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綠茶.een tea(Catechins)

DESCRIPTION:

Catechins belong to the flavan-3-ol class of flavonoids. Green tea catechins are the flavan-3-ols found in green tea leaves (Camellia sinensis). The major four catechins in green tea leaves are (-)-epigallocatechin gallate (EGCG), (-)-epicatechin gallate (ECG), (-)-epigallocatechin (EGC) and (-)-epicatechin (EC). They are all polyphenolic substances. Black tea leaves have a much lower content of these catechins. That's because black tea leaves undergo extensive fermentation, during which the majority of the catechins are enzymatically oxidized to the major pigments of black tea leaves, theaflavin and thearubigen. 

The green tea catechins make up approximately 30% of the dry weight of green tea leaves. Of the catechins, EGCG is the most abundant one in green tea leaves. Green tea, an aqueous infusion of green tea leaves, has been a popular beverage in China and Japan for centuries. In these countries, it is thought that green tea has a number of health-promoting benefits, and it is used in the management of various disorders. Epidemiological studies suggest that green tea may have cancer chemopreventive, as well as anti-atherogenic, properties. 

The possible health benefits of green tea are attributed to the catechins. These polyphenolic substances are antioxidants. EGCG appears to be the most potent antioxidant of all the green tea catechins. 

Catechins are flavonoid phytochemical compounds that appear predominantly in green tea. Smaller amounts of catechins are also in black tea, grapes, wine, and chocolate. Four polyphenol catechins in green tea include gallocatechin (GC), epigallocatechin (EGC), epicatechin (EC), and epigallocatechin gallate (EGCG). Due to their potent antioxidant capabilities, catechins, often referred to as "tea flavonoids," are being investigated for their ability to prevent cancer and heart disease. In experimental models, catechins show a wide range of protective effects, including cardioprotective, chemoprotective, and anitmicrobial properties.  

While black tea also has flavonoids, it seems to be green tea (unfermented) that has the higher amount of catechins. Green tea has about 27% catechins, with oolong tea (partially fermented) having about 23%, and black tea (fermented) at approximately 4% catechins. Researchers speculate that green tea's higher concentration of catechins is due to the way it is processed. Green tea harbors important compounds that may be reduced in black tea during the drying and fermentation process that produces black tea. Polyphenols constitute about 15% to 30% of unfermented dried green tea and most of the soluble portion of tea.  

Green tea is the second-most consumed beverage in the world (water is the first) and has been used medicinally for centuries in India and China. A number of beneficial health effects are attributed to regular consumption of green tea and dried/powdered extracts of green tea are available as dietary supplements. Green tea is prepared by picking, lightly steaming and allowing the leaves to dry. Black tea, the most popular type of tea in the U.S., is made by allowing the leaves to ferment before drying. Due to differences in the fermentation process, a portion of the active compounds are destroyed in black tea, but remain active in green tea. The active constituents in green tea are a family of polyphenols (catechins) and flavonols which possess potent antioxidant activity. Tannins, large polyphenol molecules, form the bulk of the active compounds in green tea, with catechins comprising nearly 90%. Several catechins are present in significant quantities; epicatechin (EC), epigallocatechin (EGC), epicatechin gallate (ECG) and epigallocatechin gallate (EGCG). EGCG makes up about 10-50% of the total catechin content and appears to be the most powerful of the catechins – with antioxidant activity about 25-100 times more potent than vitamins C and E. A cup of green tea may provide 10-40mg of polyphenols and has antioxidant activity greater than a serving of broccoli, spinach, carrots or strawberries. A number of commercial green tea extracts are standardized to total polyphenol content and/or EGCG content. 

MECHANISM OF ACTION:

 Green tea catechins have been found to have a number of antioxidant activities, including scavenging of such reactive oxygen species as superoxide, hydroxyl and peroxyl radicals, inhibition of lipid peroxidation, inhibition of 2'-deoxyguanosine oxidation in DNA to 8-hydroxy-2' -deoxyguanosine and inhibition of the oxidation of low-density lipoproteins. EGCG appears to have the greatest antioxidant activity of all the green tea catechins and, in some studies, it has been found to be a more potent antioxidant than ascorbate and reduced glutathione. 

The possible anticarcinogenic activity of the green tea catechins may be accounted for by a number of different mechanisms. Much of the research has been done with EGCG, and it appears that, just as EGCG appears to be the most potent antioxidant of the green tea catechins, it also may have the greatest possible anticarcinogenic activity. EGCG and also EGC and ECG have been found to induce apoptosis in some tumor cell lines. EGCG has been shown to inhibit angiogenesis. EGCG and ECG have been demonstrated to inhibit tyrosine phosphorylation of the receptor tyrosine kinase PDGF-Rbeta (platelet-derived growth factor receptor-beta) and its downstream signaling pathway and, consequently, to inhibit transformation of human glioblastoma cells. Interestingly, only the green tea catechins possessing the gallate group in their structure had this activity. Green tea catechins have also been found to upregulate the synthesis of some hepatic phase II enzymes that are involved in the detoxication (detoxification) of some xenobiotics, including chemical carcinogens. 

