Tea polyphenols prevention of cancer and optimizing health

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ABSTRACT

The tea plant Camellia sinesis is cultivated in

> 30 countries. Epidemiologic observations and laboratory studies
have indicated that polyphenolic compounds present in tea may
reduce the risk of a variety of illnesses, including cancer and coro-
nary heart disease. Most studies involved green tea, however; only
a few evaluated black tea. Results from studies in rats, mice, and
hamsters showed that tea consumption protects against lung,
forestomach, esophagus, duodenum, pancreas, liver, breast, colon,
and skin cancers induced by chemical carcinogens. Other studies
showed the preventive effect of green tea consumption against ath-
erosclerosis and coronary heart disease, high blood cholesterol con-
centrations, and high blood pressure. Because the epidemiologic
studies and research findings in laboratory animals have shown the
chemopreventive potential of tea polyphenols in cancer, the useful-
ness of tea polyphenols for humans should be evaluated in clinical
trials. One such phase 1 clinical trial is currently under way at the
MD Anderson Cancer Center in collaboration with Memorial Sloan-
Kettering Cancer Center. This study will examine the safety and
possible efficacy of consuming the equivalent of

10 cups (

2.4 L)

of green tea per day. The usefulness of tea polyphenols may be
extended by combining them with other consumer products such as
food items and vitamin supplements. This “designer-item” approach
may be useful for human populations, but it requires further study.
Am J Clin Nutr 2000;71(suppl):1698S–1702S.

KEY WORDS

Tea polyphenols, coronary heart disease,

cancer, EGCG, (

2)-epigallocatechin-3-gallate, antioxidant

INTRODUCTION

Significant progress has been made in understanding diseases

that cause alarming mortality and morbidity in humans: their
processes, possible prevention, and therapies. Cancer and coro-
nary heart disease are the most important of these disorders.
Because of research efforts over the past 30 y, it is now well
appreciated that although the causes of the major diseases are
diverse and countless, changes in dietary habits and lifestyles
may reduce their risk in many cases. Research has indicated that
many common foods have nonnutritive components, commonly
known as chemopreventive agents, that may provide protection
against a variety of illnesses, including cancer and coronary
heart disease. One such class of agents is antioxidants. The pre-
dominant mechanism of protective action of antioxidants
appears to be the destruction of free radicals.

The water extract of the dry leaves of the plant Camellia sinesis,

an evergreen shrub of the Theaceae family, is a popular beverage

commonly known as tea. A drink that contains many compounds,
including a mixture of polyphenols, tea has been consumed by
some human populations for many generations and, in some parts
of the world, has been considered to have health-promoting poten-
tial (1). Extensive laboratory research and the epidemiologic find-
ings of the past 20 y have shown that polyphenolic compounds
present in tea may reduce the risk of a variety of illnesses.

CONSUMPTION, COMPOSITION, AND CHEMISTRY
OF TEA

The tea plant C. sinensis is native to Southeast Asia but is cur-

rently cultivated in > 30 countries around the world. Tea is con-
sumed worldwide, although in greatly different amounts; it is
generally accepted that, next to water, tea is the most consumed
beverage in the world, with per capita consumption of

<120 mL/d

(2). Of the total amount of tea produced and consumed in the
world, 78% is black, 20% is green, and < 2% is oolong tea. Black
tea is consumed primarily in Western countries and in some
Asian countries, whereas green tea is consumed primarily in
China, Japan, India, and a few countries in North Africa and the
Middle East. Oolong tea production and consumption are con-
fined to southeastern China and Taiwan (2).

Green, black, and oolong teas undergo different manufactur-

ing processes. To produce green tea, freshly harvested leaves are
rapidly steamed or pan-fried to inactivate enzymes, thereby pre-
venting fermentation and producing a dry, stable product. Epi-
catechins are the main compounds in green tea, accounting for
its characteristic color and flavor.

For the production of black and oolong teas, the fresh leaves

are allowed to wither until their moisture content is reduced to
<55% of the original leaf weight, which results in the concentra-
tion of polyphenols in the leaves. The withered leaves are then
rolled and crushed, initiating fermentation of the polyphenols.
During these processes, the catechins are converted to theaflavins
and thearubigins. Oolong tea is prepared by firing the leaves
shortly after rolling to terminate the oxidation and dry the leaves.

Am J Clin Nutr 2000;71(suppl):1698S–1702S. Printed in USA. © 2000 American Society for Clinical Nutrition

Tea polyphenols: prevention of cancer and optimizing health

1–3

Hasan Mukhtar and Nihal Ahmad

1698S

1

From the Department of Dermatology, Case Western Reserve University,

Cleveland.

