Abstract: The aim of this review is to focus some light on the beneficial effects of the tea polyphenols on human health, based on various laboratory, epidemiological and clinical studies carried out on tea and tea polyphenols in the last few years. Tea is second only to water as the most consumed beverage in the world. Tea has been consumed worldwide since ancient times to maintain and improve health. The health benefits associated with tea consumption have resulted in the wide inclusion of green tea extracts in botanical dietary supplements, which are widely consumed as adjuvants for complementary and alternative medicines. Depending upon the level of fermentation, tea can be categorized into three types: green (unfermented), oolong (partially fermented) and black (highly to fully fermented). Black tea represents approximately 78% of total consumed tea in the world, whereas green tea accounts for approximately 20% of tea consumed. Tea is particularly rich in polyphenols, including catechins, theaflavins and thearubigins, which are thought to contribute to the health benefits of tea. Tea polyphenols comprise about one-third of the weight of the dried leaf and they exhibit biochemical and pharmacological activities including antioxidant activities, inhibition of cell proliferation, induction of apoptosis, cell cycle arrest and modulation of carcinogen metabolism. Several studies demonstrate that most tea polyphenols exert their effects by scavenging Reactive Oxygen Species (ROS) since excessive production of ROS has been implicated in the development of a variety of ailments including cancer of the prostate gland (CaP). Tea catechins include (-)-epicatechin (EC),(-)-epigallocatechin (EGC), (-)-epicatechin gallate (ECG) and (-)-epigallocatechin gallate (EGCG). These catechins have been shown to be epimerized to (-)-catechin (C), (-)-gallocatechin (GC), (-)-catechin gallate (CG) and (-)-gallocatechin gallate (GCG), respectively, during heat treatment. Tea polyphenols act as antioxidants in vitro by scavenging reactive oxygen and nitrogen species and chelating redox-active transition metal ions. Among the health-promoting effects of tea and tea polyphenols, the cancer-chemopreventive effects in various animal model systems have been intensively investigated; meanwhile, the hypolipidemic and antiobesity effects in animals and humans have also become a hot issue for molecular nutrition and food research. In vitro and animal studies provide strong evidence that tea polyphenols may possess the bioactivity to affect the pathogenesis of several chronic diseases, especially cardiovascular disease and cancer. Research conducted in recent years reveals that both black and green tea have very similar beneficial attributes in lowering the risk of many human diseases, including several types of cancer and heart diseases.
INTRODUCTION
Plants are the essential source of medicines. Through the advances in pharmacology and synthetic organic chemistry, the dependence on natural products, remain unchanged (Roopashree et al., 2008). In India, the majority of populations use traditional natural preparation derived from the plant material for the treatment of various diseases (Siddique et al., 2006a) and for that reason it has become necessary to assess their antimutagenic potential or mutagenic potential for modulating the action of plant extract when associated with other substances. The genotoxicity testing provides human a risk assessment. The earlier studies have shown that various plant extracts and natural plant products possess protective role against the genotoxic effects of certain estrogens, synthetic progestins and anticancerous drugs in cultured human lymphocytes (Siddique and Afzal, 2004; Siddique and Afzal, 2005a, b; Beg et al., 2007a, b; Siddique and Afzal, 2005, 2006a-c, 2007a-c, 2008a,b) and mice bone marrow cells (Siddique et al., 2006d, 2008c). Since the plant extracts have compounds that may either enhance or reduce the genotoxic effect of a particular compound, the knowledge of particular plant extract will contribute for us to form the basis of herbal medicine (Roncada et al., 2004). The antigeotoxic potential of the plant extracts have been attributed to their total phenolic content (Maurich et al., 2004). Medicinal herbs contain complex mixtures of thousands of compounds that can exert their antioxidant and free radical scavenging effect either separately or in synergistic ways (Romero- Jimenez et al., 2005).