In addition to their possible activity in preventing malignant transformation and inhibiting tumor growth, the green tea catechins may have antimetastatic potential. In this regard, EGCG has been found to inhibit the proteolytic enzyme urokinase. Urokinase is an enzyme that cancer cells may use in order to invade normal tissue and form metastases. EGCG and ECG have been demonstrated to inhibit metalloproteinase- -2(MMP-2) (also known as gelatinase A) and metalloproteinase-9(MMP-9) (also known as gelatinase B). These enzymes also appear to play an important role in tumor invasion and metastases. Finally, EGCG has been found to downregulate the expression of the androgen receptor in human prostate cancer cells in culture, consequently inhibiting androgen action. This and its inhibition of 5-alpha reductase may account for EGCG's antiproliferative effect on cultured human prostate cancer cells. 

The possible anti-inflammatory activity of the green tea catechins may, in large part, be accounted for by their antioxidant actions. EGCG has been found to inhibit the activity of the transcription factors AP-1 and NF-kappa B, both of which may mediate many inflammatory processes and both of which may be activated by reactive oxygen species. EGCG's antioxidant activity may itself mediate this inhibition. 

Again, a few different mechanisms may come into play in the possible anti-atherogenic activity of the green tea catechins. PDGF-R beta, which was discussed above, may also be involved in smooth muscle proliferation. Smooth muscle proliferation is involved in the pathogenic process of atherosclerosis. EGCG and ECG have been shown to inhibit tyrosine phosphorylation of PDGF-Rbeta and its downstream signaling pathway and, consequently, the proliferation of smooth muscle. 

The inhibition of the oxidation of low-density lipoproteins is another possible anti-atherogenic mechanism. The green tea catechins may also have antithrombotic activity and may aid in lowering total cholesterol and LDL-cholesterol levels. The antithrombotic effect appears to be at the platelet level. These catechins have been found to inhibit ADP- and collagen-induced platelet aggregation in rats. Coagulation parameters were not affected. The mechanism of the possible cholesterol-lowering effect is unclear. It is thought that the green tea catechins may stimulate the secretion of bile salts and the fecal excretion of cholesterol. 

The green tea catechins have been found to promote thermogenesis. The proposed mechanism for this is inhibition of the enzyme catechol-O-methyl-transferase. This enzyme inactivates norepinephrine.

 The mechanism of the possible antimicrobial activity of the green tea catechins is unclear.

 PHARMACOKINETICS:

 The pharmacokinetics of the green tea catechins in humans remain incompletely understood. They are absorbed from the gastrointestinal tract following ingestion, and blood levels of the various catechins have been measured. However, the extent of their absorption, as well as of their distribution, metabolism and excretion, is unclear. A recent human study indicates that the green tea catechins are mainly found in blood in the protein-rich fraction of plasma and in high-density lipoproteins. They are also found in low-density lipoproteins (LDL), but it is unclear if they are present in sufficient amounts in LDL to enhance its resistance to oxidation. Another recent human study has detected two catechin metabolites in the urine following ingestion of green tea. These metabolites are (-)-5(3', 4', 5' -trihydroxyphenyl)-gamma-valerolactone and (-)-5-(3', 4' -dihydroxyphenyl)-gamma-valerolactone. They appear to be produced by intestinal microorganisms with EGC and EC as the precursors of the above metabolites, respectively. These metabolites were also detected in the plasma and the feces. Human pharmacokinetic studies of the green tea catechins are needed in order to better understand their possible beneficial health effects.

Melting Point:  212-14°C (d)

Molecular Wt: 344

Colour & Description:  white & Crystalline

Purity:  Not less than 99%

Melting Point  242°C

Molecular Wt.. 290

58° in acetone

Colour & Description  Light brown & Crystalline 

Purity  Not less than 99%

 Melting Point  176°C

Molecular Wt.. 326

+16.9° in acetone

Colour & Description  White & Crystalline 

Purity  Not less than 99%

Several epidemiological studies have shown correlations between a higher content of flavonoids in the diet and a risk of cancer and coronary heart disease mortality . These associations were mainly ascribed to the antioxidant capacity of these compounds .

Catechins are a group of flavonoids that have attracted particular attention due to their relative high antioxidant capacity in biological systems and their abundance in the human diet. Catechins are present in vegetables and plant-derived beverages and foods, like red wine, tea, and chocolate . Chemically, catechins are polyhydroxylated flavonoids that exhibit water-soluble characteristics. The catechins that are most widely distributed in the diet are (+)-catechin (C), (–)-epicatechin (EC), (–)-epigallocatechin (EGC), (–)-epicatechin gallate (ECG), and (–)-epigallocatechin gallate (EGCG), which differ in the number and position of the hydroxyl groups in the molecule (Fig. 1).

