Download The effects of green tea polyphenols on drug metabolism

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. Nat Rev Cancer
2009;9(6):429-39
2.
Yang CS, Lambert JD. Research on tea
and health. Pharmacol Res
2011;64(2):85-6
3.
Deka A, Vita JA. Tea and cardiovascular
disease. Pharmacol Res
2011;64(2):136-45
4.
Lambert JD, Sang S, Yang CS. Possible
controversy over dietary polyphenols:
benefits vs risks. Chem Res Toxicol
2007;20(4):583-5
A good review on the possible
beneficial and adverse effects of
tea consumption.
.
5.
Schonthal AH. Adverse effects of
concentrated green tea extracts.
Mol Nutr Food Res 2011;55(6):874-85
6.
Sang S, Lambert JD, Ho CT, Yang CS.
The chemistry and biotransformation of
tea constituents. Pharmacol Res
2011;64(2):87-99
A good review on the chemistry and
biotransformation of tea constituents.
.
7.
Products List. Dietary Supplements
Labels Database. Available from: http://
dietarysupplements.nlm.nih.gov/dietary/
brand.jsp [Cited January 2012]
8.
Hou Z, Sang S, You H, et al.
Mechanism of action of (-)epigallocatechin-3-gallate:
686
Declaration of interest
This work was supported by grants from the U.S. NIH
(RO1 CA120915, RO1 CA122474, and RO1 CA133021)
and the JL Colaizzi Endowed Chair Fund.
auto-oxidation-dependent inactivation of
epidermal growth factor receptor and
direct effects on growth inhibition in
human esophageal cancer KYSE
150 cells. Cancer Res
2005;65(17):8049-56
Papers of special note have been highlighted as
either of interest () or of considerable interest
() to readers.
1.
other tea catechins could be very high, and high doses of
tea catechins may have adverse effects [4,5]. The high doses
of supplements could have significant effects on therapeutic
or preventive drugs, especially when they are taken together
in close time proximity. More research in this area is
needed. Monitoring the blood levels of drugs/metabolites
during therapy is a good practice. It may reveal differences
among individual patients due to not only genetic polymorphisms in drug transporters and drug-metabolizing
enzymes, but also dietary practices, such as consumption
of tea and dietary supplements.
9.
Lu H, Meng X, Yang CS. Enzymology
of methylation of tea catechins and
inhibition of
catechol-O-methyltransferase by (-)epigallocatechin gallate.
Drug Metab Dispos 2003;31(5):572-9
10.
Lu H, Meng X, Li C, et al.
Glucuronides of tea catechins:
enzymology of biosynthesis and
biological activities. Drug Metab Dispos
2003;31(4):452-61
11.
Lu H. Mechanistic studies on the
Phase II metabolism and absorption of
tea catechins. Toxicology. The State
University of New Jersey; Rutgers, New
Brunswick: 2002
12.
Vaidyanathan JB, Walle T.
Glucuronidation and sulfation of the tea
flavonoid (-)-epicatechin by the human
and rat enzymes. Drug Metab Dispos
2002;30(8):897-903
13.
14.
Sang S, Lee MJ, Yang I, et al. Human
urinary metabolite profile of tea
polyphenols analyzed by liquid
chromatography/electrospray ionization
tandem mass spectrometry with
data-dependent acquisition.
Rapid Commun Mass Spectrom
2008;22(10):1567-78
Sang S, Lambert JD, Hong J, et al.
Synthesis and structure identification of
Expert Opin. Drug Metab. Toxicol. (2012) 8(6)
thiol conjugates of (-)-epigallocatechin
gallate and their urinary levels in mice.
Chem Res Toxicol 2005;18(11):1762-9
15.
Leslie EM, Deeley RG, Cole SP.
Toxicological relevance of the multidrug
resistance protein 1, MRP1 (ABCC1)
and related transporters. Toxicology
2001;167(1):3-23
16.
Hong J, Lambert JD, Lee SH, et al.
Involvement of multidrug
resistance-associated proteins in
regulating cellular levels of (-)epigallocatechin-3-gallate and its methyl
metabolites. Biochem Biophys
Res Commun 2003;310(1):222-7
17.
Hong J, Lu H, Meng X, et al. Stability,
cellular uptake, biotransformation, and
efflux of tea polyphenol (-)epigallocatechin-3-gallate in
HT-29 human colon adenocarcinoma
cells. Cancer Res 2002;62(24):7241-6
18.
