later, they could also bind to certain drugs. These phenolic transferases (UGT) and sulfotransferases (SULT), to form groups also make tea catechins potent antioxidants. In addition glucuronides and sulfates as metabolites, which are then elim- Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Lib of Chinese Aca Med Sciences on 08/06/13 to the quenching of reactive oxygen species, tea catechins can inated from the body (Figure 2). Because of the polyphenolic chelate trace elements, such as iron and copper, and this action structure, catechins are rather water soluble and are not likely prevents the formation of reactive oxygen species. On the other to undergo Phase I metabolism by CYP enzymes. In addition hand, tea catechins can be auto-oxidized, possibly catalyzed by to the methylation reaction catalyzed by COMT, tea cate- trace amounts of copper and iron, at slightly alkaline or even chins are conjugated by UGT and SULT to glucuronides neutral conditions. This property makes tea catechins pre- and sulfates [6]. oxidants in generating superoxide radical and hydrogen perox- Studies of EGCG and EGC glucuronidation reveal that ide [8]. The presence of vicinal phenolic groups also allows EGCG-4"-O-glucuronide is the major metabolite formed by catechins to be easily oxidized to form quinones, which can human, mouse and rat microsomes [10]. Mouse small intestinal generate oxidative stress by redox cycling. To prevent such microsomes have the highest catalytic efficiency (Vmax/Km) reactions from happening in vivo, mammalian cells possess 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 X X

Phase I Phase I CYP enzymes CYP enzymes

XOH XOH

UGT UGT Phase II Phase II ST ST X-conj X-conj X-conj MRP X-conj X-conj MRP2 MRP 1 MRP2 X X 1 X

Bile

Enterocyte Hepatocyte Systemic circulation Fecal Fecal excretion Urine excretion excretion

Figure 2. Drug absorption, biotransformation and excretion. For personal use only. X-conj: X-conjugate.

liver, human liver, rat liver and rat small intestine. Of the microorganisms in the intestine. Three metabolites, 5-(3’,4’,5’- 12 human UGT isoforms studied, the intestinal-specific trihydroxyphenyl)-g-valerolactone, 5-(3’, 4’-dihydroxyphenyl)- UGT1A8 having the highest catalytic efficiency, UGT1A1 and g-valerolactone and 5-(3’,5’-dihydroxyphenyl)-g-valerolactone, 1A9 also had high glucuronidation activity toward EGCG. have been identified [6]. With EGC, EGC-3’-O-glucuronide is the major product At high doses, EGCG can form cysteine adducts in vivo, formed by microsomes from mice, rats and humans with EGCG-2"-cysteine and EGCG-2’-cysteine [14]. These meta- the liver microsomes having a higher efficiency than intes- bolites can be detected in the urine following administration tinal microsomes. EGCG is also time- and concentration- of EGCG at doses of 200 -- 400 mg/kg, i.p. or 1500 mg/kg, dependently sulfated by human, mouse and rat liver cytosol [11]. i.g. These metabolites are probably formed as a result of oxi- The rat has the greatest activity followed by the mouse and the dation of EGCG to a quinone or semiquinone, which then human. It has been reported that EC also undergoes sulfation reacts with the sulfhydryl groups in vivo.Theextensive catalyzed by human and rat intestinal and liver enzymes in cyto- depletion of sulfhydryl groups could lead to toxicity, and Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Lib of Chinese Aca Med Sciences on 08/06/13 sol, with the human liver enzyme being the most efficient [12]. indeed hepatotoxicity has been observed with these EGCG Further studies have revealed that SULT1A1 is largely responsi- doses [14]. ble for this activity in the liver, whereas both SULT1A1 and Active efflux has been shown to limit the bioavailability and SULT1A3 are active in the human intestine. The results from cellular accumulation of many compounds. The multidrug Sang et al. [13] from data-dependent tandem mass spectrometric resistance-associated proteins (MRP) are ATP-dependent analysis of mouse urine samples after intraperitoneal or efflux transporters that are expressed in many tissues. intragastic administration of EGCG have shown that methyl- MRP1 is located on the basolateral side of cells, and is present ated EGCG (or glucuronidated or sulfated EGCG) can be in nearly all tissues, and serves to transport compounds from further glucuronided and/or sulfated (or methylated) to form the interior of the cells into the interstitial space [15]. By con- mixed (methylated and conjugated) EGCG metabolites. Tea trast, MRP2 is located on the apical surface of the intestine, catechins are known to undergo metabolic degradation by kidney and liver, where it transports compounds from the