Figure 1.  Chemical structure of catechins.

Increasing evidence suggests that lipoprotein oxidation is involved in the development of cardiovascular lesions. Thus, plasma antioxidants may play a role by protecting lipoproteins from oxidation, then delaying or preventing the development of cardiovascular pathologies.

To assess the relevance of catechins as antioxidants in human plasma, the in vitro capacity of catechins to prevent plasma lipid oxidation was, and to delay the oxidation of other plasma antioxidants. Since the antioxidant capacity of the catechins has been largely related to the presence and positions of the hydroxyl groups, the relationship between the chemical structure of several catechins and their antioxidant capacity in plasma was studied.

 RESEARCH SUMMARY:

 Though epidemiological data are mixed with respect to the effects of green tea consumption on the incidence of cancer, the predominant data suggest that green tea confers protective effects against many cancers. The incidence of prostate cancer, for example, is the lowest in the world in China, a country with high green tea consumption. Esophageal cancer risk has been found to be reduced by 60% in those who consume two to three cups of green tea daily in China. And smokers in Japan are reportedly less likely to develop lung cancer if they regularly consume green tea. 

A prospective cohort study of 8,552 Japanese found a significant inverse relationship between green tea consumption and cancer incidence. Females consuming more than 10 cups of green tea daily had the most notable protection, compared with those consuming less than three cups per day. 

Green tea consumption has also been associated with a better outcome in some with breast cancer. Higher intakes of green tea (mean: 8 cups/day), compared with lower intakes (mean: 2 cups/day), are associated with a significantly reduced recurrence rate and a longer disease-free period, particularly among premenopausal women with histologically classified stage I and II breast cancer. Stage III cancer patients did not appear to benefit from green tea consumption. Among the specific green tea-related benefits noted in the stage I and II patients were decreased numbers of axillary lymph node metastases. 

Preliminary associations have now been made between higher green tea consumption and reduced levels of breast, prostate, stomach, pancreas, colon and lung cancers. 

Additionally, both green tea generally, and green tea catechins specifically, have shown efficacy in combating several cancers in animal models of carcinogenesis and in vitro tests. Epigallocatechin-3-gallate (EGCG) especially has shown marked anti-cancer effects against breast, colon, prostate, pancreatic, skin, bladder, lung, stomach, ovarian, leukemic and liver cancer, among others. EGCG has been shown to induce apoptosis in several of these cancer types while leaving normal cells unaffected. EGCG has also been shown to inhibit urokinase, a proteolytic enzyme often required for cancer growth. Further, angiogenesis has been shown to be significantly inhibited by EGCG. Recently, EGCG demonstrated an ability to inhibit androgen activity in an androgen-responsive prostate cell line. 

Green tea and its catechins have protected against a broad range of chemically induced cancers in in vitro and animal studies. Those effects have been reported in all stages of some cancers. Additionally, green tea has been reported to enhance the activity of some anti-cancer drugs. It has increased concentrations of doxorubicin, for example, in some cancer cells without also increasing doxorubicin concentrations in normal cells. 

The incidence of cardiovascular disease in China is about 80% lower than in developed countries. High consumption of green tea in China has been associated with this notable decreased risk of cardiovascular disease. Numerous epidemiological studies have associated higher intakes of green tea with decreased risk of atherogenesis in Japan and elsewhere. In vitro and animal studies have shown that green tea and its catechins, especially EGCG, can help prevent oxidation of LDL-cholesterol. Recently, a human study demonstrated that EGCG inhibits phospholipid hydroperoxidation in plasma. Mixed results have been reported on the ability of green tea to significantly reduce LDL-cholesterol oxidation in humans. One recent study produced results suggesting that daily consumption of seven to eight cups of green tea might reduce LDL-cholesterol oxidation to an extent possibly sufficient to reduce the risk of cardiovascular disease. In in vitro and animal studies green tea and its catechins have reduced total cholesterol and LDL-cholesterol levels, have exhibited anti-thrombotic effects and have inhibited the proliferation of smooth muscle, activities that further suggest anti-atherogenic properties. 

Green tea and its constituents have exhibited a variety of anti-inflammatory effects, raising hopes that they might be helpful in treating some forms of arthritis, dermatosis, gout and other inflammatory conditions. In an animal model of inflammatory polyarthritis with similarities to human rheumatoid arthritis, green tea polyphenols, in three experiments, significantly reduced the incidence of arthritis (33 to 50%), compared with controls (84 to 100%). Inflammatory cytokines, tumor necrosis factor and interferon-gamma and RA-specific immunoglobulin-G were all reduced in the animals given the green tea polyphenols. 

