A potential prodrug for a green tea polyphenol proteasome inhibitor: evaluation of the peracetate ester of (-)-epigallocatechin gallate [(-)-EGCG

Green tea has been shown to have many biological effects, including effects on metabolism, angiogenesis, oxidation, and cell proliferation. Unfortunately, the most abundant green tea polyphenol (-)-epigallocatechin gallate or (-)-EGCG is very unstable in neutral or alkaline medium. This instability leads to a low bioavailability. In an attempt to enhance the stability of (-)-EGCG, we introduced peracetate protection groups on the reactive hydroxyls of (-)-EGCG (noted in text as 1). HPLC analysis shows that the protected (-)-EGCG analog is six times more stable than natural (-)-EGCG under slightly alkaline conditions. A series of bioassays show that 1 has no inhibitory activity against a purified 20S proteasome in vitro, but exhibits increased proteasome-inhibitory activity in intact leukemic cells over natural (-)-EGCG, indicating an intercellular conversion. Inhibition of cellular proteasome activity by 1 is associated with induction of cell death. Therefore, our results indicate that the protected analog 1 may function as a prodrug of the green tea polyphenol proteasome inhibitor (-)-EGCG.     

Methylation suppresses the proteasome-inhibitory function of green tea polyphenols

Under physiological conditions, biotransformation reactions, such as methylation, can modify green tea polyphenols (GTPs) and therefore limit their in vivo cancer-preventive activity. Although a recent study suggested that methylated polyphenols are less cancer-protective, the molecular basis is unknown. We previously reported that ester bond-containing GTPs, for example (-)-epigallocatechin-3-gallate [(-)-EGCG] or (-)-epicatechin-3-gallate [(-)-ECG], potently and specifically inhibit the proteasomal chymotrypsin-like activity. In this study, we hypothesize that methylated GTPs have decreased proteasome-inhibitory abilities. To test this hypothesis, methylated (-)-EGCG and (-)-ECG analogs that can be found in vivo were synthesized and studied for their structure-activity relationships (SARs) using a purified 20S proteasome. The addition of a single methyl group on (-)-EGCG or (-)-ECG led to decreased proteasome inhibition and, as the number of methyl groups increased, the inhibitory potencies further decreased. These SARs were supported by our findings from in silico docking analysis published recently. Previously, we synthesized a peracetate-protected (-)-EGCG molecule, Pro-EGCG (1), to enhance its cellular permeability and stability, and current HPLC analysis confirms conversion of Pro-EGCG (1) to (-)-EGCG in cultured human leukemic Jurkat T cells. Furthermore, in this study, peracetate-protected forms of methylated GTPs were added in intact Jurkat T cells to observe the intracellular effects of methylation. Peracetate-protected, monomethylated (-)-EGCG induced greater cellular proteasome inhibition and apoptosis than did peracetate-protected, trimethylated (-)-EGCG, consistent with the potencies of the parent methylated analogs against a purified 20S proteasome. Therefore, methylation on GTPs, under physiological conditions, could decrease their proteasome-inhibitory activity, contributing to decreased cancer-preventive effects of tea consumption.     

Green tea catechins: a fresh flavor to anticancer therapy

Green tea catechins have been extensively studied for their cancer preventive effects. Accumulating evidence has shown that green tea catechins, like (?)-epigallocatechin-3-gallate, have strong anti-oxidant activity and affect several signal transduction pathways relevant to cancer development. Here, we review the biological properties of green tea catechins and the molecular mechanisms of their anticancer effects, including the suppression of cancer cell proliferation, induction of apoptosis, and inhibition of tumor metastasis and angiogenesis. We summarize the efficacy of a single catechin and the synergetic effects of multiple catechins. We also discuss the enhanced anticancer effects of green tea catechins when they are combined with anticancer drugs. The information present in this review might promote the development of strategy for the co-administration of green tea catechins with other anticancer drugs to increase the potency of currently available anticancer medicine. This new strategy should in turn lower the cytotoxicity and cost of anticancer treatment.     

