Green tea, the everyday beverage for hundreds of millions in Japan and China (see Box 1), has emerged as the latest ‘miracle drug' for preventing just about any ailment humans can suffer from. Unlike patented medicines, green tea has no toxic or harmful side effects, not surprisingly, as its use goes back thousands, if not hundreds of thousands of years. It is cheap and widely available, and if the avalanche of scientific evidence proves right, it could do more than anything else to deliver health to the nation. So why aren't governments in the industrialised nations encouraging people to drink green tea for health? It would cut down on sicknesses and death, avoid drugs and drug side effects that have come to be accepted as almost inevitable, improve national productivity, and save billions from the national health budget.
It would also put the pharmaceutical industry out of a lot of business selling numerous expensive patented drugs targeted at the individual diseases.
Tea consumption through the ages
Tea has been brewed from the leaves of Camellia sinensis in China as far back as 2737 BC, while archaeological evidence reveals that infusions of leaves from various wild plants including tea might have been consumed for more than 500 000 years . Tea was traditionally used to reduce inflammation, improve blood flow, treat infectious diseases, purify the body and maintain mental equilibrium.
Today, it is the most popular beverage worldwide, second only to water, and per capita worldwide consumption is approximately 40L/y. About 3 billion kilograms of tea are produced and consumed annually and growing at a rate of 2.1 percent a year.
Commercial teas come in three major categories: unfermented green, fully fermented black, and semi-fermented oolong. Most of the tea consumed in the world is black tea, with green tea accounting for 20 percent. Tea contains more than 4 000 chemical compounds that may affect the human body, but most attention has been focussed on the polyphenolic compounds (see Box 2)
The Food and Drug Administration (FDA) in the United States, widely criticised for ‘fast-tracking' pharmaceutical drugs over the past decade , issued a rejection of health claims that drinking green tea contributes to preventing cardiovascular diseases in May 2006 , and less than a year before, issued a rejection of health claims of green tea preventing cancers  ( Green Tea Against Cancers , this series). But the medical and scientific community apparently disagree.
The “Asian paradox”
“We do not yet have a full explanation for the ‘Asian paradox,' which refers to the very low incidence of both heart disease and cancer in Asia, even though consumption of cigarettes is greater than in most other countries,” said Bauer Sumpio, M.D., professor and Chief of Vascular Surgery in the Department of Surgery at Yale University, New Haven, Connecticut, USA .
Sumpio is lead author of an article in the Journal of the American College of Surgeons published also in May 2006  reviewing nearly 150 scientific publications on green tea including reports on numerous epidemiological, clinical and experimental studies. The evidence suggests that the average 1.2 litres of green tea consumed daily by many people in Asia may hold the key to the Asian paradox. The active chemicals are generally thought to be the green tea polyphenols, the most abundant (and effective) of which is (-)-epigallocatechin-3-gallate (EGCG) (see Fig 1, Box 2).
Green tea polyphenols
Green tea is rich in the polyphenolic compounds – bonded benzene rings with multiple hydroxyl groups. Polyphenols are classified by structure into flavonoids and non-flavonoids, and those in tea are mainly flavonoids. Catechins make up 80 percent of the flavonoids in green tea. The levels of catechins are generally 30 to 50 percent lower in black teas , as some catechins are converted into theaflavins.
Tea catechins exist as two stereochemical isomers (forms), catechins and epicatechins, depending on the configuration of the 3',4'-dihydroxyphenyl and hydroxyl groups at the 2- and 3- positions of the C-ring (see Fig. 1). Each stereochemical isomer, in turn, exists as two optical isomers:(+) and (-), which are mirror images of each other; (-)-catechin can be modified by esterification with gallic acid. Theaflavins are formed by enzyme-catalysed dimerization (two molecules joining) of catechins.
Tea polyphenols are strong antioxidants, but they seem to have a wide variety of biological effects not directly related to antioxidation (see main text). Evidence also suggests that the biological effects of green tea are over and above those that can be ascribed to individual catechins such as EGCG, or even a mixture of green tea polyphenols.