680 Expert Opin. Drug Metab. Toxicol. (2012) 8(6) The effects of green tea polyphenols on drug metabolism

bloodstream into the lumen, urine and bile, respectively bioavailability and metabolic pattern of tea catechins in (Figure 2). Studies on EGCG uptake showed that indo- miceweresimilartothoseinhumans;however,thebioavail- methacin (an MRP inhibitor) increased the intracellular ability of tea catechins in rats was much lower and the meta- accumulation of EGCG, EGCG 4"-O-methyl-EGCG and bolic pattern was less similar to humans [20-24].Chowet al. 4’,4"-di-O-methyl-EGCG by 10-, 11- and 3-fold in [26] studied the pharmacokinetics of EGCG in humans after Madin-- Darby canine kidney (MDCKII) cells with overex- ingesting 200 -- 800 mg of EGCG as Polyphenon E (a stan- pressing of MRP-1 [16]. Similarly, treatment of MRP-2 dardized tea catechin preparation containing 65% EGCG). overexpressed MDCKII cells with MK-571 (an MRP-2 The authors found that the Cmax of free (unconjugated) inhibitor) resulted in more than a 10-fold increase in the EGCG ranged from 73.7 to 438 mg/l (0.16 -- 0.96 µM), intracellular levels of EGCG and its methylated metabolites. depending on the dose administered. Treatment of HT-29 human colon cancer cells with indo- The black tea polyphenols, because of their larger molecu- methacin also resulted in increased intracellular accumulation lar weights and greater number of phenolic groups, have of EGCG and its methylated and glucuronidated metabo- extremely low or no systemic bioavailability. Mulder et al. lites [17]. P-glycoprotein (P-gp) is another important drug [27] reported that the Cmax of theaflavins in human plasma efflux protein. Treatment of P-gp-overexpressing MDCKII and urine was only 1 and 4.2 ng/ml, respectively, following cells with a variety of P-gp inhibitors, however, resulted in consumption of 700 mg of pure theaflavins mixture, equiva- no significant effects on the intracellular levels of EGCG or lent to about 30 cups of black tea. Neither theaflavins its metabolites. These data suggest a role for MRPs, but not mono- nor di-gallates were detectable in this study. P-gp, in affecting the bioavailability of EGCG. The involvement of drug transporters and metabolizing 4. The effects of tea catechins on drug enzymes in the uptake, biotransformation and elimination absorption, biotransformation and of EGCG has been discussed previously [18]. The apical loca- elimination tion of MRP2 suggests that it acts to limit the bioavailability of EGCG by actively exporting EGCG in the enterocyte The effects of tea catechins on drug metabolism have been back into the intestinal lumen either before or after EGCG studied by many investigators, and this topic has been is methylated by COMT or glucuronidated by UGT. The reviewed [5,18,28]. Tea catechins may affect the biological fate of remaining fraction of EGCG would then be absorbed into drugs at different levels. They may physically bind to drugs the portal circulation, enter the liver and be methylated or and reduce their absorption and biological activities. Tea cate- conjugated, and then could subsequently be effluxed by chins may affect the activities or expression levels of drug trans-

For personal use only. MRP2 located on the canalicular membrane of the hepato- porters and drug-metabolizing enzymes. The results of some cytes. MRP1, located on the basolateral membrane of studies during the past decade are summarized in two tables enterocytes and hepatocytes, is expected to increase the and reviewed in this section. Table 1 summarizes the effect of bioavailability of EGCG; however, this point remains to tea catechins on drug transporters and drug-metabolizing be demonstrated. The influence of MRP1 and MRP2 on enzymes in vitro and Table 2 summarizes the effect of green tea the bioavailability of EGCG in vivo is likely to depend on catechins on drug metabolism in animal models and in humans. the tissue distribution of each efflux protein. It was reported that the transcript level of MRP2 was more than 10-fold 4.1 Direct interaction between tea catechins and drugs higher than that of MRP1 in the human jejunum [19]; there- There are two well-studied examples that illustrate the impact fore, efflux of EGCG by MRP2 may be predominant in the of direct binding of tea catechins to drugs. The interaction intestine, resulting in a decrease in bioavailability. between EGCG and sunitinib was first observed in clinic by The pharmacokinetics of tea catechins have been studied Ge et al. [29] that tea drinking disturbed the symptom control in rats, mice and humans [20-26]. For example, human studies of sunitinib in a clinical case of metastatic renal cell carci- showed that after oral administration of 20 mg green tea noma. Subsequent studies found that EGCG directly binds solids/kg body weight, it took 1.3 -- 1.6 h for the catechins with sunitinib to form a precipitate in solution and to form Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Lib of Chinese Aca Med Sciences on 08/06/13 to reach maximum levels in the blood (Tmax) [24].Themax- sticky semisolid contents in the mouse stomach. As a conse- imum plasma concentrations (Cmax)forEGCG,EGCand quence, the plasma concentrations of sunitinib are markedly EC were 0.17, 0.73 and 0.43 µM, respectively. The half- lower. A second example is the interaction between EGCG lives (t½) were 3.4, 1.7 and 2.0 h for EGCG, EGC and and bortezomib that green tea catechins effectively block EC, respectively. Since green tea solids contain higher the therapeutic effect of bortezomib in cell lines and in an ani- amounts of EGCG than EGC and EC, these data suggest mal model reported by Golden et al. [30]. Bortezomib, a pro- that the bioavailability of EGCG is comparatively lower. In teasome inhibitor, is a drug used for the treatment of humans, approximately 70% of the EGCG existed in the multiple myeloma and mantle cell lymphoma. It was shown free (unconjugated) form, whereas EC and EGC were pres- that such an interaction occurred only with boronic acid- ent mainly in the conjugated forms [24]. Methylated forms based proteasome inhibitors, such as MG-262 or PS-IX, but of EGCG and other catechins were also observed [24].The not with non-boronic acid proteasome inhibitors, such as