Plant flavanoids and antimutagenicity: One or the other kind of chemical is being used for almost every activity in our daily life. A large number of substances such as drugs, cosmetics, pesticides and petroleum products have been established as mutagens (Marshall et al., 1976; Hahn et al., 1991) Ames Test confirmed that several components of the human diet contains a great variety of natural mutagens or ‘nature`s pesticides`(Kawai et al., 2006). The main danger of such wide spread and inadvertant exposure lies in the danger of their potential of enhancing genetic load. The environmental mutagens are attributed to several human ills like cancer, atheroscerlosis and ageing (Jensen et al., 1990). Thus, the increasing wide use of these mutagens in almost every sphere of human life, requires an urgent need for studies on the possibility of intervention through antimutagenic action. A large number of natural substances are capable of inactivating environmental mutagens. The characterization of these substances is also important for the possibility of intervention using them as chemotherapeutic or prophylactic agents against human ill healths attributable to mutations. These substances are termed as antimutagens (Yamamoto and Gaynor, 2006). They are found in various food items in variable quantities. The chemicals present in plants like Flavanoids, Vitamins A, C, E, Beta- carotenes etc. are some of the important antimutagens. Ames Test has been used generally to identify and characterise antimutagenic potentials of natural plant extracts (Azizan and Blevins, 1995). Flavonoids are widely distributed in plants fulfilling many functions including producing yellow or red/blue pigmentation in flowers and protection against attack by microbes and insects. These flavanoids have been found to possess antitumor properties in animal models (Kandaswami et al., 2005). The term Flavonoids according to IUPAC Compendium of Chemical Terminology refers to a class of plant secondary metabolites. They can be classified into:
| • | Flavonoids, derived from 2-phenylchromen-4-one (2-phenyl-1,4-benzopyrone) structure |
| • | Isoflavonoids, derived from 3-phenylchromen-4-one (3-phenyl-1,4-benzopyrone) structure |
| • | Neoflavonoids, derived from 4-phenylcoumarine (4-phenyl-1,2-benzopyrone) structure |
Plant polyphenols like quercetin, rutin, catechins, chlorogenic acid, pyrocatechol etc. exhibit antimuagenicity against N- Methyl N-Nitrosoguanidine, Benzo (α) pyrene and UV- induced mutations in Ames Test. Dietary research on the impact of foods and beverages on human health has been globally dominant in the last decade. Flavonoids, a group of phenolic compounds occurring abundantly in vegetables, fruits and green plants, attracted special attention as they showed high antioxidant property. The antioxidants are known to prevent cellular damage caused by reactive oxygen species. Catechins are highly potent flavonoids present in tea and serve perhaps as the best dietary source of natural antioxidants. The tea shrub (genus Camellia, family Theaceae) [chromosome number (2n = 30)] is a perennial evergreen with its natural habitat in the tropical and sub tropical forests of the world. Cultivated varieties are grown widely in its home countries of South and South East Asia, as well as in parts of Africa and the Middle East. Based on differences in morphology between Camellia sinensis var. assamica and Camellia sinensis var. sinensis, botanists have long asserted a dual botanical origin for tea (Yamamoto et al., 1994). Camellia sinensis var. assamica is native to the area from Yunnan province, China to the northern region of Myanmar and the state of Assam in India. Camellia sinensis var. sinensis is native to eastern and southeastern China (Yamamoto et al., 1994). Historical references to tea date back to 5,000 years. Tea was consumed even earlier by the indigenous peoples of China. Tea recorded as having medicinal value in a Chinese medical book (Maciocia, 2005). In Chinese and Indian traditional medicine, tea has been used for: treatment of insomnia, calming effects, mental and visual clarity, thirst quenching, detoxification of poisons, improving digestion, prevention of indigestion, breaking down oils, fats, body temperature regulation improving urination, speeding bowel evacuation, treatment of dysentery, loosening of phlegm, strengthening of teeth, treatment of epigastric pain, treatment of skin fungus, reducing hunger and longevity.
Tea processing: Leaves of Camellia sinensis soon begin to wilt and oxidize if not dried quickly after picking. The leaves turn progressively darker because chlorophyll breaks down and tannins are released. This process, enzymatic oxidation, is called fermentation. Tannins, a group of simple and complex phenol, polyphenols and flavonoid compounds produced by plants, are relatively resistant to digestion or fermentation (Abe et al., 2008). The next step in processing is to stop the oxidation process at a predetermined stage by heating, which deactivates the enzymes responsible. Processing involves following steps (Werkhoven, 1978):
| • | Withering (the process of letting leaves lose moisture content after plucking; often the first step in the processing of tea) |
| • | Rolling (ruptures cell walls allowing the polyphenols to become oxidized).s |
| • | Fermenting (the process of the polyphenols becoming oxidized) |
| • | Firing (Halts the fermentation process and begins desiccation) |
| • | Drying (reduces moisture content to make the final product more stable) |
The various types of tea are made by different combinations of these processes.