Figure 1. Tea polyphenols
EGCG has been shown to play a key role in preventing hardening of the arteries. It reduces the amount of blood platelet aggregation, regulates lipids, and inhibits the proliferation and migration of smooth muscle cells, all of which are important factors in reducing cardiovascular disease. EGCG also prevents the growth of certain tumours.
Tea, according to studies reviewed, improves gastrointestinal function and alcohol metabolism; it improves kidney, liver and pancreatic function, protects skin and eyes and alleviates arthritis.
Tea has been used in managing and preventing allergies, diabetes, bacterial and viral infections, tooth cavities, to reduce or cure disease with an inflammatory component and to improve neurological and psychological health.
Green tea reduces risks from cardiovascular disease and cancer
Sumpio and colleagues  cited numerous studies to support the idea that green tea reduces the risks of cardiovascular disease as well as cancer, and additional reports documenting this have appeared since their review.
A meta-analysis on 17 studies published in 2001 reported 11 percent decrease in myocardial infarction when three cups of tea were consumed daily.
A prospective cohort study published in 2002 involving 1 935 patients with a history of myocardial infarction found that age- and gender-adjusted mortality was reduced with tea drinking. Moderate tea drinkers (less than 14 cups of tea/week) presented a relative risk of 0.69, while heavy tea drinkers (14 cups or more /week) presented a relative risk of 0.61 compared with non-drinkers.
Another prospective study involving 8 552 Japanese men and women published in 1997 found a relative risk for cardiovascular disease of 0.52 for men and 0.82 for women who consumed more than 10 cups of green tea a day compared with those consuming less than 3 cups. This study also found a decreased relative risk for cancer of 0.54 for men and 0.57 for women who drank more than 10 cups of green tea per day compared with those who drank less than 3 cups. Furthermore, there was delayed cancer onset for those who drank the larger quantities of green tea: up to 7 years for women, and 3 years for men.
In a case-control study published in 1988, epidemiologists in Japan reported a decrease of gastric cancer in subjects consuming more than 10 cups of green tea per day.
A review of cohort studies in 1998 suggest green tea protects against many cancers including esophageal, stomach, pancreatic, colon, and urinary bladder cancers.
A population-based, case-control study of breast cancer among Chinese, Japanese and Philippine women conducted in Los Angeles County involved 501 breast cancer patients and 594 matched controls. It found no decreased breast cancer risk from drinking black tea, only from drinking green tea. The relative risks adjusted for ethnicity, geographic location and food consumption were 1.00, 0.71 and 0.53 for people drinking no green tea, 0-85.7 mL/day, and more than 85.7 mL/day respectively.
A clinical trial published in 2004 involving 1 507 men and women in Taiwan ages 20 years and older found that habitual consumption of 120 mL/d of green tea or oolong tea for at least one year considerably reduced the risk of hypertension (high blood pressure). After adjusting for different confounding factors such as age, gender, personal and family medical history, dietary and lifestyle factors the risk of hypertension compared to non-drinkers was reduced by 46 percent for those who drank 120 to 599 mL/d, and by 65 percent for those who drank 600mL/d or more .
The Ohsaki National Health Insurance Cohort Study was initiated in 1994, and involved 40 530 Japanese adults aged 40 to 79 years with no history of stroke, coronary heart disease or cancer at baseline. Participants were followed up for up to 11 years for all cause mortality. Green tea consumption was inversely associated with mortality due to all causes and due to cardiovascular disease, but not cancer .
In another study, 203 patients who underwent coronary angiography were enrolled, and green tea consumption was significantly higher in patients without coronary artery disease than in those with the disease .
How green tea delivers its health benefits
As green tea is rich in polyphenols, also known as flavonoids, investigations on how green tea delivers its health benefits have focussed on green tea flavonoids, and a plethora of cellular and molecular effects have been documented .
Heart disease and cancers
The association between flavonoid intake and heart disease was assessed. Three prospective epidemiologic studies: the Seven Countries Study, the Zutphen Elderly Study and a Finnish cohort study, all published in the 1990s, revealed a clear inverse correlation between mortality rates from coronary heart disease and flavonoid intake.