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 Study results Ref.

CYP1A Suppressed expression by tea catechins [76] Induced expression by Aquila green tea + lemon [36] CYP1A1 Inhibition of activity by catechins [33] Induced expression by green tea extract, EGCG, Aquila green [37,34,36] tea + lemon, Aquila red tea + pear CYP1A2 Inhibition of activity by catechins, green tea extract [33,34] Induced expression by green tea extract [37,34] CYP2A6 Inhibition of activity by EGCG [33] CYP2C Induced expression by green tea extract [37] CYP2C9 Inhibition of activity by EGCG [33] CYP2D6 Induced expression by green tea extract [37] CYP2E1 Inhibition of activity by EGCG [33] Induced expression by green tea extract [37] CYP3A Inhibition of activity by green tea extract [66] CYP3A4 Inhibition of activity by green tea catechins, green tea extract, [33-35,77] EGCG No effect on activity by catechins [78] Induced expression by Nestea white tea + apricot, Nestea lemon, [36] Nestea green tea + lemon, Nestea red tea + pear, Nestea peach, Aquila black tea + lemon NADPH-CYP reductase Inhibition of activity by EGCG [33] UGT Inhibition of activity by epicatechin [38] UGT1A1 Inhibition of activity by EGCG [40] No effect on activity by catechins [78] UGT1A4 Inhibition of activity by EGCG [39] SULT Inhibition of activity by epicatechin [38] Phenol SULT Inhibition of activity by EGCG [79] GSTP1 Induced expression by green tea extract [44] NQO1 Induced expression by green tea extract [44] COMT Inhibition of L-DOPA methylation by EGCG [32] P-glycoprotein Inhibition of activity by tea polyphenols, EGCG [48,46,47,45]

For personal use only. Suppressed expression by tea polyphenols [50] MRP2 Inhibition of activity by green tea extract [51] BCRP Inhibition of activity by EGCG [45] b-glucuronidase Inhibition of activity by EGCG [80]

BCRP:Breast cancer resistance protein.

-- MG-132, PS-1 or nelfinavir (Viracept ). The structure basis potent inhibitor with IC50 values of 0.07 0.2 nM. These for the binding is that the 1,2-diol groups in catechins are concentrations are within the range of concentrations found able to form covalent cyclic boronate moieties with boronic in the plasma following consumption of normal doses of acid, resulting in strong single-pair reversible functional group green tea, suggesting that these effects may be observable interactions [30]. in vivo. Whether green tea consumption would inhibit the These examples are of clinical relevance because many cancer methylation of L-DOPA, and thus enhance its efficiency in, patients consume substantial amounts of dietary supplements for example, patients with Parkinson’s disease taking that contain tea catechins and other herbal extracts. More L-DOPA therapy, remains to be studied. On the other hand, Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Lib of Chinese Aca Med Sciences on 08/06/13 studies in this area are needed. Kim and Hong [31] studied consumption of large quantities of green tea-based supple- the interactions between EGCG and commonly consumed ments by individuals taking COMT inhibitors, such as over-the-counter drugs and found that EGCG did not affect Parkinson’s disease patients, may produce oxidative stress- the stability of the drugs studied. It would be interesting to related side effects. Molecular modeling studies have shown study the possible binding between EGCG and drugs. that the strong binding of EGCG to COMT was due to the formation of a hexa-coordination complex with the active 4.2 Effects of catechins on drug-metabolizing site Mg2+ of COMT and interaction between the 4¢¢-OH enzymes and transporters in vitro of EGCG and Lys144-NH2. The binding of EGCG to It has been shown that tea catechins inhibit the COMT- COMT was stabilized by hydrophobic interactions between mediated methylation of 3,4-dihydroxy-L-phenylalanine the D-ring of EGCG and Trp38, Leu198, Pro174 and (L-DOPA) in human liver cytosol [32]. EGCG was the most Trp143 of COMT [32]. EGCG may also inhibit COMT,

682 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 Study results Ref.

