Doi:10.1016/j.jamcollsurg.2006.01.018

Green Tea, the "Asian Paradox,"and Cardiovascular Disease Bauer E Sumpio, MD, PhD, FACS, Alfredo C Cordova, MD, David W Berke-Schlessel, BS, Feng Qin, MD,Quan Hai Chen, MD Archeologic findings have revealed that infusions of 75% to 80%of the 140 million cups of tea consumed leaves from various wild plants, including the tea plant, might have been consumed for more than 500,000 Next to green tea, one of the most highly consumed yLegends from China and India indicate that use products in Asia is cigarettes. Evidence strongly associates of tea occurred as far back as 2,737 years BC when the cigarette smoking with cardiovascular events, including Chinese Emperor Shen Nung, "Divine Healer," found myocardial infarction, stroke, peripheral vascular disease, himself with a beverage harboring a pleasant aroma and aggravation of stable angina pectoris, vasospastic angina, refreshing taste after dried leaves accidentally blew into rethrombosis after thrombolysis, restenosis after angio- hot boiling waterThis ancient practice associated with plasty, and even sudden death, and medicinal purposes, lifestyle customs, and nutritional These pathologic conditions occur as a result of a num- beliefs was progressively introduced to countries world- ber of detrimental effects leading to atherogenesis, in- wide by tradesmen and travelers Tea was used to cluding an increase in levels of fatty acids, LDL, and very reduce inflammation, improve blood flow, treat infec- LDL, and a decreased turnover of HDL cholesterol.
tious diseases, purify the body, and maintain mental Smoking has also been correlated with aggravation of The people of Japan, China, India, and hypertension, promotion of platelet aggregation, and England elevated tea from a simple beverage to a social modulation and proliferation of vascular endothelial custom, bestowing tea consumption a preferential place cells (EC) and smooth muscle cells Using a bovine aortic vascular SMC scrape injury model, as Scientific validation has slowly accumulated and shown by our laboratorya mitogen-activated protein green tea has attracted more followers as the word has kinases p38 and p44/42 mediated SMC migration spread about its health and medicinal properties. A re- would result as a consequence of nicotine exposure.
cent survey conducted in the US among cancer patients Despite the high consumption of tobacco, Asia and using herbal remedies revealed that green tea was the Japan in particular have among the lowest incidences of most common herb used in 54% of Tea is the arteriosclerosis and lung cancer per capita It has most widely consumed beverage in the world, second been postulated that this paradox, the "Asian Paradox," ex- only to water,with a worldwide per capita consump- ists as a result of the high consumption of green tea in tion of 40 L per yearApproximately 3 billion kilograms this region, and most benefits occur when approxi- of tea are produced and consumed annually and this mately 1.2 L of green tea are consumed every day. For number is growing at a rate of 2.1% per yearIn the example, a Japanese epidemiologic involving Western World, black tea is preferred, and in the Asian 1,371 men older than 40 years of age reported the asso- countries green tea is the primary drink. The practice of ciation between the consumption of ⬎ 10 cups (1,500 drinking iced tea is spreading from the US, where it mL) of green tea a day with a decreased serum concen- began during the early 20th century. It now accounts for tration of total cholesterol, LDL, and triglycerides, andwith an increased HDL concentration. A recent meta-involving 10 cohort studies and 7 case-control Received October 31, 2005; Revised December 7, 2005; Accepted January studies, reported an 11% decrease in myocardial infarc- tion when 3 cups of tea (tea type not specified) were From the Department of Vascular Surgery, Yale University School of Medi-cine, New Haven, CT.
consumed daily. Risk of myocardial infarction was seen Correspondence address: Bauer E Sumpio, MD, PhD, FACS, Department of to be reduced by 44% in individuals drinking ⱖ 1 cup Surgery, Vascular Surgery Section, Yale University School of Medicine, 333Cedar St, New Haven, CT 06520-8062. email: [email protected] (237 mL) of tea per day compared with nondrinkers, in 2006 by the American College of Surgeons ISSN 1072-7515/06/$32.00 Published by Elsevier Inc.
Green Tea and Cardiovascular Disease J Am Coll Surg to 7 years later in women who drank ⱖ 10 cups per day Acronyms and Abbreviations compared with those who drank ⱕ 3. In the case of the ⫽ endothelial cells men, there was also a delay, but of only 3 years. Epide- EGCG ⫽ (-)-epigallocatechin-3-gallate miologists from Japan have also reported in a case- MMP ⫽ matrix metalloproteinase control based on 139 cases of newly diagnosed ⫽ reactive oxygen species ⫽ smooth muscle cells gastric cancer and 278 gender-matched and year ofbirth-matched controls, a decreased risk of gastric canceramong subjects with green tea consumption ⬎ 10 cups a study involving 340 patients with age-, gender-, and community-matched contrIn a prospective cohort In the US and other Western countries, arteriosclero- studywhich involved 1,935 patients with a history of sis and its clinical sequelae, such as myocardial infarc- myocardial infarction, age- and gender-adjusted mortal- tion, stroke, and peripheral vascular disease, account for ity was lower among moderate tea (green or black tea) almost 40% of all mortalityConcomitant evidence is drinkers (⬍ 14 cups of tea/wk) presenting a relative risk emerging from Western nations that green tea, primarily of 0.69, and in heavy drinkers (14 cups of tea/wk) with because of the high concentration of polyphenolic fla- a relative risk of 0.61, when compared with nondrinkers.
vonoids, is a potential tool in the prevention of arterio- Another prospective cohort studyincluding 8,552 sclerosis. Hollman and assessed the associa- Japanese men and women, revealed a decreased relative tion between flavonol intake and cardiovascular disease risk for cardiovascular disease of 0.52 for men, 0.82 for through six prospective epidemiologic studies. In the women, and 0.72 for both genders for those consuming Seven Countries Studythe Zutphen Elderly S ⬎ 10 cups of green tea per day compared with those and in a Finnish cohora clear inverse correlation with consuming ⬍ 3 cups. This same study demonstrated a mortality rates from coronary heart disease was ob- decreased relative risk for cancer of 0.54 for men, 0.57 served. In vitro indicate that the polyphenol for women, and 0.59 for both genders, again for those (-)-epigallocatechin-3-gallate (EGCG) and, to a lesser consuming ⬎ 10 cups of green tea per day compared extent, other catechins in green tea, decrease oxidation with those drinking ⬍ 3 cups per day. Among cancer of LDL and inhibit SMC and EC proliferation, poten- patients, there was a delayed cancer onset for those who tially reducing the risk of arteriosclerosis. These vascular drank larger quantities of green tea. Cancer appeared up effects of EGCG are thought to be a result of its antiox- Table 1. Lifestyle Factors and Mortality from Cardiovascular Disease and Lung Cancer* *Source: World Health Organization, Global Market Information. Database (Euromonitor), †Percentage of total population who smoked at least one cigarette a day.
