Tea Polyphenols and Cancer PreventionMona Eadington
In areas of the world where people regularly consume large amounts of tea, like Japan and China, it has been observed that there seems to be a reduced incidence of some cancers (Kuroda and Hara, 1999). In recent years, there has been a growing interest in investigating this connection and determining if tea consumption may actually be preventing cancer in these people. Tea is already the most popular beverage in the world, and now it is becoming the center of attention for much of the scientific and medical community.
There are three main methods of processing tea, to produce green tea (20%), black tea(78%), and oolong tea (2%). Together, these teas are consumed on a regular basis by over two thirds of the worlds population. Green tea is the most popular form in China and Japan, and is considered to have the most potent anti-cancer properties. The processing of green tea, which involves steaming or drying fresh tea leaves, causes the least amount of oxidation of the leaves. Black tea, on the other hand, gets its characteristic flavor from the process of aerobic oxidation, or "fermentation", that takes place before the leaves are dried. Oolong tea is intermediate between green tea and black tea, and is only partly oxidized.
Researchers at National Taiwan University and Taiwan Tea Experiment Station have investigated the composition of leaves of the three different types of tea, also taking into account the age of the leaves, as well as the time of year they were harvested (Lin et al, 1996). Using HPLC analysis, the most significant chemicals found in green tea were the polyphenols, especially catechins. Theaflavins composed the most significant chemicals in black tea. The chemical structures of some of the most abundant polyphenols are shown in Figure 1. Using the water from brewing Longjing tea, the least oxidized form of green tea, the greatest concentrations were, in descending order, (-)-epigallocatechin-3-gallate (EGCG), (-)-epigallocatechin (EGC), (-)-epichatechin-3-gallate (ECG), (-)-epicatechin (EC), and theaflavins. The theaflavins, thearubigins, and bisflavanols of black tea were not as well characterized. Most anti-cancer research has focused on EGCG, as it is the chemical that has thus far shown the most promise. Some studies do include other catechins and theaflavins, as well as caffeine, since it is also a major component of tea.
Figure 1. Structures of polyphenols found in green tea.
HPLC analysis was also used to determine that the highest concentrations of polyphenols were found in fresh, young Longjing leaves picked in the summer. Total polyphenols were 1.57 times higher in summer than in spring, and 1.93 times higher in young leaves than in old. Longjing (unfermented green tea) had the highest concentration of polyphenols, whereas Assam (most fermented black tea) had the lowest concentration. Oolong tea (semi-fermented) had intermediate concentrations. A 1.25 % Longjing tea water extract, presumably similar in composition to tea beverages consumed by humans, contained 97.80 m g/ml of EGCG.
There have been numerous epidemiological studies that link green tea consumption with reduced cancer rates and later onset of cancer. A 9-year study done by the Saitama Cancer Center Research Institute in Japan looked at the amount of green tea consumed among a cohort of 8552 individuals (Fujiki et al, 1998). The 384 people who developed cancers during that time were divided up according to whether they consumed less than 3 cups of green tea per day, 4 to 9 cups per day, or over 10 cups per day. In those who drank more than ten cups of tea per day, the onset of cancer was found to be 8.7 years later among females, and 3.0 years later among males, than in those who drank less than 3 cups per day.
Some studies have compared different cities, towns and villages throughout China and Japan, relating their regional cancer rates to the frequency of green tea consumption (Kuroda and Hara, 1999). In Naka-kawane, one of Japans best green tea producing regions, the mortality rates from stomach cancer were one third (in females) to one fifth (in males) of the national average. In Okinawa, where lung cancer mortality is very high, it was found that women who drank more than 10 cups of green tea daily had a risk of lung cancer that was 0.38 times that of non-daily drinkers. In men who drank more than 10 cups daily, the risk was 0.57. These studies and others like them suggest that drinking green tea, a common, inexpensive beverage, may be able to reduce the risk of some cancers by up to one half or more.
Tea extracts, especially EGCG, have been experimentally shown to inhibit growth of several lines of tumor cells. At the National Taiwan University (Lin et al, 1996), pure EGCG and Longjing tea water extract were both found to inhibit cell growth in A-431 epidermal tumor cells. Inhibition occurred in a dose dependent manner. This study also looked at the effect of ECGC on normal cells by applying the compound to mouse normal, immortal, and tumor cells. Even at very high concentrations, ECGC had virtually no effect on the normal cells. However, at higher concentrations, it severely inhibited growth and was cytotoxic to the tumor cells and immortal cells.
Another study found that growth of PC-9 human lung cancer cells was inhibited by ECG, EGCG and EGC, in descending order of inhibition (Fujiki et al, 1998). The authors of this study also used 3H labeled EGCG to determine how easily the chemical is incorporated into cells. They found that incorporation of the labeled EGCG into PC-9 cells was time dependent. After 24 hours, the radioactive marker was found in the cytosol, in the nuclei, and in the membranes. In order to also evaluate the bioavailability of tea Polyphenols, they intubated mice by mouth and administered 3H labeled EGCG into their stomachs. After 24 hours, radioactivity was detected in the mouse liver, kidney, brain, and lungs, indicating that EGCG was readily taken up into all of these organs.