Animal studies Cytochrome P450s Induction of CYP1A1 by Japanese green tea in Wistar rats [53] Induced expression of CYP1A2 by green tea extract in [52] Sprague-Dawley rats Induction of CYP2B by green tea extract in Sprague-Dawley rats [54] Inhibition of AHH (CYP1A1) activity by green tea catechins in Wistar rats [56] Inhibition of CYP3A, CYP3A4 by green tea extract, EGCG [66,69,68,67] (?) Suppressed expression of CYP1A2, CYP2E1 by green tea catechins in [55] Kunming mice Suppressed expression of CYP3A by green tea extract in Sprague-Dawley [54] rats No effect on CYP1A2, CYP3A by Japanese green tea in Wistar rats [53] Cytochrome b5 and Inhibition by green tea catechins [56,55] reductase Nrf2 and heme oxygenase-1 Induction by EGCG in Wistar rats [57] GST, UGT Induction of GST by Sunphenon green tea extract, green tea catechins [58,56] Induction of UGT by green tea catechins in Wistar rats [56] No effect on UGT by green tea in Fischer rats [81] GCL Induced expression by EGCG in mice [61] g-Glutamyltransferase I Induced expression by EGCG in mice [61] P-glycoprotein Inhibition by EGCG, ECG [72,69,70] (?), [68,67] (?), [71,82] Midazolam Increased bioavailability by green tea extract in Sprague-Dawley rats [66] Clozapine Decreased bioavailability by green tea extract in Sprague-Dawley rats [52] Bortezomib Decreased bioavailability by green tea catechins [30] Irinotecan, Diltiazem, Increased bioavailability by EGCG [72,69,70,68,67,71,83] Verapamil, Nicardipine, Tamoxifen, Doxorubicin, 5-Fluorouracil Human Studies Cytochrome P450s No effect on CYP1A2, CYP2D6, CYP2C9, CYP3A4 by Polyphenon E, green [73,74] For personal use only. tea extract Reduction of CYP3A4 activity by 20% by Polyphenon E (a mixture of 65% [73] EGCG and other catechins), green tea catechins GST Induction by Polyphenon E [75] Reduced activity by Polyphenon E [75] Sunitinib Decreased bioavailability by EGCG [29]

AHH: Aryl hydrocarbon hydroxylase; GCL: Glutamate-- cysteine ligase.

and other methyltransferase activities, indirectly by depleting can serve as their inducers. EGCG has been shown to inhibit S-adenosyl-L-methionine (SAM). It was observed that treat- UGT activities, such as UGT1A1 and 1A4, and SULT as ment of mice with EGCG (200 -- 2000 mg/kg, i.g.) dose well [38-40]. Mohammed et al. [40] used the formation of estra- dependently decreased levels of SAM and S-adenosyl-L- diol-3-O-glucuronide (E-3-G) as an assay of UGT1A1 activity homocysteine (SAH) in the liver and small intestine. The and found the activity was inhibited to 50% by an EGCG con- µ maximal decreases in SAM and SAH were 83.8 and 33.8%, centration (IC50) of 7.8 g/ml, a concentration achievable Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Lib of Chinese Aca Med Sciences on 08/06/13 respectively, in the liver. In the small intestine, the magni- in vivo. Another study found that EGCG inhibited µ tude of decrease was 17.8 and 12.1% for SAM and SAH, UGT1A4 at an IC50 value of 33.8 g/ml [39]. A study by respectively [18]. Fong et al. [38] observed that epicatechin exhibited a slightly Since CYP enzymes are a key family of enzymes in catalyzing stronger inhibitory effect on sulfation than on glucuronidation Phase I metabolism of drugs, their modulation by green tea cat- in the Phase II metabolism of baicalein. echins has received much attention. Whereas the inhibition of Glutathione-S-transferase (GST) plays a key role in the detox- the activities of CYP1A1, 1A2, 2A6, 2C9, 2E1 and 3A4 has ification of electrophilic species by catalyzing the conjugation of been reported in studies in vitro [33-35], induction of the expres- these compounds to glutathione [41]. GST exists as 17 isoforms sion of CYP1A1, 1A2, 2D6, 2E1, 3A4 in cell lines has also been divided into four classes (a, µ, p and q), which are important reported [34,36,37]. These results are in agreement with our for Phase II metabolism. One possible mechanism for the general understanding that many inhibitors of CYP enzymes induction of Phase II metabolism by dietary polyphenols is