Cell and cell culture studies indicate that EGCG, and to a lesser extent other catechins in green tea, decrease oxidation of low density lipoprotein (LDL) and inhibit the proliferation of smooth muscle cell and endothelial cells, thereby potentially reducing the risk of arteriosclerosis. EGCG also prevents blood vessel and tube formation, causing cessation of cancer growth and preventing certain types of tumours from spreading.
EGCG can act on platelets and other cells to prevent platelet aggregation as shown in many experiments on isolated cells or cell cultures, suggesting that green tea polyphenols have antithrombotic action in preventing blood clots.
Green tea can produce weight loss through the activation of thermogenesis (producing heat by burning fat), thereby reducing obesity, one of the risk factors of heart disease.
Green tea inhibits smooth muscle cell invasion through the basement membrane barrier of the blood vessels, a key event involved in the development and progression of arteriosclerosis (hardening of the arteries) and injury-induced vascular remodelling. EGCG reduces the expression of a matrix metalloproteinase that is important in the migration and growth of endothelial cells and smooth muscle cells.
EGCG induces the transcription factor nuclear factor- k B that promotes smooth muscle cell death. Several catechins especially EGCG inhibit the endothelial growth factor, a key protein involved in blood vessel formation. The sum of these activities results in the cessation and potentially the reversal of various vascular diseases and cancer growth.
New data from 1 031 healthy Caucasian men 35-59 years old, part of a large cross-sectional community based study in Ghent University, Belgium, focusing on job stress and health, show that tea drinkers were less obese, smoked less and drank less alcohol and coffee. The inflammation markers, C-reactive protein, serum amyloid A and haptoglobin, were significantly inversely associated with tea consumption . The authors conclude that tea drinking might be of interest in reducing the inflammatory process underlying cardiovascular disease.
Tea catechins are potent inhibitors of carcinogenesis at the three stages of cancer development: initiation, promotion and progression . Polyphenols from green tea can prevent the formation of nitrosamines in cancer initiation. Nitrosamines are carcinogens also found in tobacco. Tea polyphenolics inhibit the formation of heterocyclic amines, genotoxic carcinogens found in cooked meat and fish, and associated with pancreatic, colon, and breast cancers. EGCG shows the strongest effects against mutations, DNA scissions, and nonenzymic interception of superoxide anions that damage DNA. Another tea polyphenol, ECG is one of the most efficient enzymatic scavengers of free radicals, directly neutralising procarcinogens.
A new study from several universities in Tainan, Taiwan showed that pu-erh tea (a black tea fermented for a long time), green tea, oolong tea, and black tea all have strong antimutagenic action against a number of mutagens including aflatoxin B1 
With respect to cancer promotion, EGCG inhibits the protein kinase activator, an enzyme involved in the cell activation process leading to promotion of tumours . EGCG induces cellular senescence by strongly inhibiting telomerase activity, limiting the cancer cells' lifespan in leukaemia and in solid tumours. EGCG blocks activator protein-1, a signal transducer associated with the development of skin cancer and other tumours
With regard to cancer progression, numerous reports indicate that tea polyphenols inhibit the growth of malignant cells and induce cell death. EGCG inhibits urokinase, a proteolytic enzyme necessary for cancer growth, tissue invasion and metastasis (cancer spreading).
A significant number of reports indicate that naturally occurring green tea polyphenols/flavonoids can protect neurons in many ways, through antioxidant/radical scavenging, anti-inflammation and iron-chelation. A cross-sectional analysis published in 2006 found that higher consumption of green tea among the elderly in Japan is associated with lower prevalence of cognitive impairment . The subjects were 1 003 Japanese aged 70 years and older. The relative risks for cognitive impairment associated with different frequencies of green tea consumption were 1.00 for 3 cups and less a week, 0.62 for 4-6 cups/week or 1 cup/day, and 0.46 for 2 cups or more a day. This may explain the relatively lower prevalence of dementia, especially Alzheimer's disease in Japan than in Europe and North America.
In line with the in vivo findings, many cell culture studies have demonstrated that EGCG protected neurons against neurotoxins, and via numerous molecular mechanisms. Researchers at the Eve Topf Center for Neurodegenerative Diseases and Technion, Haifa, Israel, have recently demonstrated that very low levels of EGCG (1 m M) promoted the survival of neurons by enhancing short-term degradation of the cell-death Bad protein . This low concentration is less than one-hundredth of those that destroy cancer cells [4, 5].