The young shoots or flushes are plucked and processed into green (unfermented), black (fermented), oolong (red, partially fermented) or yellow (partially fermented) teas. In fermented teas, the action of leaf oxidizing enzymes, convert the tannins and catechins in tea leaves into brown/red colored products.
Tea is a rich source of polyphenols called flavonoids, the effective
antioxidants found throughout the plant kingdom. The slight astringent,
bitter taste of green tea is attributed to polyphenols. A group of flavonoids
in green tea are known as catechins, which are quickly absorbed into the
body and are thought to contribute to some of the potential health benefits
of tea. The fresh tea leaves contain four major catechins as colourless
water soluble compounds: epicatechin (EC), epicatechin gallate (ECG),
epigallocatechin (EGC) and epigallocatechin gallate (EGCG) (Zhu et
al., 2000) (Fig. 1). EGCG makes up about 10-50%
of the total catechin content and appears to be the most powerful of the
catechins. In a fresh tea leaf, catechins can be up to 30% of the dry
weight. Catechins are highest in concentration in white and green teas,
while black tea has substantially less content due to its oxidative preparation.
Catechin levels reported for black teas ranged from 5.6-47.5 mg g-1.
In green teas catechin levels ranged from 51.5-84.3 mg g-1,
with epigallocatechin gallate (EGCG) being the main catechin in Chinese
and Indian green teas. Tea contains theanine and the stimulant caffeine
at about 3% of its dry weight, translating to between 30 and 90 mg per
0.25 L cup depending on type and brand and brewing method. Tea also contains
small amounts of theobromine and theophylline. Tea also contains fluoride,
with certain types of brick tea made from old leaves and stems having
the highest levels. The health benefits of tea ranging from a lower risk
of certain cancers to weight loss and protection against Alzheimer`s,
have been linked to the polyphenol content of the tea. Green tea contains
between 30 and 40% of water-extractable polyphenols, while black tea (green
tea that has been oxidized by fermentation) contains between 3 and 10%.
Oolong tea is semi-fermented tea and is somewhere between green and black
tea. Dried green tea leaves contain about 30-40% Catechins, 3-6% Caffeine,
~310 mg polyphenols per 6 ounces, while black tea (Crushed tea leaves
→ Polyphenol oxidase → Oxidation? Polymerization) contains 3-10%
Catechins, 2-6% Theaflavins, > 20% Thearubigins, 3-6% Caffeine, ~340
mg polyphenols per 6 ounces. (According to Nutritional Science Research
Group, Division of Cancer Prevention). Both catechins and theaflavins
have recently received much attention as protective agents against cardiovascular
disease and cancer. (Imai and Nakachi, 1985; Buschman, 1998; Yang, 1999).
They are also believed to have a wide range of other pharmaceutical benefits,
including antihypertensive (Henry and Srepens-Larson, 1984; Hara et
al., 1987), antioxidative (Zhang et al., 1997; Halder and Bhaduri,
1998) hypolipidemic (Chan et al., 1999; Kono et al., 1992)
activities.
| Fig. 1: | Main catechin components of green tea polyhenols |
| Fig. 2: | Main polyphenols found in black and oolong tea |
Most of the green tea catechins, during the manufacture of black tea, are oxidized and converted into orange or brown products known as theaflavins (TF) and thearubigins (TR). These compounds retain the basic C6-C3-C6 structure and are thus still classified as flavonoids. Theaflavins consist of two catechin molecules joined together and account for about 10% of the converted catechins, whereas the thearubigins are more complex flavonoid molecules, whose structural chemistry are still unknown and may account for up to 70% of flavonoids in black tea. The major TF in black and oolong tea are theaflavin (TF1), theaflavin-3-gallate (TF2A), theaflavin-3`-gallate (TF2B) and theaflavin-3,3`-digallate (TF3) (Zhu et al., 2000) (Fig. 2). Theaflavins and Thearubigins are responsible for the characteristic color and flavor of black tea. Hence it is rightly quoted by Bernard-Paul Heroux, a Basque Philosopher that There is no trouble so great or grave that cannot be much diminished by a nice cup of tea.
The health benefits of tea ranging from a lower risk of certain cancers to weight loss and protection against Alzheimer`s, have been linked to the polyphenol content of the tea (Table 1-4). It is generally believed that possible beneficial health effects of tea polyphenols are due to their anti-oxidant activity, wrote lead author Hui Cheng Lee from the National University of Singapore.