2

Presented at the 17th Ross Research Conference on Medical Issues, held

in San Diego, February 22–24, 1998.

3

Address reprint requests to H Mukhtar, Department of Dermatology,

Case Western Reserve University, 11100 Euclid Avenue, Cleveland, OH
44106. E-mail: hxm4@po.cwru.edu.

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Normal oolong tea is considered to be about half as fermented as
black tea. The fermentation process results in oxidation of simple
polyphenols to more complex condensed polyphenols to give
black and oolong teas their characteristic colors and flavors.

The composition of the tea leaves depends on a variety of fac-

tors, including climate, season, horticultural practices, and the
type and age of the plant. The chemical composition of green tea
is similar to that of the leaf. Green tea contains polyphenolic
compounds, which include flavanols, flavandiols, flavonoids,
and phenolic acids and account for 30% of the dry weight of green
tea leaves. Most of the polyphenols in green tea are flavanols,
commonly known as catechins; the major catechins in green tea are
(

2)-epicatechin, (2)-epicatechin-3-gallate, (2)-epigallocatechin,

and (

2)-epigallocatechin-3-gallate (EGCG). In black teas, the

major polyphenols are theaflavin and thearubigin. The structures
of the major polyphenolic compounds present in green and black
tea are shown in Figure 1.

TEA POLYPHENOLS AND THE RISK OF CANCER

Abundant experimental and epidemiologic evidence accumu-

lated mainly in the past decade from several centers worldwide
provides a convincing argument that polyphenolic antioxidants
present in green and black tea can reduce cancer risk in a variety
of animal tumor bioassay systems (2–4). Most of the studies
showing the preventive effects of tea were conducted with green
tea; only a few studies assessed the usefulness of black tea (2).
These studies showed that the consumption of tea and its
polyphenolic constituents affords protection against chemical
carcinogen– or ultraviolet radiation–induced skin cancer in the
mouse model. Tea consumption also affords protection against
cancers induced by chemical carcinogens that involve the lung,
forestomach, esophagus, duodenum, pancreas, liver, breast,
colon, and skin in mice, rats, and hamsters. We reviewed this

area of research (2), and the bioavailability of the polyphenols
from tea has been established by others (5). The relevance of the
extensive laboratory information for human health can be
assessed only through epidemiologic observations, however,
especially in a population with high cancer risk.

Much of the cancer-preventive effects of green tea are medi-

ated by EGCG , the major polyphenolic constituent of green tea
(2). One cup (240 mL) of brewed green tea contains up to 200 mg
EGCG. Many consumer products, including shampoos, creams,
drinks, cosmetics, lollipops, and ice creams, have been supple-
mented with green tea extracts and are available in grocery stores
and pharmacies.

The use of biochemical modulators in cancer chemotherapy

has been studied extensively (6). The adverse effects of modu-
lating drugs can be life threatening, and their use increases the
patient’s medication burden as well. Thus, the substances used in
diet and beverages should be studied for their potential as bio-
chemical modulators that could increase the efficacy of therapy.
In this regard, Sadzuka et al (6) showed that the oral administra-
tion of green tea enhanced the tumor-inhibitory effects of dox-
orubicin on Ehrlich ascites carcinomas implanted in CDF

1

and

BDF

1

mice. The study showed that green tea treatment increases

the concentration of doxorubicin in tumor but not in normal tis-
sue. If these observations can be verified in human populations,
they may have relevance to cancer chemotherapy.

TEA POLYPHENOLS AND THE RISK OF CORONARY
HEART DISEASE

Coronary heart disease is most prevalent in the Western world,

probably as a result of the lifestyle in this part of the world, which
includes a diet high in saturated fats and low physical activity,
and the large proportion of the population who smoke cigarettes
and have high blood pressure. A variety of epidemiologic

TEA POLYPHENOLS

1699S

FIGURE 1. Major polyphenols present in green and black tea.

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studies showed the preventive effect of green tea consumption
against atherosclerosis and coronary heart disease (see refer-
ences 1 and 7 and the references therein). Tea consumption has
also been shown to reduce the risk of high blood cholesterol con-
centrations and high blood pressure (8). In addition, studies in
experimental animals showed the preventive effect of green tea
against atherosclerosis (9).