‡Data refers to estimates of apparent consumption based on cigarette production, imports, and exports during the most recent 3-y moving average between 1992and 2000.
§1 kg ⫽ approximately 311 cups (60⫺70 lb leaves ⫽ 20 lb dry tea ⫽ 2,800 cups tea).
CAD, coronary artery disease.
Vol. 202, No. 5, May 2006 Green Tea and Cardiovascular Disease idant properties.EGCG has also been reported to pre- and black tea is the result of a 60- to 90-minute reaction vent angiogenesis and tube formation, causing cessation of cancer growthand preventing certain types of tu- Polyphenols are bonded benzene rings with multiple mors from Angiogenesis inhibition is hydroxyl groups Polyphenols are categorized by thought to be due primarily to specific receptor block- structure into flavonoids and nonflavonoids, with the age, which alters certain cell regulatory functions, in- chemicals found in tea being mainly flavonoids. All cluding apoptosis of SMC and EC.Vascular endo- three types of teas contain compounds called catechins; thelial growth factor binding to its receptors can be which are currently thought to be primarily responsible reduced by EGCG, affecting downstream signaling.
for the beneficial effects of tea.Green tea has the Data collected from the World Health Organization highest concentration of catechins per gram of dried on lifestyle factors and mortality from cardiovascular leaves compared with black and oolong teas and is the disease and lung cancer, shown in reveal in- best dietary source of this compound. In green tea, cat- creased levels of mortality in countries such as Ireland echins represent 80% of flavonoids, although in black and the United Kingdom, where, in fact, black tea, and tea they only represent 20% to 30% Each tea not green tea, is heavily consumed. Asian countries such contains primarily four different types of catechins including: as Japan and Korea, where green tea is consumed exclu- sively, on the other hand, have lower mortality rates, and (-)-epigallocatechin-3-gallate (EGCG).Other impor- suggesting beneficial properties. In this article, the most tant dietary sources of catechins are red wine, black grapes, recent and relevant data associated with green tea's pu- apples, and chocolate.The most important flavonols in tative cardiovascular protective effects will be reviewed tea are quercetin, kaempferol, and rutin. They are more to provide insight on the clinical significance of its widely distributed and can also be found in red wine, black grapes, apples, onions, cherries, berries, grape-fruits, and cruciferous vegetables.Tea also contains COMPOSITION OF GREEN TEA phenolic acids, including mainly caffeic, gallic, and Tea derives from the leaves of the plant Camellia sinensis, quinic acids, and is an excellent source of methylxan- and is reported to contain nearly 4,000 bioactive chem- thines, containing approximately one-third the amount of ical compounds, one-third of which are polyphenols.
caffeine compared with coffee.A cup of tea contains 40 to EGCG, the major catechin in tea, accounts for 10% of 55 mg of caffeine, and a cup of coffee contains 125 to 150 the total weight Camellia sinensis is indigenous to India and the Far East countries, primarily China andJapan.Three different types of tea: green (no "fermen- METABOLISM AND BIOAVAILABILITY tation"), oolong (moderate "fermentation"), and black In healthy volunteers, drinking green tea resulted in a cat- (complete "fermentation") tea can be derived from this echin concentration in plasma between 0.2% to 2% of the When tea leaves at harvest are withered and im- ingested amount, with a maximal concentration after 1.4 to mediately steamed or heated, the polyphenol oxidase 2.4 hours after consumption.The half-life of EGCG is that is present in the leaves is inactivated, yielding green about 5 hours, although that for (-)-epigallocatechin and tea. If the leaves are harvested, withered, rolled, and epicatechin are shorter, between 2.5 and 3.4 hours.The crushed, the polyphenol oxidase is liberated and is bio- latter two can be partly recovered in urine, although EGCG chemically oxidized, which in turn leads to polymeriza- cannot. In humans, a studyusing radioactively labeled tion of the polyphenols. Polyphenols are converted to catechins demonstrated the efficient metabolism of this fla- dimers and polymers, mainly theaflavins and thearubi- vonoid. Little is known about the bioavailability of theafla- gins. These products are responsible for the characteris- vins and thearubigins, the black tea polyphenols; they both tic yellowish-orange to reddish-brown color of these teas appear to be absorbed. Adding milk to the beverage, as and for physiologic and biochemical properties compa- customized in Great Britain, does not reduce polyphe- rable with those of catechins, but with considerably less nols' bioavailability as this produces no change in the antioxidant effects This process is stopped by blood polyphenol On the other hand, drying the product in a stream of hot air. Oolong tea is milk has been reported to reduce the antioxidant activity produced when this reaction time is about 30 minutes, of tea in vivoThe effects of green tea might be less


Green Tea and Cardiovascular Disease J Am Coll Surg Figure 1. Biochemical composition of green tea. (Reprinted from: Dufresne CJ, Farnworth ER. A review of latest research findings on thehealth promotion properties of tea, J Nutr Biochem 2001;12:405, with permission).
variable than black tea in this respect, as milk is not used can reduce lipid, starch, and protein digestibility, affect for green tea in Japan or other Asian countries.
insulinemic and glycemic responses, increase excretion Polyphenols have an especially strong affinity for pro- of fats, and reduce absorption of cholesterTea poly- line rich proteins such as casein, milk, gelatin, and saliva, phenols have an important interaction with transition and also interfere with the absorption of other com- metal ions, strongly inhibiting nonhaem iron absorption pounds in the The most effective binding capacity in the gastrointestinal tract by forming insoluble com- is held by the large, flexible, and poorly water soluble plexes with this With a varied diet, iron By binding to digestive enzymes, tannins absorption is unaffected; in vegetarian diets, it is advised Vol. 202, No. 5, May 2006 Green Tea and Cardiovascular Disease Table 2. Tea Biochemical Compounds Responsible for structure and contributes to atherogenesis in several Taste, Flavor, and Color ways. First, oxidized LDL has cytotoxic properties that Biochemical compounds can promote endothelial injury. It can also act as a che- moattractant for circulating monocytes, leading to their increased accumulation within plaques. Oxidized LDL Slight astringency and ashyness has also been reported to inhibit the egression of macro- Bitterness and briskness phages from plaques. Lipid and protein oxidation have been correlated with an increase in arteriosclerosis, dia- Phenyl ethanol, Benzaldehyde, betic complications, and a reduction in the immune Nerolidol, Methyl salicylate Linalool, Linalool oxide To prevent cell injury, free radicals can be inhibited by antioxidants and by compartmentalization. The detoxi- fication process occurs through a multistage enzyme sys- tem, where molecules activated by phase I enzymes such as NADPH, p450, and cytochrome, are converted into Flavonol glycosides electrophilic water soluble compounds. They are then conjugated for their inactivation to detoxifying mole- cules, such as glutathione and UDP-glucoronosyl, be- fore their excretion.Antioxidants from nutrients such as tocopherol, ascorbic acid, and carotenoids, which in- cludes lycopenes and polyphenols, contribute to theoverall protection of cell integrity and the immune func- that green tea be consumed between meals to avoid a tion, in conjunction with the cell's constitutive enzy- reduction in the already limited amount of available matic and nonenzymatic protection against RO irIn rats, zinc absorption inhibition has been ob- Polyphenols' antioxidant activity can prevent DNA served, although results for copper remain unclear. Poly- lipid hydroperoxide f phenols also affect the bioavailability of sodium and alu- photograph-enhanced lipid peroxidation.They present minum; it does not interfere with that of calcium, scavenging activity against free superoxide radicals,and peroxynitrite.They also altermany catalytic activities of enzymes, notably the oxida- POLYPHENOL ANTIOXIDANT ACTIVITY tive ones,and can modify the process of protein phos- Free radicals are molecules or atoms with an unpaired phorPolyphenols can inhibit the formation of electron. The unpaired electron results in a high level of the harmful N-nitroso compound, which is the result of reactivity because the free radical "seeks" another elec- the reaction of endogenous or exogenous nitrosating tron to fulfill a pair. Free radicals are a natural byproduct agents when exposed to nitrogen-containing com- of cellular metabolism, but are also generated by the They prevent formation of metal-catalyzed external action of ultraviolet radiation, toxic substances, free radicals by chelating iron and copper.Flavonoids ozone, cigarette smoke, microbial attacks, and even in- can contribute to cells overall antioxidant protection tensive exercise.These free radicals include: hydroxyl mechanism by sparing ␤-carotene, urate, and vitamins radical, nitric oxide, hypochlorous acid, peroxynitrite, singlet oxygen, and alkoxyl radical, among others.