METHODS
Studies on tea polyphenols were done through computerized literature searches using the following databases: Medline, Abstract (Pubmed), Embase, Amed, Google Advanced Search. Only studies indicating the type of tea polyphenols and biological effects of tea and tea polyphenols were included. No language restrictions were imposed. Various studies on tea polyphenols have been summarized in tabular form as follows.
RESULTS AND DISCUSSION
Thus we have seen that all of the above findings clearly report the important biological effects of tea polyphenols. Green tea, being a rich source of polyphenols, contributes to various beneficial health effects (Cabrera et al., 2006).
Tea and cancer: As interpreted from the above data, it follows
that (EGCG) epigallocatechin gallate, a major catechin of found in green
tea, has possible role in chemoprevention and chemotherapy of various
types of cancers mainly prostate cancer (Siddiqui et al., 2006a,
2007e; Lyn-Cook et al., 1999) and colon cancer (Xiao et al.,
2008; Yuan et al., 2007) (Table 1, 2).
EGCG inhibits the growth of gastric cancer by reducing VEGF production
and angiogenesis and is a promising candidate for anti-angiogenic treatment
of gastric cancer (Zhu et al., 2007). Green tea extracts contain
a unique set of catechins that possess biologic activity in antioxidant,
antiangiogenesis and antiproliferative assays that are potentially relevant
to the prevention and treatment of various forms of cancer (Cooper et
al., 2005a,b). Green tea and (-)-epigallocatechin gallate (EGCG) are
now acknowledged cancer preventives in Japan and has made it possible
for us to establish the concept of a cancer preventive beverage (Fujiki
et al., 2002). Green tea polyphenols inhibit angiogenesis and metastasis
(Isemura et al., 2000; Ju et al., 2007) and induce growth
arrest and apoptosis through regulation of multiple signaling pathways.
Catechins are involved in cellular thiol-dependent activation of mitogenic-activated
protein kinases (Opare Kennedy et al., 2001). Specifically, EGCG
regulates expression of VEGF, matrix metalloproteinases, uPA, IGF-1, EGFR,
cell cycle regulatory proteins and inhibits NFk B, PI3-K/Akt, Ras/Raf/MAPK
and AP-1 signaling pathways, thereby causing strong cancer chemopreventive
effects (Shankar et al., 2007a). (-) -EGCG revealed a wide range
of target organs for cancer prevention (Fujiki, 2005). Both (-)-epigallocatechin-3-gallate
and theaflavin-3,3`-digallate (major green and black tea polyphenols,
respectively) inhibit the phosphorylation of c-jun and p44/42 (ERK 1/2).
The galloyl structure on the B ring and the gallate moiety are important
for the inhibition (Yang et al., 2000). Most of the relevant mechanisms
of cancer prevention by tea polyphenols are not related to their redox
properties, but are due to the direct binding of the polyphenol to target
molecules, including the inhibition of selected protein kinases, matrix
metalloproteinases and DNA methyltransferases. It has been shown that,
through several mechanisms, tea polyphenols present antioxidant and anticarcinogenic
activities, thus affording several health benefits (González de
Mejia, 2003). Animal studies offer a unique opportunity to assess the
contribution of the antioxidant properties of tea and tea polyphenols
to the physiological effects of tea administration in different models
of oxidative stress. Most promising are the consistent findings in animal
models of skin, lung, colon, liver and pancreatic cancer that tea and
tea polyphenol administration inhibit carcinogen-induced increases in
the oxidized DNA base (Frei and Higdon, 2003). Green tea polyphenols and
EGCG treatment were also found to induce apoptosis and inhibit the proliferation
when the tumor tissue sections were examined by immunohistochemistry (Thangapazham
et al., 2007). It has been confirmed by various techniques that
EGCG inhibits telomerase and induces apoptosis in drug-resistant lung
cancer cells (Sadava et al., 2007). EGCG may be useful in the chemoprevention
of breast carcinoma in which fatty acid synthase (FAS) overexpression
results from human epidermal growth factor receptor (HER2 or/and HER3
signaling) (Pan et al., 2007). EGCG inhibits the growth of gastric
cancer by reducing VEGF production and angiogenesis and is a promising
candidate for anti-angiogenic treatment of gastric cancer (Zhu et al.,
2007). EGCG inhibited the in vitro growth of invasive bladder carcinoma
cells and decreases the migratory potential of bladder carcinoma cells
(Rieger-Christ et al., 2007). Black tea polyphenols, theaflavins
may have a major impact on the chemoprevention of oral cancer, than the
green tea polyphenols (Chandra and Mohan, 2006). EGCG has a preventive
effect on the growth of liver and pulmonary metastases of orthotopic colon
cancer in nude mice and this anticancer effect could be partly caused
by activating the Nrf2-UGT1A signal pathway (Yuan et al., 2007).