EFFECTS OF TEA POLYPHENOLS AGAINST OTHER
DISEASES

Many studies have shown that the consumption of tea or its

polyphenols can afford protection against diseases other than
cancer and coronary heart disease. A few of these studies are as
follows: Weisburger (10) showed that tea is protective against
stroke; Fujita (11) and Kao and P’eng (12) reported that tea con-
sumption lowers the risk of osteoporosis; Imai and Nakachi (13)
reported protection against liver disease; Horiba et al (14), Ter-
ada et al (15), and Young et al (16) reported that tea consumption
provides protection against bacterial infection; and Nakayama et
al (17) and Tao (18) found that tea provides protection against
viral infection.

ANTIINFLAMMATORY EFFECTS OF TEA

In several studies from our laboratory and elsewhere, the

polyphenolic fraction from green tea was shown to protect
against inflammation caused by certain chemicals, such as 12-O-
tetradecanoylphorbol-13-acetate, a principal irritant in croton oil
(2, 19, 20), or by ultraviolet radiation B (290–320 nm) (21).
Green tea has also been shown to be effective against the
immunosuppression caused by ultraviolet radiation B (2, 22). In
addition, green tea polyphenols have shown protection against
cytokines induced by tumors (23).

MECHANISMS OF BIOLOGICAL EFFECTS OF TEA

Because tea consumption has been shown to have protective

effects against a variety of diseases, defining the mechanisms of
the biological effects of tea is important. In addition, elucidation
of mechanisms may provide additional opportunities to intervene
at other targets. Initial mechanistic studies (reviewed in reference
2) regarding the cancer chemopreventive effects of green tea or its
polyphenols largely focused on 1) protection against mutagenic-
ity and genotoxicity, 2) inhibition of biochemical markers of
tumor initiation, 3) inhibition of biochemical markers of tumor
promotion, 4) effects on detoxification enzymes, 5) trapping of
activated metabolites of carcinogens, and 6) antioxidant and free
radical scavenging activity. Novel mechanistic work to define the
anticarcinogenic effects of polyphenolic extracts from green tea
and its constituents has been pursued; recent advances in this area
are described in the following sections.

Green tea activates mitogen-activated protein kinases

The activation of mitogen-activated protein kinases by green

tea polyphenols was shown to be a potential signaling pathway
in the regulation of phase II enzyme gene expression mediated
by an antioxidant-responsive element (24). In this study, green
tea polyphenols induced chloramphenicol acetyltransferase
(CAT) activity in human hepatoma HepG2 cells transfected with
a plasmid construct containing an antioxidant-responsive ele-

ment and a minimal glutathione S-transferase Ya promoter linked
to the CAT reporter gene. This result indicates that green tea
polyphenols stimulate the transcription of phase II detoxifying
enzymes through the antioxidant-responsive element. In addi-
tion, green tea polyphenol treatment of HepG2 cells resulted in a
significant activation of extracellular signal–regulated kinase 2
and c-Jun N-terminal kinase 1, which are members of the mitogen-
activated protein kinase family. Green tea polyphenol treatment
also increased messenger RNA amounts of the immediate-early
genes c-jun and c-fos.

EGCG inhibits urokinase activity

A widely publicized study showed that the anticancer activity

of EGCG in green tea might be due to inhibition of the enzyme
urokinase (u-plasminogen activator), one of the most frequently
expressed enzymes in human cancers (25). With the use of
molecular modeling, the authors showed that EGCG binds to
urokinase, blocking His 57 and Ser 195 of the urokinase catalytic
triad and extending toward Arg 35 from a positively charged loop
of urokinase. This computer-based calculation was verified by
quantifying the inhibition of urokinase activity with a spec-
trophotometric amidolytic assay. The validity of this finding has
been challenged, however (26).

Green tea induces apoptosis and cell cycle arrest

In recent years, apoptosis has become a challenging area of

biomedical research. The life spans of both normal and cancer
cells within living systems are thought to be significantly affected
by the rate of apoptosis, a programmed type of cell death that dif-
fers from necrotic cell death and is regarded as a normal process
of cell elimination (27). It follows that the chemopreventive
agents that can modulate apoptosis and thereby affect the steady
state cell population may be useful in the management and ther-
apy of cancer. Many cancer-chemopreventive agents induce apo-
ptosis and, conversely, several tumor promoters inhibit apoptosis
(28–30). It is reasonable, therefore, to assume that chemopreven-
tive agents that have proven effects in animal tumor bioassay sys-
tems or human epidemiologic studies on the one hand and that
induce apoptosis of cancer cells on the other hand may have
wider implications for the management of cancer. Only a few
chemopreventive agents are known to cause apoptosis, however
(31). We found that EGCG induced apoptosis and cell cycle arrest
in human epidermoid carcinoma cells A431 (32). Importantly, we
also found that the apoptotic response of EGCG was specific to
cancer cells, because the induction of apoptosis was also
observed in human carcinoma keratinocytes HaCaT, human
prostate carcinoma cells DU145, and mouse lymphoma cells LY-R
but not in normal human epidermal keratinocytes.

