Review Article

Received: 23 May 2013, Accepted: 07 June 2013

ISSN: 2321-2969

Int. J. Pharm. Biosci. Technol. To cite this Article: Click here

International Journal of Pharma Bioscience and Technology. 2013; 1(2): 54-63

Journal home page: www.ijpbst.com

MOLECULAR MECHANISMS AND BIOLOGICAL IMPLICATIONS OF GREEN TEA POLYPHENOL, (-)-EPIGALLOCATECHIN -3- GALLATE
Chitra Subramani1*, Ramesh Kumar Natesh2
Captain Srinivasa Murti Drug Research Institute for Ayurveda CCRAS, Dept. of AYUSH, Ministry of Health and Family Welfare, Government of India, Anna Hospital Campus, Arumbakkam, Chennai-600106, Tamil Nadu, India
2 1

C.L. Baid Metha College of Pharmacy, Thoraipakkam, Chennai-600097, Tamil Nadu, India Corresponding Author* E-mail address- chiresh2006@gmail.com

ABSTRACT: Plants constitute a vital part of the biological system in which we exist and are indispensable to humans in every aspect of life. Its major percentage of naturally occurring material used as drugs by people all over the world. The use of plants as food and medicines when man started his life on this planet. Now people started to realize the value of plants as drugs after they felt the serious side effects of modern medicine. The practice of wide usage of plants as medicinal agents is prevalent for centuries in various parts of the world, the most prominent of which are Chinese system of medicine, ayurvedic, siddha and unani system of medicine in India. The realization that there is something interesting in the properties of these medicinal plants dawned with the advent of chemistry in the late 18th century. Chemists gradually started isolating pure substances from various anatomical parts of medicinal plants and concluded that certain active compounds are responsible for the therapeutic actions of the plants. It has been estimated that only 10-15 % of 2,50,000 to 7,50,000 existing species of higher plants have been surveyed for biologically active compounds for the study of its phytochemistry and pharmacology. This review paper deals with the advances in study of green tea, which is the second most consumed beverage in the World after water. Green tea catechins are the flavan-3-ols found in green tea leaves, of the catechins. Out of the various catechins found in green tea, (-)-Epigallocatechin-3-gallate (EGCG) is the most abundant one in green tea leaves. It is the most potent antioxidant polyphenols associated with anti-atherogenic, antitumor and anti-mutagenic activities. Key words: Green tea; Apoptosis; (-)-Epigallocatechin-3-gallate; Atherosclerosis; Oxidative stress

INTRODUCTION Green tea, an evergreen shrub of the Theaceae family native to eastern Asia, and is cultivated extensively in India, China, Japan, Indonesia, Sri Lanka, Turkey, and Pakistan, as well as other parts of the World, such as Africa and South America [1]. It originally came from China; so also called as Chinese green tea. It has been used medicinally for centuries in India and China. The leaves are 415 cm long and 2-5 cm broad. Fresh leaves contain about 4% caffeine. The young, light green leaves are preferably harvested for tea production; they have short white hairs on the underside. Leaf of Subramani et al different ages, produce varying tea qualities, since their chemical compositions are different. Usually, the tip (bud) and the first two to three leaves are harvested for processing. This hand picking is repeated every one to two weeks. Green tea is prepared by picking, lightly steaming and allowing the leaves to dry whereas black tea is fermented before drying. Tea, (the dried form of the leaf) has been widely consumed as a beverage for more than 4000 years, and its medicinal properties have been extensively studied with scientific methods in this decade. Green tea has been also used for other applications such as to Pg. 54