Synthetic analogs of green tea polyphenols as proteasome inhibitors

BACKGROUND: Animal, epidemiological and clinical studies have demonstrated the anti-tumor activity of pharmacological proteasome inhibitors and the cancer-preventive effects of green tea consumption. Previously, one of our laboratories reported that natural ester bond-containing green tea polyphenols (GTPs), such as (-)-epigallocatechin-3-gallate [(-)-EGCG] and (-)-gallocatechin-3-gallate [(-)-GCG], are potent and specific proteasome inhibitors. Another of our groups, for the first time, was able to enantioselectively synthesize (-)-EGCG as well as other analogs of this natural GTP. Our interest in designing and developing novel synthetic GTPs as proteasome inhibitors and potential cancer-preventive agents prompted our current study. MATERIALS AND METHODS: GTP analogs, (+)-EGCG, (+)-GCG, and a fully benzyl-protected (+)-EGCG [Bn-(+)-EGCG], were prepared by enantioselective synthesis. Inhibition of the proteasome or calpain (as a control) activities under cell-free conditions were measured by fluorogenic substrate assay. Inhibition of intact tumor cell proteasome activity was measured by accumulation of some proteasome target proteins (p27, I kappa B-alpha and Bax) using Western blot analysis. Inhibition of tumor cell proliferation and induction of apoptosis by synthetic GTPs were determined by G(1) arrest and caspase activation, respectively. Finally, inhibition of the transforming activity of human prostate cancer cells by synthetic GTPs was measured by a colony formation assay. RESULTS: (+)-EGCG and (+)-GCG potently and specifically inhibit the chymotrypsin-like activity of purified 20S proteasome and the 26S proteasome in tumor cell lysates, while Bn-(+)-EGCG does not. Treatment of leukemic Jurkat T or prostate cancer LNCaP cells with either (+)-EGCG or (+)-GCG accumulated p27 and IkappaB-alpha proteins, associated with an increased G(1) population. (+)-EGCG treatment also accumulated the pro-apoptotic Bax protein and induced apoptosis in LNCaP cells expressing high basal levels of Bax, but not prostate cancer DU-145 cells with low Bax expression. Finally, synthetic GTPs significantly inhibited colony formation by LNCaP cancer cells. CONCLUSIONS: Enantiomeric analogs of natural GTPs, (+)-EGCG and (+)-GCG, are able to potently and specifically inhibit the proteasome both, in vitro and in vivo, while protection of the hydroxyl groups on (+)-EGCG renders the compound completely inactive.     

Crude tea extracts decrease the mutagenic activity of N-methyl-N'-nitro-N-nitrosoguanidine in vitro and in intragastric tract of rats

The effects of tea extracts and their ingredients, catechins and L-ascorbic acid (AsA), on the mutagenicity of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were examined in vitro and in the stomachs of rats using E. coli WP2 and S. typhimurium TA100. The extracts of green tea and black tea leaves decreased the mutagenic activity of MNNG to E. coli WP2 in vitro in a desmutagenic manner. Catechins such as (-)-epigallocatechin from green tea leaves and the low-molecular-weight tannin fraction isolated from black tea extract with HP-20 resin also exhibited inhibitory effects against the mutagenic activity of MNNG. A desmutagenic effect of AsA on MNNG-induced mutagenicity was observed depending on the dose, though it was complicated. The effects were also demonstrated in the stomachs of rats by assaying the bacterial mutagenic in vitro; the tea extracts previously given orally to rats reduced the mutagenic activity of MNNG remarkably, though simultaneous administration showed less effect. The effectiveness of tea extracts for the decrease of MNNG-induced mutagenesis in vitro and in vivo suggests that the habitual drinking of tea may reduce the tumor-initiating potency of MNNG-type nitrosoureido compounds if they are formed in the stomach.     

Effect of tea catechins on mitochondrial DNA 4977-bp deletions in human leucocytes

The catechins in green tea have antioxidative and antimutagenic effects. We examined the effect of green tea enriched with catechins on the presence of mitochondrial DNA (mtDNA) with a common 4977-bp deletion mutation (mtDNA4977) in human leucocytes. Ten healthy females [aged 20.80 +/- 1.03 years] drank 350 ml of catechin-rich tea daily after supper for 5 weeks. Blood samples were collected twice before, and twice after 5 weeks of consuming the tea. Deletions in mtDNA were analyzed using the nested polymerase chain reaction (PCR). We identified a common mtDNA4977 deletion in nine participants before drinking the tea. However, this mtDNA4977 deletion was not evident in leucocytes from most of the participants 5 weeks after drinking the tea. Catechins found in tea might contribute to the maintenance of health status by reducing damage to mtDNA and by maintaining the capacity of mtDNA for oxidative phosphorylation.     