Expert Opin. Drug Metab. Toxicol. (2012) 8(6) 683 C. S. Yang & E. Pan

through the antioxidant response element (ARE) and nuclear Whereas Jang et al. [52] reported an increase in CYP1A2 factor-erythroid 2-related factor 2 (Nrf2)-mediated signaling. expression by green tea extracts, Chen et al. [55] reported a This signaling cascade responds to electrophiles, oxidants and reduction of both CYP1A2 and CYP2E1 mRNA and protein dietary antioxidants resulting in increased transcription of genes levels by tea catechins. The expressions of cytochrome b5 and encoding GSTs, UGTs, NAD(P)H quinone oxidoreductase- b5 reductase have also been shown to be decreased by treat- 1 (NQO1), hemeoxygenase-1 (HO-1) and others [42]. ments with tea catechins [55,56]. Because these enzymes are Chen et al. reported that treatment of HepG2 cells with involved in some of the CYP-catalyzed reactions, this effect 25 -- 250 µM EGCG for 24 h resulted in a 2- to 11-fold increase may decrease related drug metabolism. In a study on the in ARE promoter activity [43]. Induction of GSTP1 and effects of EGCG on the Nrf2 and HO-1 signaling pathway, NQO1 expression by green tea extracts has also been reported EGCG was found to partially alleviate cisplatin nephrotoxi- in human lung cell lines [44]. The increase in NQO1 mRNA city by inducing Nrf2 and HO-1 [57]. Supplementation of levels was more pronounced than that of GSTP1. tea catechins caused an increase in activity of both UGT Several studies have indicated the inhibition of P-gp and GST, while supplementation with Sunphenon (contain- and breast cancer resistance protein (BCRP) activity by ing 76.6% catechins) resulted in enhanced activity of GST EGCG [45-48]. The accumulation of rhodamine-123, a P-gp in the intestine [56,58]. A number of studies have shown that substrate, in the multidrug-resistant cell line CHRC5 dietary catechins can increase the expression of GST isoforms increased 3-fold in the presence of tea catechins, suggesting in the liver, GI tract and other tissues, but the results were not an inhibition of the efflux of drugs by P-gp [46]. Treatment consistent [59,60]. Shen et al. showed that treatment of mice of P-gp-overexpressing KB-C2 human epidermal carcinoma with EGCG (200 mg/kg, i.g.) resulted in a number of cells with 100 µM EGCG decreased the P-gp-mediated Nrf2-dependent gene expression changes in the small intes- efflux of Rhodamine-123 by approximately twofold [49]. tine and liver [61]. These included a 2- to 2.7-fold increase A study by Qian et al. [47] measured the intracellular accumu- in the expression of glutamate-cysteine ligase (GCL) and a lation of doxorubicin in drug-resistant KB-A1 cells and 6-fold increase in the expression of g-glutamyltransferase I noted that it increased upon administration with EGCG in in the liver. This study demonstrates modulation of a concentration-dependent manner, thus indicating that ARE-mediated gene expression by EGCG in vivo [61]. EGCG modulated P-gp activity. Mei et al. [50] observed that Catterall et al. found that intragastric treatment of rats with EGCG and other catechins modulated P-gp activity by inhi- theaflavins (20 mg/kg) for 4 weeks reduced CYP1A1 activity biting the ATPase activity of P-gp in KB-A1 cells. The study in the intestine, but not in the liver [62]. Because of the lack also found that 40 µg/ml of tea catechins and 10 µg/ml of of systemic bioavailability of theaflavins, they may not reach

For personal use only. EGCG downregulated the expression of P-gp [50]. Green tea the liver. Theaflavins also decreased the protein levels of extract has also been reported to inhibit the activity of CYP2E1 in intestinal microsomes from rats in the same MRP2 at 1 mg/ml, but not at 0.01 or 0.1 mg/ml [51]. study. Because of the wide consumption of black tea poly- It should be pointed out that because of the strong binding phenols, their effects on drug-metabolizing enzymes and of tea catechins to purified proteins or microsomes, some of drug transporters deserve further studies. the reported inhibition of activity could be due to nonspecific Multidrug resistance efflux pumps, including MRPs and binding. In this sense, the studies in vivo are more relevant. P-gp, are responsible for limiting the bioavailability and efficacy of a number of pharmaceutical agents, including cancer 4.3 Effects of green tea catechins on chemotherapeutics, antibiotics and others [63,64]. A number drug-metabolizing enzymes and drug transporters of studies showed that dietary catechins inhibited the activity in vivo of these efflux pumps. Qian et al. [47] showed that EGCG In animal studies, several studies have indicated the induction could modulate P-gp in vivo. The authors found that cotreat- of CYP1A1, 1A2, 2B and 3A by green tea extracts, but the ment of nude mice bearing P-gp-overexpressing tumors with results are inconsistent, possibly due to the different experi- EGCG and doxorubicin showed a 10-fold increase in tumor mental conditions used [52-55]. The induction of CYP1A2 growth inhibition compared with mice treated with EGCG Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Lib of Chinese Aca Med Sciences on 08/06/13 expression (by twofold) by green tea extract was observed by or doxorubicin as single agents [47]. This increased growth Jang et al. [52]. These authors noted, however, that green tea inhibition was correlated with a 51% increase in tumor- extracts were unlikely to affect the pharmacokinetics of cloza- associated doxorubicin. Similar results have been observed pine, an antipsychotic medication, because the rate of elimi- with kaempferol, which dose dependently increased the nation of the drug in green tea extract-treated and control accumulation of Rhodamine-123 in KB-C2 cells [65]. groups was similar [52]. Niwattisaiwong et al. [53] found that Japanese green tea extracts had no significant effect on 4.4 Effects of catechins on the bioavailability and CYP3A or CYP1A2 activity, but it increased CYP1A1 activity metabolism of drugs in rats. However, a reduction of CYP3A expression and an Through interactions at different stages of the drug metabolism increase in CYP2B expression were found with repeated process, green tea catechins can affect the bioavailability treatments of green tea extracts in Sprague-Dawley rats [54]. of drugs. In addition to the direct binding of catechins to