Int. J. Pharm. Biosci. Technol. flavor food products, and its essential oil has been applied in perfumes and cosmetics [2]. No toxic effect has been reported on the drinking of up to 10 cups of green tea per day [3]. Most of its biological activities such as lipid-lowering, antimicrobial, anti-obesity, anti-cancer and antimutagenesis are found to be related to its polyphenol constituents, especially the tea catechins. Chemical Composition of Green Tea The chemical composition of green tea varies with climate, season, horticultural practices, and age of the leaf. Green tea contains a very high value of tannins, caffeine, theanine, chlorophylls, pheophytins, carotenoids, flavonoids and catechin polyphenols. Tannins act as astringents, shrinking tissues and contracting structural proteins in the skin and mucosa and they may aid in protection against infection [2]. Caffeine plays a significant role in the anti- mutagenic effects of green tea in some cases, especially in the prevention of UVinduced skin cancer [4]. L-theanine is an amino acid found in high concentration which decreases blood pressure and also it has synergistic activity along with anti-cancer drugs [5]. Chlorophylls a and b, pheophytins a and b, lutein, beta carotene are some of the other active components of green tea and has antioxidant properties [6] as well anti carcinogenic [7] and anti-genotoxic activity [8]. Catechins constitute about 30% of the dry weight of fresh tea leaf [9] although total catechin content varies widely depending on clonal variation, growing location, seasonal or light variation, and altitude. Catechins are present in nearly all varieties of green teas and the major constituents of green tea are catechin (Fig.1 & 2) which includes EC (epicatechin), EGC (epigallocatechin), ECG (epicatechin-3-gallate), and EGCG.

Fig.2: Structure of Major Polyphenol in Green Tea Of these, EGCG constitutes 10-50% by weight and appears to be the most prevalent and powerful catechins of green tea with antioxidant property about 100 and 25 times more potent than vitamin C and E respectively. EGCG and its role in life style disorders Role in Oxidative Stress The antioxidant efficacy of polyphenols, as evaluated by a battery of tests, indicates that they can inhibit lipid hydroperoxide formation [10]. Scavenging property of polyphenols has been demonstrated against a spectrum of offensive oxidants, like superoxide radicals [11, 12], free radicals [13], and peroxinitrite [14, 15]. The biological benefits of EGCG are generally attributed to their antioxidant activity to scavenge the free radical, oxygen [16]. The antioxidant activity increased in the following order: EC> ECG>EGC> EGCG due to the number of hydroxyl groups present in the structure. EGCG play an important role in protecting against free-radical DNA damage by the ionizing radiation or ultraviolet radiation which in turn inhibits lipid peroxidation (Fig.3). EGCG helps to neutralize dietary carcinogens, works with enzymes and other antioxidants in the intestine, liver and lungs to prevent the activation of certain carcinogens before they damage DNA, as a free radicals scavenger. EGCG's anti-oxidant action protects cells from lipid peroxidation and DNA damage induced by reactive free radicals [17, 18]. EGCG from green tea shows broad spectrum benefits that include both antioxidant activity against free radicals and normalization of metal metabolism. In a preliminary study on EGCG, researchers have identified more genes Pg. 55

Fig.1: Relative Catechin polyphenol content of Green Tea

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Int. J. Pharm. Biosci. Technol. and proteins that can be used as biomarkers to study the unique metabolic benefits of EGCG. apoptotic protein Bcl-2 with a concomitant upregulation in pro-apoptotic protein Bax (Fig. 4).

Fig.3: Free Radical Scavenging Action of EGCG

Fig.4: Mechanism of Action of EGCG in Cancer Anti-apoptotic protein Bcl-2 has been associated with cell survival and to inhibit programmed cell death, whereas increase in pro - apoptotic protein Bax results in apoptosis [25]. EGCG treatment induces mitochondrial disruption and thus releases cytochrome C, induction of Apaf-1, and cleavage of caspase-3 and poly (ADP-ribose) polymerase [26]. EGCG, may be effective in preventing cancer of the prostate [27], breast [28], head and neck carcinoma cells [29], pancreas [30], bladder [5], ovarian [31], leukemia [32], oral leukoplakia [33], laryngeal carcinoma [4], UV-induced skin cancer [34, 35], cervical cancer [36], lung [37], and gastrointestinal tract cancer [5]. EGCG strongly and directly inhibits telomerase, a ribonucleoprotein that maintains telomeres and has been implicated in tumorigenesis [38]. As a novel anti-cancer agent for treatment of cancers, EGCG is promising and the mechanism has not been fully understood. The treatment of Hep2 cells with EGCG leads to decreased cell viability, inhibition of the growth and proliferation, induces apoptosis and increases the activity of caspase-3 in a dose-dependent manner [4]. EGCG exerts its inhibitory effect to inhibit IFN- elicited tyrosine phosphorylation of STAT1 rather than to modulate the amounts of STAT1 protein [19]. EGCG inhibits growth and angiogenesis through molecular mechanisms by which the primary Pg. 56

The anti-oxidative action of EGCG may not account for the inhibition of STAT1 (signal transducers and activators of transcription-1) activation [19]. EGCG is known for its antioxidative property and may have role in protection in cytokine-induced pancreatic -cell damage, which is partly mediated by suppression of NF-B or iNOS (inducible nitric oxide synthase) activity [20, 21].