Other chronic diseases
Green tea has been associated with the prevention and treatment of many other systemic disorders. In diabetes, green tea can reduce blood glucose levels and suppress the activity of glucose transporters in the intestinal epithelium reducing dietary glucose intake .
Green tea has anti-inflammatory properties and EGCG was reported to inhibit histamine release by 90 percent in rat cell culture. This anti-inflammatory effect may also benefit people suffering from arthritis.
In terms of kidney disease, catechins increase sodium and prostaglandin E 2 excrection and improves renal circulation.
Green tea modulates the activity of the intestinal microflora and improves bowel function.
Antimicrobial and antiviral action
Green tea protects against infections through its antibacterial and antiviral activity . Extracts of green tea inhibit the effects of Campylobacter jejuni, E. coli , Helicobacter pylori , Vibrio cholerae , Salmonella , Shigella , Clostridium , Mycoplasma , Pseudomonas and Cryptococcus .
A recent investigation found that Pu-erh tea, green tea, oolong tea and black tea all have antimicrobial action against Staphylococcus and Bacillus , but not E. coli .
Crude extracts of green tea as well as two of its main constituents, EGCG and ECG strongly inhibit the growth of the malarial parasite, Plasmodium falciparum in vitro, with IC50 (concentrations giving 50 percent inhibition) in the tens of micromoles/L range . EGCG and ECG also potentiate the effect of artemisin, lowering the IC50 of artemisin from 14 nM to 8.4 nM and 9.5 nM respectively.
Tea strongly inhibit viruses including rotavirus and influenza A virus in animal cell cultures.
The green tea flavonoid, EGCG, was found to inhibit the replication of HIV-1 , the human immunedeficieny virus generally supposed to cause AIDS disease (but see Unraveling AIDS ). In a new report, researchers at Sheffield University UK, and Baylor College of Medicine and Texas Children's Hospital in the US, demonstrated that EGCG binds to CD4 - the cell surface receptor for HIV-1 entry into cells – with extraordinary high affinity, with a binding constant approximately 10 nanomoles/L, thereby preventing the HIV-1 surface glycoprotein gp120 from binding to human CD4+ T cells, the first stage in gaining entry to the cells.
In another report published in 2005, researchers at the Lindsley F. Kimball Research Institute, New York Blood Center, in the US, and Southern Medical University Guangzhoug, Guangdong, in China, demonstrated that green tea as well as black tea polyphenols can inhibit HIV-replication by blocking the formation of a ‘fusion bundle' by the HIV-1 surface glycoprotein gp41, at micromolar concentrations, a hundredth of those that kill cancer cells. Virus-cell fusion is necessary for the virus to enter the cell. The most effective was the green tea polyphenol, 2',2”-bisepigallocatechin digallate (BGCDG) with a CC50 (concentration giving 50 percent inhibition of viral cell fusion) of 0.64 m M, while that of the major green tea polyphenol EGCG was 3.44 m M. The CC50 of black tea TF2B (epitheaflavin-3'-gallate) was 1.28 m M, and that of TF3 (theaflavin digallate), 1.96 m M.
Numerous animal studies corroborated the main findings
Numerous animal studies corroborated the results of human studies and studies on cells and cell cultures, and many potential mechanisms of action have been identified. Some of the animal experiments involve drastic interventions and creation of disease models, and it is questionable whether they are justifiable on ethical grounds, as they add so little to what we already know from human and other non-animal studies.
The evidence is strong
Sumpio and colleagues' comprehensive review covers papers published 2005 and earlier .
They concluded that more studies are needed to better understand green tea's mode of action, particularly at the cellular level. But they also state that, “The evidence is strong that green tea consumption is a useful dietary habit to lower the risk and treat a number of chronic diseases.”
“Prevention is the best cure.” They continue, “The consumption of 6 to 10 cups of tea per day might constitute an aid to increased health, longevity and quality of life.”
They also suggest tea as a potential solution to some of the major health problems of the elderly and society.
New studies have added further weight to the evidence on the health benefits of green tea and its importance in addressing current major health problems  ( Green Tea Against Cancers , this series).