The inhibitory effect of (-)-EGCG on activation of the epidermal growth
factor receptor is associated with altered lipid order in HT29 colon cancer
cells (Adachi et al., 2007). Activation of Forkhead box O transcription
factor (FOXO3a) by the green tea polyphenol epigallocatechin-3-gallate
induces estrogen receptor alpha expression reversing invasive phenotype
of breast cancer cells (Belguise et al., 2007). (-)-EGCG inhibits
Her-2/neu signaling, proliferation and transformed phenotype of breast
cancer cells (Pianetti et al., 2002).
| Table 1: | Studies carried out on catechins, green tea polyphenols |
| Table 2: | Studies carried out on Epigallocatechin-3-gallate (-)-EGCG |
| Table 3: | Studies carried out on Epicatechin or Epicatechin gallate (ECG) |
| Table 4: | Studies carried out on Theaflavins and thaerubigins (black tea polyphenols) |
Skin and tea polyphenols: The outcome of the several experimental studies suggests that green tea possess anti-inflammatory and anticarcinogenic potential, which can very well be exploited against a variety of skin disorders (Katiyar et al., 2000b, 2001). Green tea polyphenols act as chemopreventive, naturally healing and anti-aging agents for human skin (Hsu, 2005). (-)- EGCG is the major and most photoprotective polyphenolic component of green tea (Katiyar et al., 2007). The inhibition of UV light-induced DNA damage in the form of cyclobutane pyrimidine dimers (CPDs) in the skin by green tea polyphenols treatment may, at least in part, be responsible for the inhibition of photocarcinogenesis (Katiyar et al., 2000a) (Table 1). Green tea polyphenol induces caspase 14 in epidermal keratinocytes via MAPK pathways and reduces psoriasiform lesions in the flaky skin mouse model (Hsu et al., 2007b). Signal transducers and activators of transcription (STATs) play a critical role in signal transduction pathways. Phosphorylation of STAT1 (Ser727) occurs through PI-3K, ERKs, p38 kinase, JNKs, PDK1 and p90RSK2 in the cellular response to UVB. The aflavins and EGCG show an inhibitory effect on UVB-induced STAT1 (Ser727), ERKs, JNKs, PDK1 and p90RSK2 phosphorylation (Zykova et al., 2005). EGCG inhibits 12-O-tetradecanoylphorbol-13-acetate (TPA) induced DNA binding of NF-kappaB and CREB by blocking activation of p38 MAPK, which may provide a molecular basis of COX-2 inhibition by EGCG in mouse skin in vivo (Kundu and Surh, 2007). ECG dose-dependently attenuates UVB-induced keratinocyte death. Moreover, ECG markedly inhibited UVB-induced cell membrane lipid peroxidation and H2O2 generation in keratinocytes, suggesting that ECG can act as a free radical scavenger when keratinocytes were photodamaged (Huang et al., 2007). EGCG prevents UVB-induced skin tumor development in mice and this prevention is mediated through: (a) the induction of immunoregulatory cytokine interleukin (IL) 12; (b) IL-12-dependent DNA repair following nucleotide excision repair mechanism; (c) the inhibition of UV-induced immunosuppression through IL-12-dependent DNA repair; (d) the inhibition of angiogenic factors and (e) the stimulation of cytotoxic T cells in a tumor microenvironment (Katiyar et al., 2007).