These polyphenols, administered orally and topically, have also protected against chemical- and solar-induced skin inflammations in animal experiments. Significant protection against UVB-radiation was reported in one experiment utilizing hairless mice. Oral feeding was more effective than topical application in this case. 

Recently, a green tea extract was tested to see if it could help reduce the risk of cutaneous squamous cell carcinoma and melanoma in subjects whose psoriasis and some other skin diseases were being treated with a combination of psoralens and exposure to ultraviolet A radiation. While this combination treatment has been shown to be very effective, it has also been shown to significantly increase skin cancer risk. In the recent study alluded to above, a green tea extract, given pre- and post-treatment, significantly prevented the DNA damage and inflammatory processes associated with the combination treatment in animals and in human subjects.

 Anther recent study reached the conclusion that green tea extracts increase energy expenditure and fat oxidation in humans. These thermogenic effects were said to go beyond green tea's thermogenic caffeine effects and to be synergistic with them. Compared with placebo, 90 mg of EGCG and 50 mg of caffeine produced a significant 4% increase in 24-hour energy expenditure and a significant decrease in 24-hour respiratory quotient in healthy men. Supplementation with 50 mg of caffeine alone did not have significant thermogenic effects.

 The researchers concluded that "green tea has thermogenic properties and promotes fat oxidation beyond that explained by its caffeine content per se. The green tea extract may play a role in the control of body composition via sympathetic activation of thermogenesis, fat oxidation, or both."

 Finally, there is in vitro evidence that green tea and its catechins have some antiviral and other antimicrobial activities. Recently, various green tea catechins were shown to inhibit extracellular release of vero toxin from enterohemorrhagic Escherichia coli.

Figure 2.  Effect of catechins on (Panel A) TBARS formation and (Panel B) AT and (Panel C) BC depletion. Human plasma was incubated at 37°C with 50 mM AAPH for 300 min in the absence or presence of different concentrations of catechins (5–100 µM). TBARS formation is expressed as the percentage of the value obtained when plasma was incubated in the absence of added catechins. AT and BC are the percentages of the basal value. SEM was smaller than 5%. EGC (open circle); EGCG (square); ECG (triangle); EC (inverted triangle); C (diamond).

Table I.  IC₅₀ for Catechin Inhibiting Plasma TBARS Formation, and AT and BC Depletion。

Figure 3.  Effect of catechins on the kinetics of (Panel A) TBARS formation and (Panel B) AT depletion. Human plasma was incubated at 37°C with 50 mM AAPH in the absence (filled circle) or presence of 100 µM catechins: EGC (open circle); EGCG (square); ECG (triangle); EC (inverted triangle). TBARS formation is expressed as the amount of fluorophere formed during the incubation. AT is the percentage of the zerotime value. SEM was smaller than 5%.

Effect of Catechins on the Kinetics of AA Depletion:
    The effects of the addition of different catechins on AA depletion were studied in a human plasma pool that contained an initial concentration of AA of 57.0 ± 6.4 µM. Figure 4shows the remaining concentration of AA in human plasma as a function of the time of incubation in the presence of 50 mM AAPH. The addition of catechins (100 µM, initial concentration) did not modify the kinetics of depletion of AA, which was completely depleted by 60 min.

Figure 4.  Effect of catechins on AA depletion. Human plasma was incubated at 37°C with 50 mM AAPH in the absence (filled circle) and presence of 100 µM catechins: EGC (open circle); EGCG (square); ECG (triangle); EC (inverted triangle). SEM was smaller than 10%.

 Kinetics of Antioxidant Depletion and TBARS Formation:
　

The kinetics of EC and ECG depletion were studied using the experimental conditions described above (Fig. 5). Plasma was incubated with 50 mM AAPH and supplemented with 100 µM EC or ECG. A 60-min lag phase in the depletion of EC or ECG was observed, after which the depletion of the catechins started following a first-order kinetic decay. This lag phase was independent of the type of catechin tested, and of catechins' initial concentrations, finishing when AA depletion was almost complete (Lotto SB, Fraga CG, unpublished data). In the EC-supplemented plasma, a linear decrease in AT concentration was observed (15% depletion at 240 min). TBARS were detected only after 240 min of incubation, increasing exponentially until 360 min. In the ECG-supplemented plasma, AT concentration did not change during the 360-min incubation. Meanwhile, plasma TBARS were not modified until 240 min (Fig. 5).

Figure 5.  Kinetics of antioxidant depletion and TBARS formation. Human plasma was incubated at 37°C with 50 mM AAPH in the presence of 100 µM (Panel A) EC or (Panel B) ECG. EC and ECG (filled circle), AA (open square), and AT (open circle) are expressed as a percentage of the zerotime value. TBARS formation (open triangle) is expressed as the amount of fluorophere formed during the incubation. SEM was smaller than 10%.