Research has also been done to determine the chemical mechanism by which green tea polyphenols could prevent cancer. Inhibition of certain enzymes necessary for tumor cell growth has been extensively investigated. Urokinase (uPA) is an important proteolytic enzyme for metastatic cells to invade tissues and form tumors, and is one of the most commonly overproduced enzymes in human cancers. At the University of Toledo, Medical College of Ohio (1997), it was found that EGCG inhibits uPA activity in a dose dependent manner. uPA activity was quantified spectroscopically. Compared to amiloride, a well-known uPA inhibitor, the same concentration of EGCG was much less effective. However, EGCG is not toxic and can be consumed at far greater concentrations without ill effects. The researchers at the University of Toledo postulate that uPA inhibition is the main mechanism of anti-cancer activity of green tea polyphenols.
Another study looked at Activator Protein 1 (AP-1), a transcription factor important for tumor-promoter induced neoplastic transformation (Dong et al, 1997). Inhibition of AP-1 by EGCG, as well as by theaflavins, was investigated as a possible cancer prevention mechanism. Epidermal growth factor (EGF) and 12-0-tetreadecanylphorbol-13-acetate (TPA) were used to induce AP-1 cell transformation. Both EGCG and theaflavins inhibited AP-1 activity in a concentration-dependent manner. Caffeine was also tested in this study, and was found to have no effect on TPA or EGF AP-1 activity. As a possible mechanism for inhibition, it was shown that EGCG and theaflavins inhibited the DNA-binding activity of AP-1, as well as the phosphorylation of Ser 63 and Ser 73 in the activated AP-1 complex. The authors of this study conclude that inhibition of AP-1 activation and DNA-binding by EGCG and theaflavins is an important mechanism in prevention of tumor-promoter induced transformation. In reality, there may be several different means of cancer prevention employed by tea polyphenols. Numerous other mechanisms of action have been examined, including antioxidant and free radical scavenging properties (Zhao et al, 1989).
In the study just described, tea polyphenols were shown to inhibit transformation induced by EGF and TPA. However, there are many, many other chemicals that are known carcinogens. A number of studies have been performed to assess the effects of tea polyphenols on the mutagenicity of other major types of carcinogens. Mutagenicity of benzo[a]pyrene (BP), an environmental polycyclic aromatic hydrocarbon and known procarcinogen, was inhibited 95% or more by isolated green tea polyphenols (Weisburger et al, 1996 and Wang et al, 1989). Aflatoxin B1 is a procarcinogen that, once metabolically activated, binds to proteins and DNA. Its activity was also strongly inhibited in both of the aforementioned studies. Inhibition of these and other polycyclic aromatic hydrocarbons may result from interaction of EGCG with cytochrome P-450, and dependent enzymes, responsible for metabolic activation of procarcinogens (Wang et al, 1989).
Using the Ames test, green tea polyphenols were found to inhibit mutagenicity of several heterocyclic and aromatic amines that are known to be carcinogenic (Weisberger et al, 1996). Mutagenicity of 2-Acetylaminofluorene and 2-aminoanthracene was inhibited by 90 % or more by a 3 mg dose of polyphenols. The mutagenicity of two heterocyclic amines found in fried foods, 2-Amino-3-methylimidazo[4,5-f]quinoline and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, were both inhibited by 80 90 % by just 1 mg of polyphenols.
One of the more significant carcinogens found to be inhibited by tea polyphenols is 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK), an important component of tobacco (both smoking and chewing tobacco). Inhibition of carcinogenicity of this chemical may be related to decreased lung cancer rates in mice who are exposed to NNK and given green tea (Weisbuger et al, 1996).
However, not all of the carcinogenic chemicals tested were inhibited by tea polyphenols. Mutagenic activity of 1-Nitropyrene and 2-chloro-4-methylthiobutanoic acid failed to exhibit any significant inhibition at doses of up to 3 mg of polyphenols (Weisberger et al, 1996). It was postulated that the differences in inhibition is due to differences in metabolic activation of these carcinogens. Even though green tea polyphenols may not inhibit carcinogenicity of every chemical studied, the broad spectrum of carcinogens that are inhibited still make tea a promising source of cancer fighting products.
The evidence regarding EGCG and green tea indicates great potential as cancer preventatives. Unlike most modern medical cancer treatments, tea is cheap and nontoxic. It appears to have a wide range of target organs. Its inhibitory effects on the growth of cancer cells is well established. The researchers at the Saitama Cancer Research Institute probably summed it up the best when they concluded that "green tea cannot prevent every cancer, but it is the cheapest and most practical method for cancer prevention available to the general public" (Fujuki et al, 1998).
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Copyright © 2000 Amethyst Schlecht and Koni Stone
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