EGCG and a variety of other polyphenols are antioxi- Reactive oxygen species (ROS) deleterious effects on cel- dants and have the ability to neutralize free radicals. The lular membranes and internal structures might contrib- antioxidant potential of EGCG is far greater than vita- ute to the onset of cardiovascular disease, cancer, and mins E and which, along with glutathione and super- impairment of the immune function by altering the me- oxide dismutase, are the cell's main internal defense.
tabolism. DNA, LDL, and other intracellular and extra- EGCG and other antioxidants have the ability to prevent cellular molecules are susceptible to damage by free rad- and protect against oxidative damage occurring on LDL icals. When a free radical attacks LDL, it changes its molecules, and have an antiatherosclerotic eEGCG Green Tea and Cardiovascular Disease J Am Coll Surg inhibition of oxidative damage is dose-dependent. A low reported to affect phospholipase A2 activity and the an- concentration of EGCG of 0.25 ␮M resulted in an antiox- tithrombotic reaction of platelets. This data suggest that idant protective effect of 13%, although a concentration of green tea polyphenols have antithrombotic action ex- 10.00 ␮M had a 68% effect. EGCG is a potent antioxi- plained primarily by antiplatelet activity, with relative dant because it has three polyphenolic benzene rings, sparing of the coagulation function.
yielding eight hydroxyl hydrogens per molecule. Eachhydroxyl hydrogen enhances the ability of EGCG to be POLYPHENOL EFFECTS ON VASOMOTOR TONE a potent antioxidant because the polyphenolic hydro- Hypertension is an important risk factor for develop- gens will attract free radicals displacing LDL and other ment of cardiovascular complications.Antioxidants, biologic Catechin's scavenging activity is like those found in green tea, are very useful in protect- associated with the number of o-dihydroxy and ing and restoring endothelial function.The balance in o-hydroxyketo groups, the number of C2-C3 double the endothelium between vasodilators, such as nitric ox- bonds, the concentration, the solubility, accessibility to ide and ROS, and vasoconstrictors, such as thrombox- the antioxidant by the active group, and the stability of ane and isoprostane, contributes to vascular resistance the reaction product.In green tea, EGCG has the and endothelium-dependent contraction.There is most potent antioxidant effects because of its four dihy- clinical and experimental evidence that tea phytochemi- droxy groups.
cals can also improve endothelial function.In an ep-idemiologic study, tea consumption was shown to be POLYPHENOL MODULATION OF inversely associated with systolic blood pressure.In a PLATELET AGGREGATION clinical involving 1,507 men and women from Cardiovascular disease can be the result of numerous Taiwan ages 20 years and older, researchers found that stimuli, one being platelet aggregation. Platelets will ag- the habitual consumption of ⱖ 120 mL/d of moderate gregate in blood vessels for a variety of reasons, including strength green or oolong tea for at least 1 year, consider- vessel damage and disease. The primary purpose of ably reduced risk of hypertension developing. After ad- platelets is to aid in the repair of the damaged blood justing for different confounding factors, such as age, vessel by forming clots that plug holes in the vessel wall gender, personal and family medical history, dietary and preventing additional blood loss. Platelet aggregation lifestyle factors, they observed that compared with non- can sometimes lead to adverse consequences, including habitual tea drinkers, risk of hypertension developing strokes and myocardial infarctions.
decreased by 46% for those who drank 120 to 599 EGCG can act on platelets and other cells to prevent mL/d, and was reduced by 65% for those who drank ⱖ platelet aggregation. It can inhibit platelet-activating 600 mL on a daily basis.
factor, decreasing the "stickiness" of platelets and de- Several animal studies have also reported a consistent creasing the probability of platelet aggregation.Kang hypotensive effect on rats exposed to green tea and investigated the effects of EGCG on mu- In precontracted aortic rings in rats, puri- rine pulmonary thrombosis in vivo, human platelet aggre- fied catechins evoked endothelium-dependent va- gation ex vivo and in vitro, and on coagulation parameters.
sorelaxation by means of nitric oxide release from the In mice, they observed that EGCG prevented death caused endothelium.EGCG acts as a natural activator of by pulmonary thrombosis in a dose-dependent manner endothelial nitric oxide synthase in EC by increasing and considerably prolonged bleeding time. Ex vivo, aden- its phosphorylation by a phosphatidylinositol-3-OH- osine diphosphate- and collagen-induced rat platelet aggre- kinase-, cAMP-dependent protein kinase-, and Akt- gation was inhibited. EGCG also inhibited adenosine dependent pathway, leading to endothelial-dependent va- diphosphate-, collagen-, epinephrine-, and calcium iono- sorIn an in vivo involving stroke-prone phore A23187-induced human platelet aggregation with- spontaneously hypertensive rats, green and black tea effects out changing the activated partial thromboplastin time, on blood pressure were assessed. The amounts of poly- prothrombin time, or thrombin time. EGCG has also phenols used for this experiment correspond to those been demonstrated to block tyrosine phosphorylation present in approximately 1 L of tea. Systolic and dia- and reduce gene expression of platelet-derived growth stolic pressures were observed to be substantially lower factor-␤ receptor. In diabetic green tea has been in both groups compared with the control group. Green Vol. 202, No. 5, May 2006 Green Tea and Cardiovascular Disease and black tea considerably decreased phosphorylated can also prevent obesity and a fatty liver by enhancing myosin light chains that were measured in the aorta noradrenaline-induced lipolysis and inhibiting pancreatic using Western blotting. Protein expression of catalase lipase activity, as observed in high-fat diet obese was also studied, and was found elevated only in thegreen tea group. 2-amino-5-(N-ethylcarboxyamido)-pentoic acid, a nynhydrin-positive compound from un- POLYPHENOL INHIBITION OF CELL processed tea leaves, has been observed to be a potent PROLIFERATION AND MIGRATION inhibitor of thrombin-stimulated thromboxane forma- Green tea has been shown to inhibit SMC invasion tion.This compound has been reported to be inhibited through the basement barrier, a key event involved in in rats taking green tea, but not in those given processed development and progression of arteriosclerosis and tea extracts. Theanin given at high doses to spontane- injury-induced vascular remodeling. Matrix metallopro- ously hypertensive rats has also been reported to mark- teinases (MMP) are considered important in migration edly decrease blood pressure.