Role in Cancer prevention The anti-carcinogenic property of EGCG can be explained by its action on the inhibition of biochemical markers of tumor initiation and promotion, induction of apoptosis, and inhibition of cell replication rates, thus retarding the growth and development of neoplasms [22, 23]. Catechin polyphenols that have antioxidant properties are known to fight against cancer [24]. EGCG mainly targets specific cell-signaling pathways responsible for regulating cellular proliferation or apoptosis. It has been also reported to inhibit the cell growth, induced G0/G1-phase cell cycle arrest, and caused apoptosis in cancer cells but not in normal cells. The mechanism was suggested to be related to a differential inhibition by EGCG of TNF- or LPSmediated NF-B activation in cancer compared to normal cells [22]. EGCG down-regulates antiSubramani et al

Int. J. Pharm. Biosci. Technol. chemical pathway involved in reduced activation of STAT3 which led to reduced tumor growth [39]. EGCG has potent efficiency to prevent the growth of a variety of cancer cells. The experiments have been performed on cultures of Hep-2 (laryngeal carcinoma cells), LoVo (colon carcinoma cells), HeLa (cervical carcinoma cells) and HS cells (normal myoepithelial cell line). EGCG was found to induce apoptosis in cells of the examined neoplastic lines in a dose-related manner [40, 41]. The observed results indicated that the activity of EGCG might be activating the DNA fragmentation factors such as poly (ADP - ribose) polymerase or deoxy ribo nucleases, which was supported by Baliga et al. [26]. EGCG is also found to be effective in increasing cancer cell death or apoptosis, mitochondrial membrane depolarization, and cytosolic cytochrome C expression. It is also effective in decreasing the growth of cancer cells, and increasing the response to chemotherapy in an animal model [42]. EGCG exerts inhibitory action on urokinase, matrix metalloproteinase, and iNOS, accounting to its anti-tumor and anti- inflammatory activity [19]. EGCG elicited a strong inhibitory action against INF- induced STAT1 activation in MDA MB 231/468, MCF-7, HepG2, and HeLa cell lines [19]. Administration of EGCG to mouse model decreases both tumor number and total tumor burden, this decreased survival was due to EGCG induced apoptosis not terminal differentiation [43]. The levels of p53 were increased in the EGCG-treated cells, with a corresponding decrease in Bcl-2 and Bid protein levels as well as an increase in the Bax level (Fig.5). In addition, EGCG induced the cytoplasmic release of cytochrome C from the mitochondria accompanied by a decreased mitochondrial membrane potential, and subsequently up regulated translocation of apoptosis - inducing factor (AIF) and endonuclease G (EndoG) into the nucleus during the apoptotic process. Taken together, these findings indicate that the p53mediated mitochondrial pathway and the nuclear translocation of AIF and EndoG play a crucial role in EGCG-induced apoptosis of Hep2 cells, which proceeds through a caspase-independent pathway [44]. EGCG induce apoptosis via multiple pathways including inhibition of NF-kB activation, binding to Fas, activation of TNF- (tumor necrosis factor)mediated signaling pathway, cell cycle arrest at G0/G1, and binding to and suppressing antiapoptotic Bcl-2 family proteins [45, 46]. Low concentrations of EGCG have been shown to preferentially inhibit the growth of many types of transformed cells but not normal cells primarily via induction of apoptosis [47, 48]. It is possible that the polyamine-induction of p53 and proapoptotic proteins such as Bax contributes to the sensitization of keratinocytes to EGCG-induced apoptosis. Moreover, it has been reported that EGCG can antagonize the anti-apoptotic effects of Bcl-2 family proteins by binding and inhibiting Bcl-2 and Bcl-xL. Also EGCG-treated mice correlated with an increased Bax: Bcl-2 ratio [46]. EGCG plays a fundamental role in cancer prevention by inhibiting many proteins as well protein kinases involved in tumor cell proliferation and survival, including the large multi-catalytic protease MMP (matrix metalloproteinase). MMP involved in tumor survival and metastasis and the epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGF), platelet-derived growth factor receptor (PDGFR), mitogen - activated protein kinase (MAPK), and IkB kinase [49]. The inhibition of EGFR and VEGF are of importance because they are known to play an essential role in angiogenesis [50] also which contributes to tumor formation [51]. The inhibition of MMP-2 and MMP-9 are also known to play an important role in the anti-carcinogenic action of green tea. EGCG has no effect on IL-6 elicited STAT3 activation in IL-6 responsive cells [52, 27]. Hence the study on EGCG clearly demonstrates that its anti- angiogenic property which was studied by us [53] and also supported by Masuda et al [29]. Fig.5: Molecular Mechanism of the Inhibition of INF- Elicited STAT1 Activation by EGCG

