Современные научные методы дали основу для укрепления здоровья эффекты зеленого чая, которые были признаны с древних времен. Многие из механизмов действия зеленого чая и его составляющая EGCG теперь известны. Например, EGCG связывает несколько белков-ферментов, подавляют их деятельность, индуцирует окислительный стресс в клетках, и инициировать передачу сигнала путем связывания с клеточной поверхности белки. Наши недавние исследования показали, что EGCG зеленого чая и может вызвать изменения в уровнях мРНК из gluconeogenic и lipogenic ферментов путем изменения уровней экспрессии соответствующих транскрипционных факторов, HNFs и SREBFs. Однако, эти результаты ставят новые вопросы о механизме, как зеленый чай и его составляющие могут вызывать изменения в уровне транскрипционных факторов. Кроме того, мы показали, что EGCG-свободной фракции зеленого чая были определенные укрепления здоровья эффектов, но активная сущность остается быть определенным. Хотя эти и другие вопросы ждут будущие исследования, эпидемиологические исследования свидетельствуют о том, что употребление зеленого чая способствует человеческого здоровья. Будущие клинические исследования с вмешательством будут предоставлять более убедительные данные о влиянии зеленого чая.
EGCG (-)-эпигаллокатехин галлат
HNF ядерный фактор гепатоцитов
ММП матриксная металлопротеиназа
NF-b ядерный фактор каппа B
PEPCK phosphoenolpyruvate carboxykinase
TNF-α фактор некроза опухоли-α
Green tea (Camellia sinensis Theaceae) was discovered in China in 3000 BC or earlier and has been known to have various medical effects.1) It was brought to Japan from China by Buddhist priests over a thousand years ago. In 1211, a Japanese Zen priest, Yeisai, published the book “Kitcha-Yojoki” (Tea and Health Promotion) in which the methodology of harvesting tea leaves, production processes for tea, and pharmacological effects were described. Nowadays, scientific evidence indicates that green tea is indeed beneficial to health and many of the components of tea have specific health-promoting effects.1–12) For example, tea catechins (Fig. (Fig.1),1), especially (−)-epigallocatechin gallate (EGCG), are considered to be associated with the anti-cancer, anti-obesity, anti-atherosclerotic, anti-diabetic, anti-bacterial, anti-viral, and anti-dental caries effects of tea. Caffeine stimulates wakefulness, decreases the sensation of fatigue, and has a diuretic effect. Theanine and γ-aminobutyric acid act to lower blood pressure and regulate brain and nerve functions. Vitamin C is an anti-scorbutic, prevents cataracts, and strengthens the immune system.
For about 20 years, we have examined the biological activities of green tea and its major polyphenolic compound catechins. In the present article, we review the health-promoting beneficial effects of green tea mainly based on our own published results.
Anti-metastatic and anti-cancer activities
Much attention has been paid to the anti-cancer activity of green tea and tea catechins with animal and cell experiments.1–5,7–12) In 1993, we reported that EGCG, the major catechins in green tea, inhibited the adhesion of cancer cells to endothelial cell layers.13) We also found that EGCG prevented cancer cells from attaching to fibronectin14) and laminin,15) two components of the endothelial basement membrane.16,17) These findings suggested green tea to have an anti-metastatic effect (Fig. (Fig.2).2). Indeed, we found that a green tea infusion was effective at preventing cancer cell metastasis using in vivo and in vitro models.18) The peroral administration of green tea infusion reduced the number of lung colonies of mouse Lewis lung carcinoma cells in a spontaneous metastasis system. The experiments with artificially reconstituted basement membrane indicated that the green tea infusion and its constituent catechins prevented cancer cells from the penetration through the basement membrane. These findings were consistent with those of Taniguchi et al. who reported that EGCG inhibited lung metastasis in mouse B16 melanoma cell lines.19)
Since the metastatic process includes the degradation of the basement membrane containing type IV collagen (Fig. (Fig.2),2), green tea catechins may inhibit collagenases or matrix metalloproteinases (MMPs). We observed that EGCG was a strong inhibitor for MMP-2 and MMP-9 derived from cancer cells20,21) and MMP-3 (stromelysin).22) Since EGCG binds to some proteins including fibronectin in blood plasma,23,24) it could conceivably bind to MMPs directly to exhibit inhibitory activity. This was proven by an experiment using affinity chromatography.20) In later experiments, we found that EGCG inhibited the gene expression of MMPs as well.25,26)
Apoptosis is a programmed cell death and inducing apoptosis in tumor cells is a primary mechanism of action of certain anti-tumor drugs.27,28) The anti-tumor mechanism of green tea appears to include the induction of apoptosis by EGCG through production of H2O2,29) inhibition of cell-cycle progression,30) inhibition of nuclear factor kappa B (NF-κB),3,31) activation of the mitogen-activated protein kinase cascade32) and binding to a 67 kDa laminin receptor.8) In 1996, the first finding that catechins induce apoptosis was made by Hibasami et al.33) in human leukemia Molt 4B cells. We observed that EGCG induced apoptosis in human lymphoma U937 cells as evidenced by the events including formation of apoptotic bodies and degradation of DNA into nucleosomal units.34) There is a structure-function relationship in the apoptosis induction by catechins. The 5′(or 3′)-hydroxyl group in the B-ring plays an important role and a pyrogallol-type structure in a molecule is the minimum requirement for apoptosis induction35) (see Fig. Fig.11).