and growth of EC and and in vitro indicate that EGCG reduces expression of MMP. In bo- POLYPHENOL EFFECTS ON CHOLESTEROL vine aortic SMC, EGCG has been found to inhibit con- In hypercholesterolemic rats, green tea considerably re- canavalin A-induced pro-MMP-2 activation and the duced serum and liver cholesterol, the atherogenic in- gelatinolytic activity of EGCG also inhibits dex, and liver weight by lowering the deposition of lip- SMC invasion through the basement membrane barrier, ids.The levels of HDL-cholesterol and triglycerides in in a dose-dependent manner. In a rat carotid artery bal- this study remained unchanged. Other inv loon injury vascular remodeling was assessed reported that consumption by rats of tea plant leaves for when green tea extracts were added. Green tea reduced the a long period of time decreased serum levels of triglyc- area of the intima in the injured arteries by 30%, and the eride and total cholesterol, produced superoxide dis- intimal to the medial area ratio by 36.2% compared with mutase enhancement, and increased the activity of phase controls in vessels after 14 days of injury. Green tea cat- II enzymes in the liver. In hamsters fed a normal or a echins administration substantially increased expression high cholesterol diet, green tea, and black tea exhibited of tissue inhibitor of MMP-2, and reduced the levels of improved plasma lipid profiles, and reduction in LDL active MMP-2 and of the gelatinolytic net activity. This and very LDL oReduction of blood choles- evidence suggests to some extent an association between terol levels might be explained by precipitation of lipids the antiatherogenic action of catechins and the anti- and their fecal A study in sug- invasive and antimetalloproteinase activity.
gested that squalene epoxidase, a rate-limiting enzymefound in tea and involved in cholesterol biogenesis, For new blood vessels to form, angiogenesis, EC, and might also be responsible for this effect.
SMC must migrate. EGCG has been demonstrated to Green tea reduces the levels of cholesterol and triglyc- prevent angiogenesis through several mechanisms, in- erides, inhibits the action of digestive lipase, and de- cluding inhibition of EC and SMC migration, regulat- creases fat absorption, reducing body wObe- ing EC and SMC growth and survival, and inhibiting sity increases the risk for cardiovascular disease and tube formation. EGCG induces the transcription factor cancer, and a lower body weight would reduce the risk of nuclear factor-␬B, promoting SMC death. The sum of suffering from these conditions. Through sympathetic these effects results in the cessation and potentially the activation thermogenesis, green tea plays a role in the reversal of various vascular diseases and cancer growth.
control of body composition and produces weight loss.
Vascular endothelial growth factor is a key protein in- Studies have indicated that preadipocyte apoptosis can volved in It binds to the surface of EC be induced through EGCG by demonstrating a decrease and activates various cell functions including tube for- in Cdk2 expression and an increase in caspase-3 activity.
mation. It has been demonstrated that certain catechins, The treatment of Cdk2 overexpression with caspase-3 especially EGCG, inhibit vascular endothelial growth inhibitor prevented preadipocytes apoptosis through the factor. One hundred micrometers of EGCG resulted in induction of DNA fragmentation, suggesting the EGCG a cell growth inhibition rate of 55% and prevented tube apoptotic effects of Cdk2- and Tea Green Tea and Cardiovascular Disease J Am Coll Surg CANCER AND OTHER HEALTH BENEFITS men was associated with a marked decrease in cancer Similar to atherogenesis, many factors related to diet, incidence with Cohort studies suggest a protective metabolism, and the external environment modulate the effect of green tea for esophageal, stomach, pancreatic, initiation, promotion, and progression of cancer develop- colon, and urinary bladder carcinogenesis, among other ment. Cancer pathogenesis is influenced by the modifica- tion of DNA structure, enzymatic activity, and defense It should be emphasized that although green tea ap- mechanisms, which are a result of the accumulation of pears to be widely associated with protective effects for RIn vitro studies have shown tea catechins as potent cancer, other factors such as genetic differences, geo- inhibitors of carcinogenesis at the three stages of cancer graphic regions, and lifestyles should be taken into con- development.With regard to cancer initiation, in sideration. A population-based, case-control study of vitro studies have shown that polyphenols from green tea breast cancer among Chinese, Japanese, and Filipino can prevent formation of nitrosamines, which are car- women was conducted in Los Angeles County, where cinogens also found in tobaccoPhenolics in tea 501 breast cancer patients and 594 control subjects were have also been found to inhibit heterocyclic amine for- interviewed. Detailed information on lifestyle factors, These molecules are genotoxic carcinogens including diet and the intake of black and green tea, was found in cooked meat and fish, and are associated with collected. It was found that decreased breast cancer risk pancreatic, colon, and breast cancers. EGCG exhibits was unrelated to black tea intake. On the other hand, the strongest effects against mutations, DNA scissions, green tea consumption showed a substantially reduced and nonenzymatic interception of superoxide risk. The adjusted odds ratios being 1.00, 0.71, and 0.53respectively, in association with 0.0, 0 to 85.7 and On the other hand, (-)-epicatechin-3-gallate is one of ⬎ 85.7 mL green tea per day.This study suggests that the most efficient enzymatic scavengers, directly neutral- the decreased cancer risk was irrespective of genetics, izing procarcinogens, as observed in scavenging super- geographic location, and food consumption.
oxide tests and in DNA damage With respect Green tea has also been associated with prevention to cancer promotion, EGCG inhibits the protein kinase and treatment of many other systemic disorders. Of im- activator, an enzyme involved in the cell activation pro- portance in diabetes, green tea can reduce blood glucose cess leading to promotion of tumors by blocking the levels in aged ratsand suppress the activity of glucose interaction and binding between proteins and transporters in the intestinal epithelium, reducing di- EGCG induces cellular senescence by strongly inhibit- etary glucose intake.Green tea has antiinflammatory ing telomerase activity, limiting cancer cells' lifespan in properties and EGCG has been reported to considerably leukemia and in solid Studies have also reported inhibit histamine release by 90% in rat cell culture.