Lambert JD, Sang S, Lu AY, Yang CS.
Metabolism of dietary polyphenols and
possible interactions with drugs.
Curr Drug Metab 2007;8(5):499-507
A previous review on the metabolism
of green tea polyphenols and their
possible interactions with drugs.
.
19.
Taipalensuu J, Tornblom H,
Lindberg G, et al. Correlation of gene
expression of ten drug efflux proteins of
the ATP-binding cassette transporter
family in normal human jejunum and in
human intestinal epithelial Caco-2 cell
monolayers. J Pharmacol Exp Ther
2001;299(1):164-70
The effects of green tea polyphenols on drug metabolism
20.
.
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.
21.
22.
.
23.
24.
25.
.
26.
27.
28.
Chen L, Lee MJ, Li H, Yang CS.
Absorption, distribution, elimination of
tea polyphenols in rats.
Drug Metab Dispos 1997;25(9):1045-50
The first detailed pharmacokinetics
study on green tea polyphenols.
Lambert JD, Lee MJ, Lu H, et al.
Epigallocatechin-3-gallate is absorbed but
extensively glucuronidated following oral
administration to mice. J Nutr
2003;133(12):4172-7
Yang CS, Chen L, Lee MJ, et al. Blood
and urine levels of tea catechins after
ingestion of different amounts of green
tea by human volunteers.
Cancer Epidemiol Biomarkers Prev
1998;7(4):351-4
The first study on the blood and urine
levels of tea polyphenols in humans.
Chow HH, Cai Y, Alberts DS, et al.
Phase I pharmacokinetic study of tea
polyphenols following single-dose
administration of epigallocatechin gallate
and polyphenon E. Cancer Epidemiol
Biomarkers Prev 2001;10(1):53-8
Lee MJ, Maliakal P, Chen L, et al.
Pharmacokinetics of tea catechins after
ingestion of green tea and (-)epigallocatechin-3-gallate by humans:
formation of different metabolites and
individual variability. Cancer Epidemiol
Biomarkers Prev
2002;11(10 Pt 1):1025-32
Chow HH, Cai Y, Hakim IA, et al.
Pharmacokinetics and safety of green tea
polyphenols after multiple-dose
administration of epigallocatechin gallate
and polyphenon E in healthy individuals.
Clin Cancer Res 2003;9(9):3312-19
A detailed pharmacokinetics study
after multiple doses of green tea
polyphenols in humans.
Chow HH, Hakim IA, Vining DR, et al.
Effects of dosing condition on the oral
bioavailability of green tea catechins after
single-dose administration of Polyphenon
E in healthy individuals. Clin Cancer Res
2005;11(12):4627-33
Mulder TP, van Platerink CJ,
Wijnand Schuyl PJ, van Amelsvoort JM.
Analysis of theaflavins in biological fluids
using liquid chromatography-electrospray
mass spectrometry. J Chromatogr B
Biomed Sci Appl 2001;760:271-9
Choi YH, Chin YW, Kim YG.
Herb-drug interactions: focus on
metabolic enzymes and transporters.
Arch Pharm Res 2011;34(11):1843;63
29.
..
30.
..
31.
32.
..
Ge J, Tan BX, Chen Y, et al. Interaction
of green tea polyphenol
epigallocatechin-3-gallate with sunitinib:
potential risk of diminished sunitinib
bioavailability. J Mol Med (Berl)
2011;89(6):595-602
The first report on dramatic clinical
effects of tea consumption due to
interference with drug metabolism.
Golden EB, Lam PY, Kardosh A, et al.
Green tea polyphenols block the
anticancer effects of bortezomib and
other boronic acid-based proteasome
inhibitors. Blood 2009;113(23):5927-37
A clear demonstration of the
interaction between green tea
polyphenols and bortezomib.
Kim M, Hong J. Analysis of Chemical
Interactions of (-)-Epigallocatechin-3gallate, a major green tea polyphenol,
with commonly-consumed
over-the-counter drugs.
Food Sci Biotechnol 2010;19:559-64
Chen D, Wang CY, Lambert JD, et al.
Inhibition of human liver
catechol-O-methyltransferase by tea
catechins and their metabolites:
structure-activity relationship and
molecular-modeling studies.
Biochem Pharmacol
2005;69(10):1523-31
A detailed study on the inhibition of
catechol-O-methyltransferase by green
tea polyphenols.