684 Expert Opin. Drug Metab. Toxicol. (2012) 8(6) The effects of green tea polyphenols on drug metabolism

sunitinib, as previously described, there are examples for other buspirone was increased by 20%, suggesting a small reduc- mechanisms of action. For example, treatment of male tion in CYP3A activity [73]. A contribution by the inhibition Sprague-Dawley rats with green tea extracts (400mg/kg b.w./ of efflux pumps, such as P-gp, is also possible. A study by day) for 1 week resulted in a significant increase in the Cmax Donovan et al. [74] showed that daily administration of decaf- and AUC values of midazolam (Versed), a benzodiazepine feinated green tea (211 ± 25 mg) for 14 days to healthy vol- used for preanesthetic sedation. It is possible that green tea con- unteers did not alter the activities of CYP3A4 and 2D6. stituents inhibit CYP3A enzymes in the intestine, thereby Apparently, tea catechins do not significantly affect CYP enhancing the plasma levels of midazolam in the blood [66]. enzyme activities in vivo. The same group of 42 subjects The inhibitory activity of EGCG on the CYP3A enzyme sub- used by Chow et al. was also studied for the effect of family as well as P-gp leading to increased drug bioavailabilities EGCG treatment on GST [75]. The GST activity and has also been reported in several other studies. Shin et al. showed GST-p level were found to increase slightly, and the increases that the bioavailability of tamoxifen, an estrogen receptor antag- were statistically significant only in individuals with baseline onist in treating breast cancer, was increased two to threefold by activity in the lowest tertile. 3 and 10 mg/kg of EGCG in male Sprague-Dawley rats [67]. Likewise, male Sprague-Dawley rats treated with 0.05, 3 and 5. Expert opinion 10 mg/kg EGCG showed greater total AUC values than the control rats for nicardipine, a calcium channel blocker for hyperten- In this article, we described how tea catechins are handled by sion and angina [68]. The AUC value of diltiazem, another drug drug transporters and drug-metabolizing enzymes, as well as used to treat hypertension and angina, was also increased after reviewed the possible mechanisms by which tea catechins may treatment with 4 and 12 mg/kg of EGCG in rats [69]. A study affect drug metabolism. Examples are provided to illustrate on the oral pharmacokinetics of verapamil, a drug for hyperten- that tea catechins may bind to drugs directly, affect the activi- sion and angina, in male Sprague-Dawley rats concluded that ties and levels of drug transporters and modulate the activities the enhanced bioavailability of verapamil was mainly due to and levels of drug-metabolizing enzymes. Whether these the inhibition of P-gp since the AUC values of both verapamil actions take place in vivo or not depends on the specific drugs and its active metabolite, norverapamil, were increased by the involved and the levels of tea catechins ingested. There are oral treatment of 2 or 10 mg/kg of EGCG [70]. Inhibition of only limited data from human studies. In the absence of human CYP3A was also suggested from the decreased clearance of data, we can only extrapolate from results of animal studies, in verapamil. Another study by Liang et al. reported that green which different doses of catechins have been used. The doses of tea catechins, particularly EGCG at 40, 80 and 160 mg/kg, EGCG at 10 -- 20 mg/kg in rodents correspond to approxi- -- For personal use only. enhanced the bioavailability of doxorubicin, a drug used to treat mately 75 150 mg of EGCG for a person with a body weight different types of cancers, in BABL/c nu/nu mice by inhibiting of 70 kg. This dose is achievable from one cup of green tea. For P-gp efflux activity [71].Linet al. observed that irinotecan, a studies with EGCG doses of 100 -- 400 mg/kg in rodents, cor- topoisomerase I inhibitor for treatment of colon or rectal responding to 750 -- 3000 mg for one person, the doses would cancer, had a diminished bile to blood distribution ratio require more than five cups of green tea per day for humans to (AUCbile/AUCblood) after coadministration with 20 mg/kg of achieve. However, they may be achievable in individuals who EGCG in male Sprague-Dawley rats, indicating that EGCG take supplements containing high levels of EGCG and probably reduced bile efflux by inhibiting P-gp [72]. The doses other catechins. of EGCG at 10 or 20 mg/kg correspond to approximately Even though there is a common advice of taking medica- 75 or 150 mg of EGCG for a person with a body weight of tions with water instead of tea, scientific reports on this subject 70 kg. This amount can be obtained from a cup of green tea. have been lacking. The clinical observation by Ge et al. [29] on Although the inhibition of these enzymes by green tea polyphe- the clinical effect of tea drinking in a renal cell carcinoma nols can increase the blood level of some drugs, for the same patient who took sunitinib is very interesting. However, this reason, higher doses of tea polyphenols may increase the toxicity is an observation from only one case. Future clinical observa- of certain drugs. tions on the interactions between tea consumption and drug Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Lib of Chinese Aca Med Sciences on 08/06/13 A thorough study on the effect of tea catechins on drug efficacy are important. In laboratory studies, the direct interac- metabolism was studied by Chow et al. [73] in 42 healthy vol- tions between tea polyphenols and different drugs deserve more unteers using probe drugs: caffeine for CYP1A2, dextrome- attention; the interactions may be studied efficiently using thorphan for CYP2D6, losartan for CYP2C9 and buspirone modern screening approaches. Green tea should not be taken for CYP3A4. After a 4-week initial washout period, in which concomitantly with drugs known to interact with green tea volunteers refrained from any tea products, the volunteers polyphenols. For habitual tea drinkers, it is important to were subjected to 4 weeks of daily Polyphenon E administra- know that tea catechins, such as EGCG, have a Tmax of -- -- tion (corresponding to 800 mg of EGCG). The drug 1 1.5 h and a t½ of about 3 4 h. This information may metabolism phenotypic indices (the ratio of metabolite to help individuals select the time of tea consumption in relation parent compound) for CYP1A2, CYP2C9 and CYP2D6 to the time of taking medication whose interactions with green were not affected. However, the AUC of the plasma tea are not known. Because of the extensive black tea