that EGCG and theaflavin-3 to 3=-digallate causes the Quercetin also produces a concentration-dependent in- blockage of activator protein-1, a signal transducer associ- hibition of histamine release, and in antigen-activated ated with development of skin cancer and other cells, provides an antiinflammatory A marked With regard to cancer progression, numerous re- reduction in the incidence of arthritis is produced by porindicate that tea polyphenols inhibit the green tea polyphenols, as demonstrated in arthritic growth of malignant cells and can induce apoptosis.
joints in mice. This is explained by a strong reduction of Theaflavin-3,3=-digallate and EGCG have antiprolifera- inflammatory mediators, neutral endopeptidase activity, tive activities on tumors through the blockage of growth and levels of type II collagen-specific IgG.In terms of factor although EGCG has also been re- renal pathology, catechins increase sodium and prosta- ported to block cell division in G1In addition, glandin E2 excretion and improve renal circulation.
EGCG inhibits urokinase, a proteolytic enzyme neces- Progression of renal failure is suppressed, and mesangial sary for cancer growth, tissue invasion, and proliferation and glomerular sclerotic lesions are atten- In animals, tea has been shown to be bioactive against uated by consumption of green tea, as shown in nephrec- carcinogenesis in liver, skin, lung, gastrointestinal tract, tomized rats.Modulation of the activity of the intes- and hormonal-dependent In humans, tinal microflora and improvement in bowel function has consumption of ⬎ 10 cups (1,800 mL, approximately also been demonstrated.Extracts from tea have been 300 to 400 mg of EGCG) per day among women and reported to inhibit the effects of Campylobacter jejuni, C Vol. 202, No. 5, May 2006 Green Tea and Cardiovascular Disease coli, Helicobacter pylori, vibrio cholerae, Salmonella, shi- Table 3. Putative Mechanisms of Green Tea's Cardioprotec- gella, clostridium, mycoplasma, pseudomona, and Cryptococcus.Tea has also been shown to have antiviral effects, strongly inhibiting rotavirus in monkey cell culture and influenza A in animal cell culture, Sparing of antioxidants (vitamins E and C, ␤ among other virIn addition, flavonoids, in- Alteration of catalytic activity of cluding EGCG and (-)-epicatechin-3-gallate, have been Modification of protein reported to inhibit reverse transcriptase and propagation Platelet aggregation modulator of the retrovirus human immunodeficiency virus.
In conclusion, epidemiologic evidence suggests that chronic diseases, such as cardiovascular disease and can- Inhibition of PDGF ␤ cer, have a lower incidence in countries with a high in- Modification of phospholipase take of tea, particularly green tea. It is possible that those who do or do not drink tea differ in some other way that affects cardiovascular disease, ie, cigarette smoking, di- eNOS activationInhibition etary, and lifestyle factors. The "Asian Paradox" refers to the very low incidence of both heart disease and cancer Enhance superoxide in Asia, even though consumption of cigarettes is greater Enhance phase II enzymes than in most other countries. This discrepancy is Precipitation and fecal elimination of thought to have occurred as a result of a voluminous Inhibition of digestive lipase activity intake of green tea, approximately 1.2 L per day. In vitro Inhibition of pancreatic lipase activity and in vivo studies have shown that the main polyphe- Inhibition of squalene nolic component of green tea, EGCG, is responsible for Reduce LDL and VLDL these protective qualities One of the reasons Enhancement of noradrenaline-induced green tea is so beneficial to our health is the result of its Inhibition of SMC proliferation and vascular hyperplasia strong antioxidant nature, being stronger than oolong and black teas. Since EGCG is an antioxidant, it is able DNA strand breakage to prevent LDL oxidation, which has been shown to play a key role in the pathophysiology of arteriosclerosis.
Another phenomenon that increases the risk of arte- riosclerosis is platelet aggregation. EGCG has been eNOS, endothelial nitric oxide synthase; MMP, matrix metalloproteinase; shown to effectively reduce the amount of platelet aggre- NO, nitric oxide; PAF, platelet-aggregating factor; PDGF, platelet-derived gation by inhibiting certain events at the molecular level.
growth factor; SMC, smooth muscle cell; TIMP-2, tissue inhibitor metallo-proteinase; VEGF, vascular endothelial growth factor; VLDL, very low- Green tea's actions on the vasomotor tone as a lipid regulator, and in SMC proliferation and migration canenhance these cardiovascular protective effects. Studies necessary to fully elucidate and better understand green have also shown that through several means EGCG ef- tea's method of action, particularly at the cellular level.
fectively prevents angiogenesis, causing cessation of cer- In this manner, we can determine the active components tain types of tumor growth. It has been reported that tea involved in this process, perhaps with the goal of prepar- can improve gastrointestinal function, ethanol metabo- ing extracts specifically for those individuals who cannot lism, kidney, liver, and pancreatic function, stomach in- drink tea or simply dislike it. The evidence is strong that juries, skin and eye protection, and alleviation of arthri- green tea consumption is a useful dietary habit to lower tis. It has also been used in the management and the risk and treat a number of chronic diseases. Prevention prevention of allergies, diabetes, bacterial and viral in- is by far the best cure. The consumption of 6 to 10 cups of fections, dental caries, to improve neurologic and psy- tea per day might constitute an aid to increased health, chological health, and to ameliorate or cure other dis- longevity, and quality of life. Tea is becoming a popular eases that have an inflammatory component.
drink and, to some extent, it seems to be a potential solu- Despite the plethora of information, more studies are tion to some of the major health problems of the elderly Green Tea and Cardiovascular Disease J Am Coll Surg and society. It is important to reveal its role and mechanism dant flavonoids and risk of coronary heart disease: the Zutphen of action in today's lifestyle-related diseases.
Elderly Study. Lancet 1993;342:1007–1011.
22. Knekt P, Jarvinen R, Reunanen A, Maatela J. Flavonoid intake
and coronary mortality in Finland: a cohort study. Br Med J1996;312:478–481.
23. Maeda K, Kuzuya M, Cheng XW, et al. Green tea catechins
1. Gutman RL, Ryu BH. Rediscovering tea. An exploration of the
inhibit the cultured smooth muscle cell invasion through the scientific literature. HerbalGram 1996;37:33–48.
basement barrier. Atherosclerosis 2002;166:23–30.