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Int. J. Pharm. Biosci. Technol. Role in Coronary Heart Disease A variety of epidemiologic studies showed the protective effect of green tea consumption against atherosclerosis and coronary heart disease (Fig. 6) [54]. that occurs during the inflammatory process [63, 64].

Fig.7: Schematic Sketch of the Action of EGCG on Inflammation Fig.6: Molecular Mechanism of EGCG on Coronary Heart Disease Tea consumption has also been shown to reduce the risk of high blood cholesterol concentrations and high blood pressure and preventive effect against atherosclerosis in experimental animals [55, 56]. Tea catechins have potent inhibitory effects on LDL oxidation which was studied in atherosclerosis induced mice model [57]. Reduction in serum lipid levels like total cholesterol, LDL, VLDL and triglycerides by EGCG has been reported [58]. Aqueous extract of green tea reduces thromboxane levels and prevents collagen - induced platelet aggregation in rats [59,60]. Role in Anti-inflammation The polyphenolic fraction from green tea has been known to protect against inflammation caused by certain chemicals, such as 12-O-tetra decanoylphorbol-3-acetate, a principal irritant in croton oil [52], and also by ultraviolet radiation [61]. Green tea polyphenols has been shown to be effective against the immune suppression caused by ultraviolet radiation B in experimental animals and also has shown to provide protection against cytokines induced by tumors [62]. Green tea polyphenols inhibit the production of arachidonic acid metabolites such as pro-inflammatory prostaglandins and leukotrienes, resulting in a decreased inflammatory response (Fig. 7). Human and animal studies have demonstrated that EGCGs ability to block inflammatory responses to ultraviolet A and B radiation as well as significant inhibitory activity against the neutrophil migration IFN--elicited activation of STAT1 is correlated with the pathogenesis of inflammatory diseases like asthma and extra capillary proliferative glomerulonephritis. Green tea administration in mouse model have shown to prevent collageninduced arthritis because of the presence of the antioxidant polyphenols that reduces the incidence and severity of disease. The down regulation of IFN- action by EGCG provides the molecular basis for the anti-inflammatory effect of EGCG. EGCG blocks the expression of NOS II and IRF-1, two proteins deeply involved in mediating inflammatory processes (Fig. 5). EGCG, by inhibiting STAT1 activation, may play an important role in modulating the entire process of inflammation [19]. Role in Liver Diseases A preliminary green tea research study using alcohol-damaged liver cells found that green tea reduces liver cell damage as measured by gamma-glutamyl transferase (GGT). Enhanced activity of GGT was found in HepG2 cells when they were exposed to lethal dose of ethanol and which was reduced after treatment with EGCG. EGCG is also reported to prevent liver cell death [65]. Role in other disorders Skin Protection Oral consumption of green tea polyphenols, have shown to inhibit effects of chemical carcinogens and ultraviolet radiation-induced skin tumors in Pg. 58