EGCG suppresses extracellular signals and cell proliferation
through epidermal growth factor receptor binding

Liang et al (33) showed that EGCG could significantly inhibit

DNA synthesis in A431 cells. In addition, EGCG inhibited the
protein tyrosine kinase activities of epidermal growth factor
(EGF) receptor, platelet-derived growth factor receptor, and
fibroblast growth factor receptor but not of pp60

v-src

, protein

kinase C, and protein kinase A. EGCG also inhibited the phos-
phorylation of EGF receptor by EGF and blocked the binding of
EGF to its receptor. These findings suggest that EGCG might
inhibit the process of tumor formation by blocking cellular sig-
nal transduction pathways.

1700S

MUKHTAR AND AHMAD

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EGCG blocks the induction of nitric oxide synthase by
down-regulating transcription factor nuclear factor

kB

Lin and Lin (34) assessed the effects of EGCG on nitric oxide

production by murine peritoneal macrophages. Their results sug-
gest that EGCG blocked early events of nitric oxide synthase
induction by inhibiting the binding of transcription factor
nuclear factor

kB to the inducible nitric oxide synthase (iNOS)

promoter, thereby inhibiting the induction of iNOS transcription.

EGCG and theaflavins inhibit tumor promoter-induced
activator protein 1 activation and cell transformation

To examine antitumor promotion effects of EGCG and

theaflavins at the molecular level, Dong et al (35) used a JB6
mouse epidermal cell line, a system that has been used exten-
sively as an in vitro model for tumor promotion studies. EGCG
and theaflavins inhibited EGF- or 12-O-tetradecanoyl-phorbol-
13-acetate–induced cell transformation in a dose-dependent
manner. EGCG and theaflavins also inhibited activator protein 1
(AP-1)-dependent transcriptional activity and DNA binding
activity. Finally, this study showed that the inhibition of AP-1
activation occurs through the inhibition of a pathway dependent
on c-Jun N-terminal kinase.

TEA AND CLINICAL TRIALS

Because epidemiologic studies and research findings in labo-

ratory animals have shown the chemopreventive potential of tea
polyphenols in cancer, the usefulness of these polyphenols for
humans should be evaluated in clinical trials. The first such trial
is being conducted by the MD Anderson Cancer Center in col-
laboration with the Memorial Sloan-Kettering Cancer Center; MD
Anderson has obtained an Investigational New Drug application
permit from the US Food and Drug Administration to begin
phase 1 clinical trials. To examine the safety and possible effi-
cacy of consuming the equivalent of

10 cups (

2.4 L) of green

tea/d, 30 cancer patients with advanced solid tumors will be
given daily capsules of formulated powdered green tea for

6 mo

(if the treatment appears beneficial).

CONCLUSION AND FUTURE DIRECTIONS

Dietary habits influence the risk of developing a variety of

diseases, especially cancer and heart disease. The use of dietary
substances is receiving increasing attention as a practical
approach for reducing the risk of developing these diseases. Epi-
demiologic observations and laboratory studies have indicated
that tea consumption may have beneficial effects in reducing
certain types of cancer in some populations. Although a consid-
erable body of information provides evidence supporting the pre-
ventive potential of tea against cancer, a proper understanding of
the mechanisms by which tea polyphenols reduce the risk of dis-
eases is necessary to devise strategies for better health. Black tea
is the major form of tea consumed, but its chemistry, biological
activities, and chemopreventive properties, especially of the
polyphenols that are present, are not well defined.

Because information on the bioavailability of tea polyphenols

after tea consumption is limited in humans, studies on absorp-
tion, distribution, and metabolism of green and black tea
polyphenols in animals and humans are needed. After careful
evaluation of the available data and additional studies, specific

recommendations may be made for consumption of tea by
humans. The usefulness of tea polyphenols may be extended by
combining them with other consumer products, such as food
items and vitamin supplements. This “designer-item” approach
may be useful for the human population.

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1702S

MUKHTAR AND AHMAD

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