2. History of tea. Available at:
24. Aldini G, Yeum KJ, Carini M, et al. (-)-Epigallocatechin-(3)-
gallate prevents oxidative damage in both the aqueous and lipid 3. Dufresne CJ, Farnworth ER. A review of latest research find-
compartments of human plasma. Biochem Biophys Res Com- ings on the health promotion properties of tea. J Nutr Biochem 25. Hoffman CS, Sonenshein GE. Green tea polyphenol
4. Balentine DA, Wiseman SA, Bouwens LC. The chemistry of
epigallocatechin-3 gallate induces apoptosis of proliferating vascu- tea flavonoids. Crit Rev Food Sci Nutr 1997;37:693–704.
lar smooth muscle cells via activation of p53. FASEB J 2003;17: 5. Bernstein BJ, Grasso T. Prevalence of complementary and al-
ternative medicine use in cancer patients. Oncology 2001;15: 26. Chen A, Zhang L. The antioxidant (-)-epigallocatechin-3-
gallate inhibits rat hepatic stellate cell proliferation in vitro by 6. Yang YC, Lu FH, Wu JS, et al. The protective effect of habitual
blocking the tyrosine phosphorylation and reducing the gene tea consumption on hypertension. Arch Intern Med 2004;164: expression of platelet-derived growth factor-beta receptor. Am Soc Biochem Mol Biol 2003:1⫺30.
7. Vinson JA, Teufel K, Wu N. Green and black teas inhibit
27. Singh AK, Seth P, Anthony P, et al. Green tea constituent
atherosclerosis by lipid, antioxidant, and fibrinolytic mecha- epigallocatechin-3-gallate inhibits angiogenic differentiation nisms. J Agric Food Chem 2004;52:3661–3665.
of human endothelial cells. Arch Biochem Biophys 2002;401: 8. Yang CS, Landau JM. Effects of tea consumption on nutrition
and health. J Nutr 2000;130:2409–2412.
28. Kondo T, Ohta T, Igura K, et al. Tea catechins inhibit angio-
9. Yun AJ, Bazar KA, Lee PY, et al. The smoking gun: many
genesis in vitro, measured by human endothelial cell growth, conditions associated with tobacco exposure may be attribut- migration and tube formation, through inhibition of VEGF able to paradoxical compensatory autonomic response to nic- receptor binding. Cancer Lett 2002;180:139–144.
otine. Med Hypotheses 2005;64:1073–1079.
29. Fujiki H, Suganuma M, Imai K, Nakachi K. Green tea: cancer
10. Kilaru S, Frangos SG, Chen AH, et al. Nicotine a review of its
preventive beverage and/or drug. Cancer Lett 2002;188:9–13.
role in atherosclerosis. J Am Coll Surg 2001;193:538–546.
30. Fujiki H. Two stages of cancer prevention with green tea. J
11. Di Luozzo G, Pradhan S, Dhadwal AK, et al. Nicotine induces
Cancer Res Clin Oncol 1999;125:589–597.
mitogen activated protein kinase dependent vascular smooth muscle cell migration. Atherosclerosis 2005;178:271–277.
epigallocatechin gallate, the main constituent of ‘Tannin' in green 12. Imai K, Nakachi K. Cross sectional study effects of drinking green
tea. Phytother Res 1987;1:44–47.
tea on cardiovascular and liver diseases. Br Med J 1995;310:693.
32. Wang ZY, Hong JY, Huang MT, et al. Inhibition of
13. Peters U, Poole C, Arab L. Does tea affect cardiovascular dis-
ease? A meta-analysis. Am J Epidemiol 2001;15:495–503.
1-butanone-induced tumorigenesis in A/J mice by green tea and 14. Sesso HD, Gaziano JM, Buringe JE, Hennekens CH. Coffee
black tea. Cancer Res 1992;52:1943–1947.
and tea intake and the risk of myocardial infarction. Am J 33. Suganuma M, Okabe S, Oniyama M, et al. Wide distribution of
[3H](-)epigallocatechin gallate, a cancer preventive tea polyphenol, in 15. Mukamal KJ, Maclure M, Muller JE, et al. Tea consumption
mouse tissue. Carcinogenesis 1998;19:1771–1776.
and mortality after acute myocardial infarction. Circulation 34. Imai K, Suga K, Nakachi K. Cancer-preventive effects of drink-
ing tea among a Japanese population. Prev Med 1997;26:769– 16. Imai K, Suga K, Nakachi K. Cancer-preventive effects of drink-
ing green tea among Japanese population. Prev Med 1997;26: 35. Nakachi K, Matsuyama S, Miyake S, et al. Preventive effects of
drinking green tea on cancer and cardiovascular disease: epide- 17. Kono S, Ikeda M, Tokudome S, Kuratsune M. A case-control
miological evidence for multiple targeting prevention. Biofac- study of gastric cancer and diet in Northern Kyusyu, Japan. Jpn J Cancer Res 1988;79:1067–1074.
36. Weisburger JH, Chung FL. Mechanisms of chronic disease
18. American Heart Association/American Stroke Association.
causation by nutritional factors and tobacco products and their Heart disease and stroke statistics—2005 update. Available at: prevention by tea polyphenols. Food Chem Toxicol 2002;40: 19. Hollman PCH, Feskens EJ, Katan MB. Tea flavonols in car-
37. Khokhar S, Magnusdottir SG. Total phenol, catechin, and caf-
diovascular disease and cancer epidemiology. Proc Soc Exp Biol feine contents of teas commonly consumed in the United Kingdom. J Agric Food Chem 2002;50:565–570.
20. Hertog MG, Kromhout D, Aravanis C, et al. Flavonoid intake
38. Sato T, Miyata G. The nutraceutical benefit, part 1: green tea.
and long term risk of coronary heart disease and cancer in the seven countries study. Arch Intern Med 1995;155:381–386.
39. Arts IC, Hollman CH, Kromhout D. Chocolate as a source of
21. Hertog MG, Feskens EJ, Hollman PC, et al. Dietary antioxi-
tea flavonoids. Lancet 1999;354(9177):488.
Vol. 202, No. 5, May 2006 Green Tea and Cardiovascular Disease 40. Hollman PCH, Hertog MGL, Katan MB. Analysis and health
antioxidant activity by chemiluminescence. Anal Biochem effects of flavonoids. Food Chem 1996;57:43–46.
41. Rice-Evans CA, Miller NJ, Paganga G. Antioxidant properties
65. Kaneko T, Matsuo M, Baba N. Inhibition of linoleic acid
of phenolic compounds. Trends Plant Sci 1997;2:152–159.
hydroperoxide-induced toxicity in cultured human umbilical 42. Häkkinen S, Heinonen M, Kärenlampi S, et al. Screening of
vein endothelial cells by catechins. Chem Biol Interact 1998; selected flavonoids and phenolic acids in 19 berries. Food Res 66. Lin AM, Chyi BY, Wu LY, et al. The antioxidative property of
43. Pietta PG, Simonetti P, Gardana C, et al. Catechin metab-
green tea against iron-induced oxidative stress in rat brain.
olites after intake of green tea infusions. Biofactors 1998;8: Chin J Physiol 1998;41:189–194.