Cancer chemopreventive mechanisms of tea against heterocyclic amine mutagens from cooked meat

Cooking meat and fish under normal conditions produces heterocyclic amine mutagens, several of which have been shown to induce colon tumors in experimental animals. In our search for natural dietary components that might protect against these mutagens, it was found that green tea and black tea inhibit the formation of heterocyclic amine-induced colonic aberrant crypt foci (ACF) in the rat. Since ACF are considered to be putative preneoplastic lesions, we examined the inhibitory mechanisms of tea against the heterocyclic amines. In the initial studies using the Salmonella mutagenicity assay, green tea and black tea inhibited according to the concentration of tea leaves during brewing and the time of brewing; a 2-3-min brew of 5% green tea (w/v) was sufficient for >90% antimutagenic activity. N-hydroxylated heterocyclic amines, which are direct-acting mutagens in Salmonella, were inhibited by complete tea beverage and by individual components of tea, such as epigallocatechin-3-gallate (EGCG). Inhibition did not involve enhanced mutagen degradation, and EGCG and other catechins complexed only weakly with the mutagens, suggesting electrophile scavenging as an alternative mechanism. Enzymes that contribute to the metabolic activation of heterocyclic amines, namely microsomal NADPH-cytochrome P450 reductase and N, O-acetyltransferase, were inhibited by tea in vitro. Studies in vivo established that tea also induces cytochromes P450 and Phase II enzymes in a manner consistent with the rapid metabolism and excretion of heterocyclic amines. Collectively, the results indicate that tea possesses anticarcinogenic activity in the colon, and this most likely involves multiple inhibitory mechanisms.     

Potent antimutagenic activity of white tea in comparison with green tea in the Salmonella assay.

There is growing interest in the potential health benefits of tea, including the antimutagenic properties. Four varieties of white tea, which represent the least processed form of tea, were shown to have marked antimutagenic activity in the Salmonella assay, particularly in the presence of S9. The most active of these teas, Exotica China white tea, was significantly more effective than Premium green tea (Dragonwell special grade) against 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and four other heterocyclic amine mutagens, namely 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3,4,8-trimethyl-3H-imidazo[4,5-f]quinoxaline (4,8-DiMeIQx), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2). Mechanism studies were performed using rat liver S9 in assays for methoxyresorufin O-demethylase (MROD), a marker for the enzyme cytochrome P4501A2 that activates heterocyclic amines, as well as Salmonella assays with the direct-acting mutagen 2-hydroxyamino-3-methylimidazo[4,5-f]quinoline (N-hydroxy-IQ). White tea at low concentrations in the assay inhibited MROD activity, and attenuated the mutagenic activity of N-hydroxy-IQ in the absence of S9. Nine of the major constituents found in green tea also were detected in white tea, including high levels of epigallocatechin-3-gallate (EGCG) and several other polyphenols. When these major constituents were mixed to produce "artificial" teas, according to their relative levels in white and green teas, the complete tea exhibited higher antimutagenic potency compared with the corresponding artificial tea. The results suggest that the greater inhibitory potency of white versus green tea in the Salmonella assay might be related to the relative levels of the nine major constituents, perhaps acting synergistically with other (minor) constituents, to inhibit mutagen activation as well as "scavenging" the reactive intermediate(s).     

Enzymatic tannase treatment of green tea increases in vitro inhibitory activity against N-nitrosation of dimethylamine

In vitro experiments were performed to test inhibition of nitrite-mediated N-nitrosation by individual catechins, green tea, and tannase-treated green tea extracts. The extent of inhibition was measured via nitrosamine formation. Green tea with or without tannase treatment was examined to study nitrosation inhibition in order to evaluate the inhibitory activities with the structural changes of catechins present in the extracts. The results showed that the tannase-treated green tea had a greater ability to inhibit the nitrosation than green tea and ascorbic acid did. The tannase-treated green tea strongly inhibited the formation of N-nitrosodimethylamine (NDMA). Among four major catechins tested, epigallocatechin blocked the N-nitrosation efficiently, and epigallocatechin gallate was more unstable than epigallocatechin at pH 2.0 or 8.0. These results suggest that the consumption of tannase-treated green tea can reduce NDMA formation.     