Antioxidant effects of tea: (-)-Epigallocatechin-gallate ((-)-EGCG) and (-)-epicatechin-gallate ((-)-ECG) exhibit antioxidant behaviour (Ryan and Hynes, 2007). Epicatechins in green tea and theaflavins in black tea were found to be able to reduce the concentration of Reactive alpha-dicarbonyl compounds in physiological phosphate buffer conditions (Lo et al., 2006). Tea polyphenols act as antioxidants in vitro by scavenging reactive oxygen and nitrogen species and chelating redox-active transition metal ions (Lo et al., 2006). They may also function indirectly as antioxidants through 1) inhibition of the redox-sensitive transcription factors, nuclear factor-kappaB and activator protein-1; 2) inhibition of pro-oxidant enzymes, such as inducible nitric oxide synthase, lipoxygenases, cyclooxygenases and xanthine oxidase and 3) induction of phase II and antioxidant enzymes, such as glutathione S-transferases and superoxide dismutases (Frei and Higdon, 2003). White tea, having high levels of epigallocatechin-3-gallate (EGCG) and several other polyphenols than green tea has greater antimutagenic activity in comparison with green tea, perhaps due to synergistic action of major constituents or polyphenols with other (minor) constituents, to inhibit mutagen activation as well as scavenging the reactive intermediate(s) (Santana-Rios et al., 2001) (Table 1). Antioxidative properties of black tea are manifested by its ability to inhibit free radical generation, scavenge free radicals and chelate transition metal ions. Black tea, as well as individual theaflavins, can influence activation of transcription factors such as NFkappaB or AP-1. Theaflavins have been also proved to inhibit the activity of prooxidative enzymes such as xanthine oxidase or nitric oxide synthase (Luczaj and Skrzydlewska, 2005)(Table 4). Green tea polyphenols can act as a biological antioxidant in a cell culture experimental model and protect cells in culture (Park et al., 2003) and mammalian veins (Han et al., 2003) from oxidative stress-induced toxicity. Tea polyphenols also possess antimutagenic activity (Ioannides and Yoxall, 2003). This protective effect of black tea infusions may be due to the outcome of antioxidative influence of tea components (Sengupta et al., 2003). Measurement of protection against DNA scissions produce results that again show that EGCG produces the strongest protective effects. In scavenging assays using a xanthine-xanthine oxidase (enzymatic system), epicatechin gallate (ECG) shows the highest scavenging potential (Pillai et al., 1999). Compounds isolated from green tea tannin mixture show that (-)-epigallocatechin 3-O-gallate (EGCg), (-)-gallocatechin 3-O-gallate (GCg) and (-)-epicatechin 3-O-gallate (ECg) had higher scavenging activities than (-)-epigallocatechin (EGC), (+)-gallocatechin (GC), (-)-epicatechin (EC) and (+)-catechin (C), thus showing the importance of the structure of flavan-3-ol linked to gallic acid for this activity (Nakagawa and Yokozawa, 2002). Tea catechins prevent the molecular degradation in oxidative stress conditions by directly altering the subcellular ROS production, glutathione metabolism and cytochrome P450 2E1 activity (Raza and John, 2007). Tea catechins and polyphenols are effective scavengers of reactive oxygen species in vitro and may also function indirectly as antioxidants through their effects on transcription factors and enzyme activities (Higdon, 2003). EGCG scavenged superoxide radical and H2O2 in a dose dependent manner. EGCG had protective effect on DNA at low concentrations (2-30 mM), but it enhanced the DNA oxidative damage at higher concentrations (>60 mM), exhibiting a prooxidant effect on DNA (Tian et al., 2007). EGCG may attenuate the oxidative stress following acute hypoxia (Wei et al., 2004). Various age related diseases owing to free radical injury in the human body like arthritis etc. have been shown to be prevented by tea polyphenols in vivo (Haqqi et al., 1999).
Tea and cardiovascular health: Green tea is proposed to be a dietary supplement in the prevention of cardiovascular diseases in which oxidative stress and proinflammation are the principal causes (Tipoe et al., 2007). Clinical trials employing putative intermediary indicators of the disease, particularly biomarkers of oxidative stress status, suggest tea polyphenols could play a very important role in the pathogenesis of cancer and heart disease (McKay and Blumberg, 2002). Green tea and its catechins may reduce the risk of Coronary Heart Disease (CHD) by lowering the plasma levels of cholesterol and triglyceride. Studies indicate that green tea catechins, particularly (-)-epigallocatechin gallate, interfere with the emulsification, digestion and micellar solubilization of lipids, the critical steps involved in the intestinal absorption of dietary fat, cholesterol and other lipids (Koo and Noh, 2007) (Table 2). Continuous ingestion of green tea catechins from an early age prevents the development of spontaneous stroke in malignant stroke-prone spontaneously hypertensive rats (M-SHRSP), probably by inhibiting the further development of high blood pressure at later ages (Ikeda et al., 2007). EGCG, improves endothelial function and insulin sensitivity, reduces blood pressure and protects against myocardial ischemia-reperfusion (I/R) injury in spontaneously hypertensive rats (Potenza et al., 2007). Catechin (GCg or EGCg), like the nitric oxide (NO) donor, may have a therapeutic use as an NO-mediated vasorelaxant and may have an additional protective action in myocardial ischemia-reperfusion induced injury (Hotta et al., 2006) (Table 3). Tea catechins with a galloyl moiety suppress postprandial hypertriacylglycerolemia by delaying lymphatic transport of dietary fat in rats and also because postprandial hypertriacylglycerolemia is a risk factor for coronary heart disease, it is suggested suggest that catechins with a galloyl moiety may prevent this disease (Ikeda et al., 2005). Acute EGCG supplementation reverses endothelial dysfunction in patients with the coronary artery disease (Widlansky et al., 2007).