Consistent with the findings made in vitro, EGCG reduced numbers of colonic aberrant cryptic foci with an increase in apoptosis and enhanced the actions of the drug sulindac in an azoxymethane-induced model of colonic carcinogenesis.36) Gupta et al.37) showed that in autochthonous transgenic adenocarcinomas of the mouse prostate, oral infusion of green tea catechins inhibited prostate cancer development accompanied by enhanced apoptosis.
In addition, we have proposed that the involvement of the direct binding of EGCG to Fas, one of the death receptor proteins on the surface membrane of cells,38) to initiate signal transduction for apoptosis (Fig. (Fig.3).3). The Fas-Fas ligand system is one of the major pathways operating in the apoptotic cascade. The EGCG treatment of human monocytic leukemia U937 cells resulted in elevation of caspase 8 activity and fragmentation of caspase 8. The DNA ladder formation caused by the EGCG treatment was inhibited by the caspase 8 inhibitor. These findings suggested the involvement of the Fas-mediated cascade in the EGCG-induced apoptosis in U937 cells. Affinity chromatography revealed the binding between EGCG and Fas. Thus, the results suggest that EGCG-binding to cell surface Fas triggers the Fas-mediated apoptosis in U937 cells. This study was the first to demonstrate that EGCG binds to cell surface protein to exert its biological action and confirmed the usefulness of affinity chromatography with EGCG immobilized on Sepharose 4B to find out the EGCG-binding proteins as used to identify those in serum.23) The method was successfully used in several later studies to identify proteins involved in EGCG-mediated growth inhibition and apoptosis of cancer cells.39–44) Recently, an alternate method using agarose-bound m-aminophenylsulfonyl boronic acid has been developed to search for EGCG-binding proteins.45) Its use in combination with reduction-oxidation cycling staining made it possible to visualize EGCG-binding proteins. These methods23,45) have provided evidence that EGCG binds to several intracellular proteins such as vimentin and the ATP-dependent RNA helicase DDX5, indicating that EGCG can enter into the cell.
It has been well documented that cancer cells are more susceptible to apoptosis induced by EGCG than normal counterparts.46,47) There is a possibility that normal cells express larger amounts of several EGCG-binding, Fas-like decoy proteins on the cell surface than cancer cells, leading to a diminution in the concentration of EGCG available to bind Fas, resulting in resistance to apoptosis.48) We also showed that differentiated HL-60 cells were resistant to EGCG-induced apoptosis as compared with undifferentiated cells, suggesting that EGCG induces apoptosis selectively in cancer cells.49) However, the change in the expression of cell surface Fas-like decoy proteins after differentiation has yet to be examined.
The EGCG-induced change in the redox state of cancer cells32) may also be involved in the mechanism. It is important to point out that green tea contains a high molecular weight fraction which induces apoptosis in cancer cells by a mechanism including cell cycle arrest.50,51) Thus, our results support the view that drinking green tea is useful to prevent cancer.
Epidemiological and intervention studies are important to reveal the anti-cancer effects of green tea and catechins. The first impressive result was reported in 1989 by Oguni et al.52) who described that the rate of death from stomach cancer in males of the town of Nakakawane was about one fifth of the average for Japanese males overall and that this low rate might be related to the consumption of green tea. Later, it was reported that tea consumption did not correlate to the risk of stomach cancer.53,54) However, other studies revealed an inverse association between green tea consumption and distal gastric cancer among Japanese women55) and a reduced risk of stomach cancer with intake of green tea.56) The discrepancy in results may arise from factors such as differences in the type of tea consumed, in cancer etiology, in confounding lifestyle, and in genetic factors. Future epidemiological studies should include a measurement of urinary tea polyphenols, including epigallocatechin and epicatechin, and their respective metabolites to provide more reliable data on the relationship between tea consumption and cancer risk as exemplified by the study of Sun et al.2)
More convincing data for the effects of green tea were presented by Bettuzzi et al.57) who conducted a clinical trial to assess the safety and efficacy of green tea catechins for the chemoprevention of prostate cancer in individuals with high-grade prostate intraepithelial neoplasias. After 1 year of daily treatment consisting of three capsules containing 200 mg of catechin, only one tumor was diagnosed among the 30 catechin-treated men, whereas 9 cancers were found among the 30 placebo-treated men. Recently, a 15% ointment of Polyphenon® E, a defined extract of green tea catechins, proved to be efficacious and safe in the treatment of external genital warts which are non-malignant squamous cell tumors caused by infections of human papilloma viruses.58,59) These findings are encouraging further clinical studies on chemopreventive effects of green tea catechins.