A para-amino substituent on the D-ring of green tea polyphenol epigallocatechin-3-gallate as a novel proteasome inhibitor and cancer cell apoptosis inducer

Analogs of (-)-EGCG containing a para-amino group on the D-ring in place of the hydroxyl groups have been synthesized and their proteasome inhibitory activities were studied. We found that, 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. These data suggest that the acetylated amino-GTP analogs have the potential to be developed into novel anticancer agents.     

Tea polyphenols, their biological effects and potential molecular targets

Tea is the most popular beverage in the world, second only to water. Tea contains an infusion of the leaves from the Camellia sinensis plant rich in polyphenolic compounds known as catechins, the most abundant of which is (-)-EGCG. Although tea has been consumed for centuries, it has only recently been studied extensively as a health-promoting beverage that may act to prevent a number of chronic diseases and cancers. The results of several investigations indicate that green tea consumption may be of modest benefit in reducing the plasma concentration of cholesterol and preventing atherosclerosis. Additionally, the cancer-preventive effects of green tea are widely supported by results from epidemiological, cell culture, animal and clinical studies. In vitro cell culture studies show that tea polyphenols potently induce apoptotic cell death and cell cycle arrest in tumor cells but not in their normal cell counterparts. Green tea polyphenols were shown to affect several biological pathways, including growth factor-mediated pathway, the mitogen-activated protein (MAP) kinase-dependent pathway, and ubiquitin/proteasome degradation pathways. Various animal studies have revealed that treatment with green tea inhibits tumor incidence and multiplicity in different organ sites such as skin, lung, liver, stomach, mammary gland and colon. Recently, phase I and II clinical trials have been conducted to explore the anticancer effects of green tea in humans. A major challenge of cancer prevention is to integrate new molecular findings into clinical practice. Therefore, identification of more molecular targets and biomarkers for tea polyphenols is essential for improving the design of green tea trials and will greatly assist in a better understanding of the mechanisms underlying its anti-cancer activity.     

Green tea as inhibitor of the intestinal absorption of lipids: potential mechanism for its lipid-lowering effect

Animal and epidemiological studies suggest that green tea catechins may reduce the risk of cardiovascular diseases [e.g., coronary heart disease (CHD)]. The health benefit of green tea has been attributed to its antioxidant and anti-inflammatory properties; however, considerable evidence suggests that green tea and its catechins may reduce the risk of CHD by lowering the plasma levels of cholesterol and triglyceride. Although the mechanism underlying such effect of green tea is yet to be determined, it is evident from in vitro and in vivo studies that green tea or catechins inhibit the intestinal absorption of dietary lipids. Studies in vitro indicate that green tea catechins, particularly (-)-epigallocatechin gallate, interfere with the emulsification, digestion, and micellar solubilization of lipids, critical steps involved in the intestinal absorption of dietary fat, cholesterol, and other lipids. Based on the observations, it is likely that green tea or its catechins lower the absorption and tissue accumulation of other lipophilic organic compounds. The available information strongly suggests that green tea or its catechins may be used as safe and effective lipid-lowering therapeutic agents.     

Distinct effects of tea catechins on 6-hydroxydopamine-induced apoptosis in PC12 cells.

Green tea polyphenols have aroused considerable attention in recent years for preventing oxidative stress related diseases including cancer, cardiovascular disease, and degenerative disease. Neurodegenerative diseases are cellular redox status dysfunction related diseases. The present study investigated the different effects of the five main components of green tea polyphenols on 6-hydroxydopamine (6-OHDA)-induced apoptosis in PC12 cells, the in vitro model of Parkinson's disease (PD). When the cells were treated with five catechins respectively for 30 min before exposure to 6-OHDA, (-)-epigallocatechins gallate (EGCG) and (-)-epicatechin gallate (ECG) in 50-200 microM had obvious concentration-dependent protective effects on cell viability, while (-)-epicatechin (EC), (+)-catechin ((+)-C), and (-)-epigallocatechin (EGC) had almost no protective effects. The five catechins also showed the same pattern described above of the different effects against 6-OHDA-induced cell apoptotic characteristics as analyzed by cell viability, fluorescence microscopy, flow cytometry, and DNA fragment electrophoresis methods. The present results indicated that 200 microM EGCG or ECG led to significant inhibition against typical apoptotic characteristics of PC12 cells, while other catechins had little protective effect against 6-OHDA-induced cell death. Therefore, the classified protective effects of the five catechins were in the order ECG> or = EGCG>EC> or = (+)-C>EGC. The antiapoptotic activities appear to be structurally related to the 3-gallate group of green tea polyphenols. The present data indicate that EGCG and ECG might be potent neuroprotective agents for PD.     