67. Katiyar S, Mukhtar H. Tea in chemoprevention of cancer: ep-
44. Nakagawa K, Okuda S, Miyazawa T. Dose-dependent incor-
idemiologic and experimental studies. Int J Oncol 1996;8: poration of tea catechins, (-)-epigallocatechin-3-gallate and (-)-epigallocat-echin, into human plasma. Biosci Biotech Bio- 68. Chen C-W, Ho C-T. Antioxidant properties of polyphenols ex-
tracted from green and black teas. J Food Lipids 1995;2:35–46.
45. Yang CS, Kim S, Yang G-Y, et al. Inhibition of carcinogenesis
69. Chung HY, Yokozawa T, Soung DY, et al. Peroxynitrite-
by tea: bioavailability of tea polyphenols and mechanisms of scavenging activity of green tea tannin. J Agric Food Chem actions. Proc Soc Exp Biol Med 1999;220:213–217.
46. Hollman PCH, Tijburg LBM, Yang CS. Bioavailability of fla-
70. Fiala ES, Sodum RS, Bhattacharya M, Li H. (-)-Epigallocat-echin
vonoids from tea. Crit Rev Food Sci Nutr 1997;37:719–738.
gallate, a polyphenolic tea antioxidant, inhibits peroxynitriteme- 47. Serafini M, Ghiselli A, Luzzi AF. In vivo antioxidant effect of
diated formation of 8-oxodeoxyguanoside and 3-nitrotyrosine.
green and black tea in man. Eur J Clin Nutr 1996;50: 71. Middleton E Jr. Effect of plant flavonoids on immune and inflam-
48. Bravo L. Polyphenols: chemistry, dietary sources, metabolism,
matory cell function. Adv Exp Med Biol 1998;439:175–182.
and nutritional significance. Nutr Rev 1998;56:317–333.
72. Pietta P, Simonetti P. Dietary flavonoids and interaction with en-
49. Hurrell RF, Reddy M, Cook JD. Inhibition of non-haem iron
dogenous antioxidants. Biochem Mol Biol Int 1998;44:1069– absorption in man by polyphenolic-containing beverages. Br J 73. Salah N, Miller NJ, Paganga G, et al. Polyphenolic flavanols as
50. Jackson MJ, McArdle A, McArdle F. Antioxidant micronutri-
scavengers of aqueous phase radicals and as chain-breaking ent and gene expression. Proc Nutr Soc 1998;57:301–305.
antioxidants. Arch Biochem Biophys 1995;322:339–346.
51. Goldfarb AH. Nutritional antioxidants as therapeutic and pre-
74. Guo Q, Zhao B, Shen S, et al. ESR study on the structure-
ventive modalities in exercise-induced muscle damage. Can antioxidant activity relationship of tea catechins and their J Appl Physiol 1999;24:249–266.
epimers. Biochem Biophys Acta 1999;1427:13–23.
52. Kanter M. Free radicals, exercise and antioxidant supplemen-
75. Ali M, Afzal M, Gubler CJ, Burka JF. A potent thromboxane
tation. Proc Nutr Soc 1998;57:9–13.
formation inhibitor in green tea leaves. Prostaglandins Leukot 53. Hillbom M. Oxidants, antioxidants, alcohol and stroke. Front
Essent Fatty Acids 1990;40:281–283.
76. Sagesaka-Mitane Y, Miwa M, Okada S. Platelet aggregation
54. Diplock AT, Charleux J-L, Crozier-Willy G, et al. Functional
inhibitors in hot water extract of green tea. Chem Pharm Bull food science and defense against reactive oxidative species. Br J 77. Kang WS, Lim IH, Yuk DY, et al. Antithrombotic activities of
55. de Groot H, Rauen U. Tissue injury by reactive oxygen species
green tea catechins and (-)-epigallocatechin gallate. Thromb and the protective effects of flavonoids. Fundam Clin Pharma- 78. Yang JA, Chio JH, Rhee SJ. Effects of green tea catechin on
56. Meydani M, Lipman RD, Han SN, et al. The effect of long-
phospholipase A2 activity and antithrombus in streptozotocin term dietary supplementation with antioxidants. Ann NY diabetic rats. J Nutr Sci Vitaminol 1999;45:337–346.
Acad Sci 1998;854:352–360.
79. Kitiyakara C, Wilcox CS. Antioxidants for hypertension. Curr
57. Beck MA. The influence of antioxidant nutrients on viral in-
Opin Nephrol Hypertens 1998;7:531–538.
fection. Nutr Rev 1998;56:S140–S146.
80. Huang Y, Chan NW, Lau CW, et al. Involvement of endothelium/
58. Bradley J, Xu X. Diet, age, and the immune system. Nutr Rev
nitric oxide in vasorelaxation induced by purified green tea (-)epicatechin. Biochim Biophys Acta 1999;1427:322–328.
59. Grimble RF. Nutritional modulation of cytokine biology. Nu-
81. Duffy SJ, Keaney JF, Holbrook M, et al. Short- and long-term
black tea consumption reverses endothelial dysfunction in patients 60. Hughes DA. Effects of dietary antioxidants on the immune func-
with coronary artery disease. Circulation 2001;104:151–156.
tion of middle-aged adults. Proc Nutr Soc 1999;58:79–84.
82. Tijburg LBM, Mattern T, Folts JD, et al. Tea flavonoids and
61. Lampe JW. Health effects of vegetables and fruit: assessing
cardiovascular diseases: a review. Crit Rev Food Sci Nutr 1997; mechanisms of action in human experimental studies. Am J Clin Nutr 1999;70:475S–490S.
83. Yokogoshi H, Kobayashi M. Hypotensive effect of ␥-
62. Nguyen ML, Schwartz SJ. Lycopene: chemical and biological
glutamylmethylamide in spontaneously hypertensive rats.
properties. Food Technol 1999;53:38–45.
Life Sci 1998;62:1065–1068.
63. Pillai SP, Mitscher LA, Menon SR, et al. Antimutagenic/
84. Yokogoshi H, Kato Y, Sagesaka YM, et al. Reduction effect of
antioxidant activity of green tea components and related com- theanine on blood pressure and brain 5-hydroxyindoles in pounds. J Environ Pathol Toxicol Oncol 1999;18:147–158.
spontaneously hypertensive rats. Biosci Biotechnol Biochem 64. Hirayama O, Takagi M, Hukumoto K, Katoh S. Evaluation of
Green Tea and Cardiovascular Disease J Am Coll Surg 85. Hara Y. Hypotensive action of tea polyphenols. In: Hara Y, ed.
105. Ferrara N, Davis-Smyth T. The biology of vascular endothelial
Green tea: health benefits and applications. New York: Marcel growth factor. Endocr Rev 1997;18:4–25.
Dekker Inc; 2001:139–148.