Expert Opin. Drug Metab. Toxicol. (2012) 8(6) 685 C. S. Yang & E. Pan

consumption worldwide, the effects of black tea polyphenols other tea catechins could be very high, and high doses of on drug metabolism deserve more attention. There is only tea catechins may have adverse effects [4,5]. The high doses limited information on this topic. Even though these large- of supplements could have significant effects on therapeutic molecular-weight polyphenols have very low or no systemic or preventive drugs, especially when they are taken together bioavailability, they may bind to drugs directly and affect inclosetimeproximity.Moreresearchinthisareais drug transporters and drug-metabolizing enzymes in the needed. Monitoring the blood levels of drugs/metabolites intestine and affect the bioavailability of drugs. during therapy is a good practice. It may reveal differences From the studies by Chow et al. [73,75],dailyconsump- among individual patients due to not only genetic polymor- tion of 800 mg of EGCG, which is equivalent to five or phisms in drug transporters and drug-metabolizing more cups of tea, had little effect on the metabolism of enzymes, but also dietary practices, such as consumption the different types of CYP enzyme and drugs studied. We of tea and dietary supplements. may suggest that the lower doses from one or two cups of tea per day may not have a significant effect on drug metab- Declaration of interest olism, unless the drug is coadministered together with tea. Many patients and healthy people are taking dietary supple- This work was supported by grants from the U.S. NIH ments that contain high levels of catechins. As discussed, (RO1 CA120915, RO1 CA122474, and RO1 CA133021) the manufacturer’s recommended dosages of EGCG and and the JL Colaizzi Endowed Chair Fund.

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686 Expert Opin. Drug Metab. Toxicol. (2012) 8(6) The effects of green tea polyphenols on drug metabolism