Effect of green tea powder (<Emphasis Type="Italic">Camellia sinensis</Emphasis> L. cv. Benifuuki) particle size on <Emphasis Type="Italic">O</Emphasis>-methylated EGCG absorption in rats; The Kakegawa Study

Tea polyphenols, e.g., (-)-epigallocatechin-3-O-(3-O-methyl gallate (EGCG3”Me), (-)-epigallocatechin-3-O-gallate (EGCG), (-)-epigallocatechin (EGC), (-)-epicatechin-3-O-gallate (ECG), and (-)-epicatechin (EC), are believed to be responsible for the beneficial effects of tea. ‘Benifuuki’, a tea (Camellia sinensis L.) cultivar grown in Japan, is rich in the anti-allergic molecule epigallocatechin-3-O-(3-O-methyl) gallate (EGCG3”Me). Pulverized Benifuuki green tea powder (BGP) is more widely distributed than leaf tea in Japan. Japanese people mix their pulverized tea with water directly, whereas it is common to drink leaf tea after extraction. However, few studies of the effects of BGP particle size on polyphenol bioavailability have been performed. This study was conducted to investigate the absorption of catechins in rats after the intragastric administration of Benifuuki green tea. Therefore, we assessed the plasma concentrations of catechins following the ingestion of BGP with different mean particle sizes (2.86, 18.6, and 76.1 μm) or Benifuuki green tea infusion (BGI) as a control in rats. The bioavailabilities of EGCG3”Me, EGCG, ECG, EGC, and EC were analyzed after the oral administration of a single dose of Benifuuki green tea (125 mg/rat) to rats. The plasma concentrations of tea catechins were determined by HPLC analysis combined with of electrochemical detection (ECD) using a coulometric array. The AUC (area under the drug concentration versus time curve; min μg/mL) of ester-type catechins (EGCG3”Me, EGCG, and ECG) for the BGP 2.86 μm were significantly higher than those in the infusion and 18.6 and 76.1 μm BGP groups, but the AUC of free-type catechins (EGC and EC) showed no differences between these groups. Regarding the peak plasma level of EGCG3”Me adjusted for intake, BGP 2.86 μm and BGI showed higher values than the BGP 18.6 and 76.1 μm groups, and the peak plasma levels of the other catechins displayed the same tendency. The present study demonstrates that the bioavailability of ester-type catechins (EGCG and ECG) can be improved by reducing the particle size of green tea, but the plasma level of EGCG3”Me in the BGI group was similar to that in the BGP 2.86 μm group. This result suggests that drinking Benifuuki green tea with a particle size of around 2 μm would deliver the anti-allergic EGCG3”Me and the anti-oxidant EGCG efficiently.     

Inhibition by green tea catechins of metabolic activation of procarcinogens by human cytochrome P450

Catechins, major polyphenol constituents of green tea, are potent chemopreventive agents against cancers caused by chemical carcinogens in rodents. The effects of four epicatechin derivatives, epigallocatechin gallate (EGCG), epicatechin gallate (ECG), epigallocatechin (EGC) and epicatechin (EC), on the metabolic activation of benzo[a]pyrene (B[a]P), 2-amino-1-methyl-6-phenylimidazo-[4,5-b]pyridine (PhIP) and aflatoxin B(1) (AFB(1)) by human cytochrome P450 (CYP) were examined. B[a]P, PhIP and AFB(1) were activated by respective human CYP1A1, CYP1A2 and CYP3A4 expressed in the membrane fraction of genetically engineered Salmonella typhimurium (S. typhimurium) TA1538 cells harboring the human CYP and human NADPH-CYP reductase (OR), when the membrane fraction was added to S. typhimurium TA98. Galloylated catechins, ECG and EGCG inhibited the mutagenic activation potently, while EGC and EC showed relatively weak inhibitory effects. Catechins also inhibited the oxidations of typical substrates catalyzed by human CYPs, namely ethoxycoumarin O-deethylation by CYP1A1, ethoxyresorufin O-deethylation by CYP1A2 and midazolam 1'-hydroxylation by CYP3A4. The IC(50) values of catechins for the inhibition of human CYP were roughly the same as those seen in the mutagenic activation. EGCG inhibited other forms of human CYP such as CYP2A6, CYP2C19 and CYP2E1, indicating the non-specific inhibitory effects of EGCG toward human CYPs. Furthermore, EGCG inhibited human NADPH-cytochrome CYP reductase (OR) with a K(i) value of 2.5 microM. These results suggest that the inhibition of the enzyme activity of CYP is accounted for partially by the inhibition of OR.     