Tea and apoptosis: (-)-EGCG induces growth arrest and apoptosis through multiple mechanisms and can be used for cancer prevention, mainly pancreatic (Shankar et al., 2007b). EGCG could induce apoptosis in vivo in Sarcoma 180 cells through alteration in G2/M phase of the cell cycle by up-regulation of p53, bax and down-regulation of c-myc, bcl-2 and U1B, U4-U6 UsnRNAs (Manna et al., 2006) (Table 2). EGC inhibits DNA replication and consequently induces leukemia cell apoptosis (Smith and Dou, 2001). EGCG can induce apoptosis of the human gastric cancer cell line MKN45 and the effect is in a time- and dose-dependent manner. The apoptotic pathway triggered by EGCG in MKN45 is mitochondrial-dependent (Ran et al., 2007). The O-acetylated (-)-EGCG analogs possessing a p-NH(2) or p-NHBoc (Boc; tert-butoxycarbonyl) D-ring (5 and 7) act as novel tumor cellular proteasome inhibitors and apoptosis inducers with potency similar to natural (-)-EGCG and similar to (-)-EGCG peracetate (Osanai et al., 2007). (-)-EGCG might prevent alveolar bone resorption by inhibiting osteoclast survival through the caspase-mediated apoptosis (Yun et al., 2007). EGCG treatment has a dose-dependent effect on ROS generation and intracellular ATP levels in MCF-7 cells, leading to either apoptosis or necrosis and that the apoptotic cascade involves JNK activation, Bax expression, mitochondrial membrane potential changes and activation of caspase-9 and caspase-3 (Hsuuw and Chan, 2007). Interesting results has been obtained in a study that EGCG inhibits cardiac myocyte apoptosis and oxidative stress in the pressure overload induced cardiac hypertrophy. Also, EGCG prevents cardiomyocyte apoptosis from oxidative stress in vitro. The mechanism may be related to the inhibitory effects of EGCG on p53 induction and bcl-2 decrease (Sheng et al., 2007). EGCG induces apoptosis in human prostate carcinoma cells by shifting the balance between pro- and antiapoptotic proteins in favor of apoptosis (Hastak et al., 2003). Tea catechins have ability to produce H2O2 and that the resulting increase in H2O2 levels triggers Fe(II)-dependent formation of highly toxic hydroxyl radical, which in turn induces apoptotic cell death (Nakagawa et al., 2000).
Anti-microbial effects of tea: Green tea catechins ECG, CG and EGCG increase the sensitivity of methicillin-resistant Staphylococcus aureus (EMRSA-15) to oxacillin (Table 1-3). The gallate moiety was essential for the oxacillin-modulating activity of (-)- ECG (Stapleton et al., 2004). (-)-ECG alters the architecture of the cell wall of Staphylococcus aureus causing beta-lactam-resistance modification (Stapleton et al., 2007). Catechin gallates inhibit multidrug resistance (MDR) in Staphylococcus aureus (Gibbons et al., 2004) (-)-ECG also reduces halotolerance in Staphylococcus aureus suggesting that this molecule can be used to aid the preservation of salt-containing foods (Stapleton et al., 2006) (Table 3). Crude extract of green tea as well as two of its main constituents, EGCG and ECG, strongly inhibit Plasmodium falciparum growth in vitro (Sannella et al., 2007). Green tea catechins inhibit bacterial DNA gyrase by interaction with its ATP binding site (Gradisar et al., 2007). EGCG is effective in reducing acid production in dental plaque and mutans Streptococci. EGCG and epicatechin gallate inhibits lactate dehydrogenase activity much more efficiently than epigallocatechin, epicatechin, catechin or gallocatechin. (Hirasawa et al., 2006). The 3-galloyl group of catechin skeleton plays an important role on the observed antiviral activity against influenza virus (Song et al., 2005). Green tea catechins have been found to exhibit anti-Trypanosoma cruzi activity, suggesting that these compounds could be used to sterilize blood and, eventually, as therapeutic agents for Chagas disease (Paveto et al., 2004). EGCG has anticandidal activity causing blockage of the hyphal formation and has the synergism combined with Amp B against disseminated candidiasis (Han, 2007). EGCG has potential use as adjunctive therapy in HIV-1 infection owing to its binding to the T-cell receptor, CD4 (Williamson et al., 2006).Tea catechins possess antifolate activity also (Navarro-Perán et al., 2005). EGCG exhibit antifolate activity against Stenotrophomonas maltophilia (Navarro-Martínez et al., 2005).