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Int. J. Pharm. Biosci. Technol. various animal models. EGCG is also known to combat the effects of pollution, sunlight and smoking and also protects the skin from wrinkling and aging [34]. Weight Loss Green tea extract may help in weight loss by speeding up fat oxidation [66]. Studies have shown green tea extracts are capable of reducing fat digestion by inhibiting digestive enzymes by catechins present in them [67]. On the basis of the in vivo effects of EGCG on body weight loss, body fat, serum lipid nutrients, thermogenesis, and fat oxidation and of the in vitro effects of EGCG on fat cell functions. Long-term consumption of green tea may decrease the incidence of obesity and, perhaps, green tea components such as EGCG may be useful for treating obesity [68]. The mRNA levels of adipokines like leptin, resistin, adiponectin and adipsin in epididymal adipose tissue were also decreased by EGCG, the results suggested that EGCG has shown anti-obesity action through loss of adipose tissue mass, amelioration of lipid metabolism, induction of fecal lipid excretion and suppression of adipokines gene [69]. Studies with adipocyte cell lines and animal models have demonstrated that EGCG inhibits extracellular signal-related kinases, activates AMP-activated protein kinase and modulates adipocyte marker proteins, and downregulates lipogenic enzymes as well as other potential targets [70]. Anti-microbial activation EGCG has also been shown to have inhibitory effects on HIV [71] and influenza virus [72]. Tea consumption provides protection against bacterial infection [73-75]. Helicobacter pylori is associated with a gastric diseases are inhibited by EGCG [76]. EGCG binds to the specific binding site on DNA gyrase where EGCG blocks ATP and thus prevents bacterial reproduction. EGCG may play a major role on preventing the HIV to enter and infect the normal cells [77]. Activity in other metabolic disorders Tea consumption lowers the risk of osteoporosis [78, 79]. EGCG protects liver from liver diseases by reducing marker enzymes [80]. Anti-diabetic activity of green tea polyphenols and their role in enhancing the glucose metabolism was reported in experimental animals induced with diabetes [81, 82]. EGCG-containing green tea extract can lower serum glucose [83, 84]. Green tea extract protects against carbon tetrachloride-induced chronic liver damage and cirrhosis. Prevention of hepatic ischemia - reperfusion injury by green tea extract has been studied [85]. EGCG exerts potent neuroprotective actions against Alzheimer's and Parkinsons disease [86] and it is useful in the treatment of arthritis and cataracts. A new animal study have shown that EGCG from green tea in the drinking water provides protection from glaucoma for its safe profile, broad spectrum nerve protection, and reduction of damage to the eye from blood loss and other damaging risk factors. Concluding Remarks The currently available treatment methods for lifestyle disorders exhibit considerable side effects. More over the multi-drug resistance acquired by the cells especially cancer cells to the commonly used drugs has created severe impact in the use of chemotherapy in treatment. In the present situation, the use of herbal formulations or active principle of an ayurvedic plant is gaining significant importance in chemotherapy of various disorders, due to their low or no side - effects and lack of resistance by cells. A number of studies have revealed the role of a major polyphenol EGCG of green tea to have a potent anti-oxidant, anti-tumor, anti- mutagenic, anti-inflammatory, anti-atherosclerotic activity through some known mechanism. Also EGCG provide protection against HIV, osteoporosis, stroke, skin infection, and anti-microbial, etc. through unknown mechanism. Hence, further investigations are required to study the exact mechanism of action of EGCG on various metabolic disorders. REFERENCES 1. Graham H. Green tea composition, consumption and polyphenol chemistry. Preventive Medicine 1992; 21(3): 334-350. 2. Kakuda T. Neuroprotective effects of the green tea components theanine and catechins. Biological Pharmaceutical Bulletin 2002; 25 (12): 1513-1518. 3. Katiyar SK, Mukhtar H. Tea in chemoprevention of cancer: epidemiologic and experimental studies. International Journal of Oncology 1996; 8: 221-238. 4. Wang X, Hao MW, Dong K, Lin F, Ren JH, Zhang HZ. Apoptosis induction effects of EGCG in laryngeal squamous cell carcinoma cells through telomerase repression. Archives of Pharmacological Research 2009; 32 (9): 1263-1269.

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How to cite this article APA style Subramani, C., & Natesh, R. K. (2013). Molecular Mechanisms and Biological Implications of Green Tea Polyphenol (-)-Epigallocatechin -3- gallate. International Journal of Pharma Bioscience and Technology, 1(2), 5463. Elsevier Harvard style Subramani, C., Natesh, R.K., 2013. Molecular Mechanisms and Biological Implications of Green Tea Polyphenol,(-)-Epigallocatechin -3- gallate. Int. J. Pharm. Biosci. Technol. 1, 5463. Vancouver Style Subramani C, Natesh RK. Molecular Mechanisms and Biological Implications of Green Tea Polyphenol,(-)-Epigallocatechin -3- gallate. Int. J. Pharm. Biosci. Technol. 2013 Jul;1(2):5463.
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