33.
Muto S, Fujita K, Yamazaki Y,
Kamataki T. Inhibition by green tea
catechins of metabolic activation of
procarcinogens by human cytochrome
P450. Mutat Res 2001;479(1-2):197-206
34.
Netsch MI, Gutmann H, Schmidlin CB,
et al. Induction of CYP1A by green tea
extract in human intestinal cell lines.
Planta Med 2006;72(6):514-20
35.
36.
Wanwimolruk S, Wong K,
Wanwimolruk P. Variable inhibitory
effect of different brands of commercial
herbal supplements on human
cytochrome P-450 CYP3A4.
Drug Metabol Drug Interact
2009;24(1):17-35
Kamenickova A, Vrzal R, Dvorak Z.
Effects of ready to drink teas on AhRand PXR-mediated expression of
cytochromes P450 CYP1A1 and
CYP3A4 in human cancer cell lines and
primary human hepatocytes. Food Chem
2011;131:1201-6
Expert Opin. Drug Metab. Toxicol. (2012) 8(6)
37.
Yang SP, Raner GM. Cytochrome
P450 expression and activities in human
tongue cells and their modulation by
green tea extract.
Toxicol Appl Pharmacol
2005;202(2):140-50
38.
Fong YK, Li CR, Wo SK, et al. In vitro
and in situ evaluation of herb-drug
interactions during intestinal metabolism
and absorption of Baicalein.
J Ethnopharmacol 2011
39.
Mohamed ME, Frye RF. Inhibitory
effects of commonly used herbal extracts
on UDP-glucuronosyltransferase 1A4,
1A6, and 1A9 enzyme activities.
Drug Metab Dispos 2011;39(9):1522-8
40.
Mohamed MF, Tseng T, Frye RF.
Inhibitory effects of commonly used
herbal extracts on UGT1A1 enzyme
activity. Xenobiotica 2010;40(10):663-9
41.
Shimada T. Xenobiotic-metabolizing
enzymes involved in activation and
detoxification of carcinogenic polycyclic
aromatic hydrocarbons.
Drug Metab Pharmacokinet
2006;21(4):257-76
42.
Pool-Zobel B, Veeriah S, Bohmer FD.
Modulation of xenobiotic metabolising
enzymes by anticarcinogens -- focus on
glutathione S-transferases and their role
as targets of dietary chemoprevention in
colorectal carcinogenesis. Mutat Res
2005;591(1-2):74-92
43.
Chen C, Yu R, Owuor ED, Kong AN.
Activation of antioxidant-response
element (ARE), mitogen-activated
protein kinases (MAPKs) and caspases by
major green tea polyphenol components
during cell survival and death.
Arch Pharm Res 2000;23(6):605-12
44.
Tan XL, Shi M, Tang H, et al.
Candidate dietary phytochemicals
modulate expression of phase II enzymes
GSTP1 and NQO1 in human lung cells.
J Nutr 2010;140(8):1404-10
45.
Farabegoli F, Papi A, Bartolini G, et al.
(-)-Epigallocatechin-3-gallate
downregulates Pg-P and BCRP in a
tamoxifen resistant MCF-7 cell line.
Phytomedicine 2010;17(5):356-62
46.
Jodoin J, Demeule M, Beliveau R.
Inhibition of the multidrug resistance
P-glycoprotein activity by green tea
polyphenols. Biochim Biophys Acta
2002;1542(1-3):149-59
47.
Qian F, Wei D, Zhang Q, Yang S.
Modulation of P-glycoprotein function
687
C. S. Yang & E. Pan
and reversal of multidrug resistance
by (-)-epigallocatechin gallate in human
cancer cells. Biomed Pharmacother
2005;59(3):64-9
48.
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.
49.
50.
51.
52.
53.
.
54.
55.
56.
688
Zhu A, Wang X, Guo Z. Study of tea
polyphenol as a reversal agent for
carcinoma cell lines’ multidrug resistance
(study of TP as a MDR reversal agent).
Nucl Med Biol 2001;28(6):735-40
Kitagawa S, Nabekura T, Kamiyama S.
Inhibition of P-glycoprotein function by
tea catechins in KB-C2 cells.
J Pharm Pharmacol 2004;56(8):1001-5
Mei Y, Qian F, Wei D, Liu J. Reversal
of cancer multidrug resistance by green
tea polyphenols. J Pharm Pharmacol
2004;56(10):1307-14
57.