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J Pharm Pharmacol of (-)-epigallocatechin-3-gallate elicited 2009;30(2):90-3 . 2005;57(3):311-16 liver and small intestine gene expression An interesting article on the effects of profiles between C57BL/6J mice and EGCG on the pharmacokinetics of 53. Niwattisaiwong N, Luo XX, Coville PF, C57BL/6J/Nrf2 (-/-) mice. Pharm Res verapamil in rats. Wanwimolruk S. Effects of Chinese, 2005;22(11):1805-20 Japanese and Western tea on hepatic 71. Liang G, Tang A, Lin X, et al. Green tea For personal use only. P450 enzyme activities in rats. 62. Catterall F, McArdle NJ, Mitchell L, catechins augment the antitumor activity Drug Metabol Drug Interact et al. Hepatic and intestinal cytochrome of doxorubicin in an in vivo mouse 2004;20(1-2):43-56 P450 and conjugase activities in rats model for chemoresistant liver cancer. . An interesting study on the effect of treated with black tea theafulvins and Int J Oncol 2010;37(1):111-23 tea on hepatic cytochrome theaflavins. Food Chem Toxicol 72. 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Biomarkers Prev 2006;15(12):2473-6 Gen Pharmacol 1997;28(5):639-45 .. The first systematic study on the Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Lib of Chinese Aca Med Sciences on 08/06/13 hepatotoxicity in mice is significantly correlated with cytochrome 65. Kitagawa S, Nabekura T, Takahashi T, effects of green tea polyphenol P450 suppression. World J Gastroenterol et al. Structure-activity relationships of administration on cytochrome 2009;15(15):1829-35 the inhibitory effects of flavonoids on P450 activities in humans. 56. Srinivasan P, Suchalatha S, Babu PV, P-glycoprotein-mediated transport in 74. Donovan JL, Chavin KD, Devane CL, et al. Chemopreventive and therapeutic KB-C2 cells. Biol Pharm Bull et al. Green tea (Camellia sinensis) modulation of green tea polyphenols on 2005;28(12):2274-8 extract does not alter cytochrome p450 drug metabolizing enzymes in 66. Nishikawa M, Ariyoshi N, Kotani A, 3A4 or 2D6 activity in healthy 4-Nitroquinoline 1-oxide induced oral et al. Effects of continuous ingestion of volunteers. Drug Metab Dispos cancer. Chem Biol Interact green tea or grape seed extracts on the 2004;32(9):906-8 2008;172(3):224-34 pharmacokinetics of midazolam. 75. Chow HH, Hakim IA, Vining DR, et al. Modulation of human glutathione

688 Expert Opin. Drug Metab. Toxicol. (2012) 8(6) The effects of green tea polyphenols on drug metabolism

s-transferases by polyphenon e 1-naphthol in a human colon carcinoma 83. Qiao J, Gu C, Shang W, et al. Effect of intervention. Cancer Epidemiol cell line, Caco-2. Biol Pharm Bull green tea on pharmacokinetics of Biomarkers Prev 2007;16(8):1662-6 2001;24(9):1076-8 5-fluorouracil in rats and .. The first report on the induction of 80. Revesz K, Tutto A, Margittai E, et al. pharmacodynamics in human cell lines in S human glutathione -transferases by Glucuronide transport across the vitro. Food Chem Toxicol green tea polyphenols in humans. endoplasmic reticulum membrane is 2011;49(6):1410-15 . 76. Williams SN, Pickwell GV, inhibited by epigallocatechin gallate and An interesting study on the effects of Quattrochi LC. A combination of tea other green tea polyphenols. Int J green tea on pharmacokinetics of (Camellia senensis) catechins is required Biochem Cell Biol 2007;39(5):922-30 5-fluorouracil in rats. for optimal inhibition of induced 81. Marnewick JL, Joubert E, Swart P, et al. CYP1A expression by green tea extract. Affiliation Modulation of hepatic drug metabolizing † J Agric Food Chem Chung S Yang 1 PhD & Eva Pan2 PharmD enzymes and oxidative status by rooibos † Author for correspondence 2003;51(22):6627-34 (Aspalathus linearis) and Honeybush 1 77. Engdal S, Nilsen OG. In vitro inhibition (Cyclopia intermedia), green and black Professor, of CYP3A4 by herbal remedies (Camellia sinensis) teas in rats. J Agric The State University of New Jersey, frequently used by cancer patients. Food Chem 2003;51(27):8113-19 Ernest Mario School of Pharmacy, Department of Chemical Biology, Rutgers, Phytother Res 2009;23(7):906-12 82. Takizawa Y, Kitazato T, Kishimoto H, 164 Frelinghuysen Road, Piscataway, 78. Mirkov S, Komoroski BJ, Ramirez J, et al. Effects of antioxidants on drug NJ 08854-8020, USA et al. Effects of green tea compounds on absorption in in vivo intestinal ischemia/ Tel: +732 445 5360; Fax: +732 445 0687; irinotecan metabolism. reperfusion. Eur J Drug E-mail: [email protected] Drug Metab Dispos 2007;35(2):228-33 Metab Pharmacokinet 2Rutgers University, Piscataway, USA 79. Isozaki T, Tamura H. Epigallocatechin 2011;35(3-4):89-95 gallate (EGCG) inhibits the sulfation of For personal use only. Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Lib of Chinese Aca Med Sciences on 08/06/13

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