Tea consumption and weight loss: Molecular mechanisms of fatty acid synthase gene suppression by tea polyphenols (EGCG, theaflavins) may bring down-regulation of EGFR/PI3K/Akt/Sp-1 signal transduction pathways, suggesting hypolipidemic and anti-obesity effects of tea and tea polyphenols (Lin and Lin-Shiau, 2006) (Table 1). Green tea extract intake is associated with increased weight loss due to diet-induced thermogenesis, which is generally attributed to the catechin epigallocatechin gallate (Shixian et al., 2006).
Neuroprotective effect of tea: Green tea polyphenols have demonstrated neuroprotectant activity in cell cultures and animal models, such as the prevention of neurotoxin-induced cell injury (Pan et al., 2003). Recent findings from in vivo and in vitro studies concerning the transitional metal (iron and copper) chelating property of green tea and its major polyphenol, (-)-epigallocatechin-3-gallate, suggests its potential role in the treatment of neurodegenerative diseases (Mandel et al., 2006) (Table 2). EGCG may exhibit protective effects against advanced glycation endproducts (AGEs) induced injury in neuronal cells, through its antioxidative properties, as well as by interfering with AGEs-AGE receptor (RAGE) interaction mediated pathways, suggesting a beneficial role for this tea catechin against neurodegenerative diseases (Lee and Lee, 2007). Catechin gallates (through the galloyl moiety) contribute to the neuroprotective effects of both green and black teas.Not only green but also black teas may reduce age-related neurodegenerative diseases, such as Alzheimer`s disease (Bastianetto et al., 2006).
CONCLUSION
Animal and in vitro studies have provided evidence that the polyphenols found in tea may inhibit tumorigenesis in many animal models, including those for cancer of the skin, lung, oral cavity, oesophagus, stomach, small intestine, colon, liver, pancreas, bladder and prostate. The suggested mechanism of action includes the following:
| • | Antioxidant activity and scavenging free radicals |
| • | Modulating enzymes implicated in the carcinogenic process |
| • | Modifying the pathways of signal transduction, thereby positively altering the expression of genes involved in cell proliferation, angiogenesis and apoptosis, all important stages of cancer progression. |
| • | Antimicrobial actions (association between Helicobacter pylori and gastric cancer) |
Many studies on health benefits of tea have been linked to the catechin content. Epicatechin can reduce the risk of four of the major health problems: stroke, heart failure, cancer and diabetes. For cancer prevention, evidence is so overwhelming that the Chemoprevention Branch of the National Cancer Institute has initiated a plan for developing tea compounds as cancer-chemopreventive agents in human trials (Siddiqui et al., 2004). Thus, epicatechin should be considered essential to the diet. While the exact mechanisms of action are still unknown, these studies provide possible explanations. The possible beneficial health effects of tea consumption have been suggested and supported by some studies, but others have found no beneficial effects. The studies show contrast with other claims, including antinutritional effects such as preventing absorption of iron and protein, usually attributed to tannin. It is reasonable to conclude that drinking both the green and black tea is compatible with healthy dietary advice in helping to reduce the risk of cancer development, helping to maintain overall health and well-being.
ACKNOWLEDGMENTS
Thanks are due to the UGC, New Delhi for awarding the project No: 32-482/2006 (SR) to Prof Mohammad Afzal and to the Chairman, Department of Zoology, AMU, Aligarh, for providing laboratory facilities.