58.
59.
.
Netsch MI, Gutmann H, Luescher S,
et al. Inhibitory activity of a green tea
extract and some of its constituents on
multidrug resistance-associated protein
2 functionality. Planta Med
2005;71(2):135-41
60.
Jang EH, Choi JY, Park CS, et al.
Effects of green tea extract administration
on the pharmacokinetics of clozapine in
rats. J Pharm Pharmacol
2005;57(3):311-16
61.
Niwattisaiwong N, Luo XX, Coville PF,
Wanwimolruk S. Effects of Chinese,
Japanese and Western tea on hepatic
P450 enzyme activities in rats.
Drug Metabol Drug Interact
2004;20(1-2):43-56
An interesting study on the effect of
tea on hepatic cytochrome
P450 enzyme activity.
Park D, Jeon JH, Shin S, et al. Green
tea extract increases
cyclophosphamide-induced teratogenesis
by modulating the expression of
cytochrome P-450 mRNA.
Reprod Toxicol 2009;27(1):79-84
Chen X, Sun CK, Han GZ, et al.
Protective effect of tea polyphenols
against paracetamol-induced
hepatotoxicity in mice is significantly
correlated with cytochrome
P450 suppression. World J Gastroenterol
2009;15(15):1829-35
Srinivasan P, Suchalatha S, Babu PV,
et al. Chemopreventive and therapeutic
modulation of green tea polyphenols on
drug metabolizing enzymes in
4-Nitroquinoline 1-oxide induced oral
cancer. Chem Biol Interact
2008;172(3):224-34
62.
Sahin K, Tuzcu M, Gencoglu H, et al.
Epigallocatechin-3-gallate activates Nrf2/
HO-1 signaling pathway in
cisplatin-induced nephrotoxicity in rats.
Life Sci 2010;87(7-8):240-5
Tulayakul P, Dong KS, Li JY, et al. The
effect of feeding piglets with the diet
containing green tea extracts or coumarin
on in vitro metabolism of aflatoxin
B1 by their tissues. Toxicon
2007;50(3):339-48
Liu TT, Liang NS, Li Y, et al. Effects of
long-term tea polyphenols consumption
on hepatic microsomal drug-metabolizing
enzymes and liver function in Wistar
rats. World J Gastroenterol
2003;9(12):2742-4
An interesting study on green tea
polyphenol consumption on
drug-metabolizing enzymes.
Maliakal PP, Coville PF,
Wanwimolruk S. Tea consumption
modulates hepatic drug metabolizing
enzymes in Wistar rats.
J Pharm Pharmacol 2001;53(4):569-77
Shen G, Xu C, Hu R, et al. Comparison
of (-)-epigallocatechin-3-gallate elicited
liver and small intestine gene expression
profiles between C57BL/6J mice and
C57BL/6J/Nrf2 (-/-) mice. Pharm Res
2005;22(11):1805-20
Catterall F, McArdle NJ, Mitchell L,
et al. Hepatic and intestinal cytochrome
P450 and conjugase activities in rats
treated with black tea theafulvins and
theaflavins. Food Chem Toxicol
2003;41(8):1141-7
63.
Borst P, Evers R, Kool M, Wijnholds J.
A family of drug transporters: the
multidrug resistance-associated proteins.
J Natl Cancer Inst
2000;92(16):1295-302
64.
Barrand MA, Bagrij T, Neo SY.
Multidrug resistance-associated protein:
a protein distinct from P-glycoprotein
involved in cytotoxic drug expulsion.
Gen Pharmacol 1997;28(5):639-45
65.
66.
Kitagawa S, Nabekura T, Takahashi T,
et al. Structure-activity relationships of
the inhibitory effects of flavonoids on
P-glycoprotein-mediated transport in
KB-C2 cells. Biol Pharm Bull
2005;28(12):2274-8
Nishikawa M, Ariyoshi N, Kotani A,
et al. Effects of continuous ingestion of
green tea or grape seed extracts on the
pharmacokinetics of midazolam.
Expert Opin. Drug Metab. Toxicol. (2012) 8(6)
Drug Metab Pharmacokinet
2004;19(4):280-9
67.
.
68.
.
Shin SC, Choi JS. Effects of
epigallocatechin gallate on the oral
bioavailability and pharmacokinetics of
tamoxifen and its main metabolite,
4-hydroxytamoxifen, in rats.