Green tea catechins in chemoprevention of cancer: A molecular docking investigation into their interaction with glutathione S-transferase (GST P1-1)

The anti- and pro-oxidant effects of green tea catechins have been implicated in the alterations of cellular functions determining their chemoprotective and therapeutic potentials in toxiCIT000y and diseases. The glutathione S-transferases (GSTs; EC 2.5.1.18) family is a widely distributed phase-II detoxifying enzymes and the GST P1-1 isoenzyme has been shown to catalyze the conjugation of GSH with some alkylating anti-cancer agents, suggesting that over-expression of GST P1-1 would result in tumor cell resistance. Here we report the docking study of four green tea catechins and four alkylating anticancer drugs into the GST P1-1 model, as GSTs were found to be affected by tea catechins. The EGCG ligands exhibit higher docking potential with respect to the anticancer agents, with a ligand-receptor interaction pattern indicating an high conformational stability. Consequently, the competition mechanisms favourable for the green tea catechins could lead to enzyme(s) desensitisation with a reduction of the alkylating drugs metabolism. The results provide a useful theoretical contribution in understanding the biochemical mechanisms implicated in the chemotherapeutic use of green tea catechins in oxidative stress-related diseases.     

Green tea catechins in chemoprevention of cancer: a molecular docking investigation into their interaction with glutathione S-transferase (GST P1-1)

The anti- and pro-oxidant effects of green tea catechins have been implicated in the alterations of cellular functions determining their chemoprotective and therapeutic potentials in toxicity and diseases. The glutathione S-transferases (GSTs; EC 2.5.1.18) family is a widely distributed phase-II detoxifying enzymes and the GST P1-1 isoenzyme has been shown to catalyze the conjugation of GSH with some alkylating anti-cancer agents, suggesting that over-expression of GST P1-1 would result in tumor cell resistance. Here we report the docking study of four green tea catechins and four alkylating anticancer drugs into the GST P1-1 model, as GSTs were found to be affected by tea catechins. The EGCG ligands exhibit higher docking potential with respect to the anticancer agents, with a ligand-receptor interaction pattern indicating an high conformational stability. Consequently, the competition mechanisms favourable for the green tea catechins could lead to enzyme(s) desensitisation with a reduction of the alkylating drugs metabolism. The results provide a useful theoretical contribution in understanding the biochemical mechanisms implicated in the chemotherapeutic use of green tea catechins in oxidative stress-related diseases.     

The potential role of green tea catechins in the prevention of the metabolic syndrome - A review

The metabolic syndrome (MetS) represents an emerging health burden for governments and health care providers. Particularly relevant for prevention and early management of MetS are lifestyle conditions including physical activity and the diet. It has been shown that green tea, when consumed on a daily basis, supports health. Many of the beneficial effects of green tea are related to its catechin, particularly (−)-epigallocatechin-3-gallate (EGCG), content. There is conclusive evidence from in vitro and animal studies which provide the concepts for underlying functional mechanisms of green tea catechins and their biological actions. An increasing number of human studies have explored the effects of green tea catechins on the major MetS conditions such as obesity, type-2 diabetes and cardiovascular risk factors. This article provides a comprehensive overview of the human studies addressing the potential benefits of green tea catechins on the MetS.The number of human studies in this field is still limited. However, the majority of human epidemiological and intervention studies demonstrate beneficial effects of green tea or green tea extracts, rich in EGCG on weight management, glucose control and cardiovascular risk factors. The optimal dose has not yet been established.The current body of evidence in humans warrants further attention. In particular, well-controlled long-term human studies would help to fully understand the protective effects of green tea catechins on parameters related to the MetS.