Anticancer Drugs 2009;20(7):584-8
An interesting study on the effects of
EGCG on the bioavailability and
pharmacokinetics of tamoxifen in rats.
Choi JS, Burm JP. Effects of oral
epigallocatechin gallate on the
pharmacokinetics of nicardipine in rats.
Arch Pharm Res 2009;32(12):1721-5
An interesting study on the effects of
EGCG on the pharmacokinetics of
nicardipine in rats.
69.
Li C, Choi JS. Effects of epigallocatechin
gallate on the bioavailability and
pharmacokinetics of diltiazem in rats.
Pharmazie 2008;63(11):815-18
70.
Chung JH, Choi DH, Choi JS. Effects
of oral epigallocatechin gallate on the
oral pharmacokinetics of verapamil in
rats. Biopharm Drug Dispos
2009;30(2):90-3
An interesting article on the effects of
EGCG on the pharmacokinetics of
verapamil in rats.
.
71.
Liang G, Tang A, Lin X, et al. Green tea
catechins augment the antitumor activity
of doxorubicin in an in vivo mouse
model for chemoresistant liver cancer.
Int J Oncol 2010;37(1):111-23
72.
Lin LC, Wang MN, Tsai TH.
Food-drug interaction of (-)epigallocatechin-3-gallate on the
pharmacokinetics of irinotecan and the
metabolite SN-38. Chem Biol Interact
2008;174(3):177-82
73.
Chow HH, Hakim IA, Vining DR, et al.
Effects of repeated green tea catechin
administration on human cytochrome
P450 activity. Cancer Epidemiol
Biomarkers Prev 2006;15(12):2473-6
The first systematic study on the
effects of green tea polyphenol
administration on cytochrome
P450 activities in humans.
..
74.
Donovan JL, Chavin KD, Devane CL,
et al. Green tea (Camellia sinensis)
extract does not alter cytochrome p450
3A4 or 2D6 activity in healthy
volunteers. Drug Metab Dispos
2004;32(9):906-8
75.
Chow HH, Hakim IA, Vining DR, et al.
Modulation of human glutathione
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.
76.
s-transferases by polyphenon e
intervention. Cancer Epidemiol
Biomarkers Prev 2007;16(8):1662-6
The first report on the induction of
human glutathione S-transferases by
green tea polyphenols in humans.
Williams SN, Pickwell GV,
Quattrochi LC. A combination of tea
(Camellia senensis) catechins is required
for optimal inhibition of induced
CYP1A expression by green tea extract.
J Agric Food Chem
2003;51(22):6627-34
77.
Engdal S, Nilsen OG. In vitro inhibition
of CYP3A4 by herbal remedies
frequently used by cancer patients.
Phytother Res 2009;23(7):906-12
78.
Mirkov S, Komoroski BJ, Ramirez J,
et al. Effects of green tea compounds on
irinotecan metabolism.
Drug Metab Dispos 2007;35(2):228-33
79.
Isozaki T, Tamura H. Epigallocatechin
gallate (EGCG) inhibits the sulfation of
1-naphthol in a human colon carcinoma
cell line, Caco-2. Biol Pharm Bull
2001;24(9):1076-8
80.
81.
82.
Revesz K, Tutto A, Margittai E, et al.
Glucuronide transport across the
endoplasmic reticulum membrane is
inhibited by epigallocatechin gallate and
other green tea polyphenols. Int J
Biochem Cell Biol 2007;39(5):922-30
Marnewick JL, Joubert E, Swart P, et al.
Modulation of hepatic drug metabolizing
enzymes and oxidative status by rooibos
(Aspalathus linearis) and Honeybush
(Cyclopia intermedia), green and black
(Camellia sinensis) teas in rats. J Agric
Food Chem 2003;51(27):8113-19
Takizawa Y, Kitazato T, Kishimoto H,
et al. Effects of antioxidants on drug
absorption in in vivo intestinal ischemia/
reperfusion. Eur J Drug
Metab Pharmacokinet
2011;35(3-4):89-95
Expert Opin. Drug Metab. Toxicol. (2012) 8(6)
83.
.
Qiao J, Gu C, Shang W, et al. Effect of
green tea on pharmacokinetics of
5-fluorouracil in rats and
pharmacodynamics in human cell lines in
vitro. Food Chem Toxicol
2011;49(6):1410-15
An interesting study on the effects of
green tea on pharmacokinetics of
5-fluorouracil in rats.
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