106. Nicosia RF. What is the role of vascular endothelial growth
86. Abe Y, Umemura S, Sugimoto K, et al. Effect of green tea rich
factor-related molecules in tumor angiogenesis? Am J Pathol in ␥-aminobutyric acid on blood pressure of Dahl salt sensitive rats. Am J Hypertens 1995;8:74–79.
107. Shibuya M. Role of VEGF-Flt receptor system in normal and
87. Yokozawa T, Oura H, Sakanaka S, et al. Depressor effect of
tumor angiogenesis. Adv Cancer Res 1995;67:281–316.
tannin in green tea on rats with renal hypertension. Biosci 108. Mustonen T, Alitalo K. Endothelial receptor tyrosine kinase
Biotechnol Biochem 1994;58:855–858.
involved in angiogenesis. J Cell Biol 1995;129:895–898.
88. Lorenz M, Wessler S, Follmann E, et al. A constituent of green
109. Veikkola T, Karkkainen M, Claesson-Welsh L, Alitalo K. Reg-
tea, epigallocatechin-3-gallate, activates endothelial nitric ox- ulation of angiogenesis via vascular endothelial growth factor ide synthase by a phosphatidylinositol-3-OH-kinase-, cAMP- receptors. Cancer Res 2000;60:203–212.
dependent protein kinase-, and Akt-dependent pathway and 110. Mates JM, Sanchez-Jimenez FM. Role of reactive oxygen spe-
leads to endothelial–dependent vasorelaxation. J Biol Chem cies in apoptosis: implications for cancer therapy. Int J Bio- chem Cell Biol 2000;32:157–170.
89. Negishi H, Xu JW, Ikeda K. Black and green tea polyphenols
111. Yoshioka H, Akai G, Yoshinaga K, et al. Protecting effect of a
attenuate blood pressure increases in stroke-prone spontane- green tea percolate and its main constituents against gamma ously hypertensive rats. J Nutr 2004;134:38–42.
ray induced scission of DNA. Biosci Biotech Biochem 1996; 90. Yang TTC, Koo MWL. Hypocholesterolemic effects of Chi-
nese tea. Pharmacol Res 1997;35:505–512.
112. Suganuma M, Okabe S, Sueoka N, et al. Green tea and cancer
91. Lin Y-L, Cheng C-Y, Lin Y-P, et al. Hypolipidemic effect of
chemoprevention. Mutat Res 1999;428:339–344.
green tea leaves through induction of antioxidant and phase II 113. Hecht SS, Hoffmann D. Tobacco-specific nitrosamines, an
enzymes including superoxide dismutase, catalase, and gluta- important group of carcinogens in tobacco and tobacco smoke.
thione S-transferase in rats. J Agric Food Chem 1998;46: 114. Gordon M. Dietary antioxidants in disease prevention. Nat
92. Vinson JA, Dabbagh YA. Effect of green and black tea supple-
Prod Rep 1996;13:265–273.
mentation on lipids, lipid oxidation and fibrinogen in hamster: 115. Fujiki H, Suganuma M, Okabe S, et al. Mechanistic findings of
mechanisms for the epidemiological benefits of tea drinking.
green tea as cancer preventive for humans. Proc Soc Exp Biol FEBS Lett 1998;433:44–46.
93. Chopra M, Thurnham DI. Antioxidants and lipoprotein me-
116. Naasani I, Seimiya H, Tsuruo T. Telomerase inhibition, telom-
tabolism. Proc Nutr Soc 1999;58:663–671.
erase shortening, and senescence of cancer cells by tea catechin.
94. Abe I, Seki T, Umehara K, et al. Green tea polyphenols: novel
Biochem Biophys Res Comm 1998;249:391–396.
and potent inhibitors of squalene epoxidase. Biochem Biophys 117. McCarty MF. Polyphenol-mediated inhibition of AP-1 trans-
Res Commun 2000;268:767–771.
activating activity may slow cancer growth impending angio- 95. Juhel C, Armand M, Pafumi Y, et al. Green tea extract (AR25)
genesis and tumor invasiveness. Med Hypotheses 1998;50: inhibits lipolysis of triglycerides in gastric and duodenal me- dium in vitro. J Nutr Biochem 2000;11:45–51.
118. Russo M, Palumbo R, Tedesco I, et al. Quercetin and anti-
96. Dulloo AG, Duret C, Rohrer D, et al. Efficacy of a green tea
CD95(Fas/Apol) enhance apoptosis in HPB-ALL cell line.
extract rich in catechin polyphenols and caffeine in increasing FEBS Lett 1999;462:322–328.
24-h energy expenditure and fat oxidation in humans. Am J 119. Yokozawa T, Dong E, Chung HY, et al. Inhibitory effect of
Clin Nutr 1999;70:1040–1045.
green tea on injury to a cultured renal epithelium cell line, 97. Wu BT, Hung PF, Chen HC, et al. The apoptotic effect of
LLC-PK. Biosci Biotech Biochem 1997;61:204–206.
green tea (-)-epigallocatechin gallate on 3T3-L1 preadipocytes 120. Liang Y-C, Chen Y-C, Lin Y-L, et al. Suppression of extracel-
depends on the Cdk2 pathway. Agric Food Chem 2005;53: lular signals and cell proliferation by the black tea polyphenol, 98. Han LK, Takaku T, Li J, et al. Anti-obesity action of oolong tea.
121. Lin YL, Tsai SH, Lin Shiau SY, et al. Theaflavin-3-3=-digallate
Int J Obes Relat Metab Disord 1999;23:98–105.
from black tea blocks the nitric oxide synthase by down- 99. Garbisa S, Biggin S, Cavallarin N, et al. Tumor Invasion: mo-
regulating the activation of NF-kappaB in macrophages. Eur lecular shears blunted by green tea. Nat Med 1999;5:1216.
J Pharmacol 1999;367:379–388.
100. Garbisa S, Sartor L, Biggin S, et al. Tumor gelatinases and
122. Khafif A, Schantz SP, Chou T-C, et al. Quantification of
invasion inhibited by the green tea flavanol epigallocatechin- chemopreventive synergism between (-)-epigal-locatechen-3- 3-gallate. Cancer 2001:822–832.
gallate and curcumin in normal, premalignant and malignant 101. Cheng XW, Kuzuya M, Sasaki T, et al. Green tea catechins
human oral epithelial cells. Carcinogenesis 1998;19:419–424.
inhibit neointimal hyperplasia in a rat carotid arterial injury 123. Jankun J, Selman SH, Swiercz R. Why drinking green tea
model by TIMP-2 overexpression. Cardiovasc Res 2004;62: could prevent cancer. Nature 1997;387(6633):561.
124. Liao S, Umekita Y, Guo J, et al. Growth inhibition and regres-
102. Folkman J, Shing Y. Angiogenesis. J Biol Chem 1992;267:
sion of human prostate and breast tumors in athymic mice by tea epigallocatechin gallate. Cancer Lett 1995;96:239–243.
103. Cockerill GW, Gamble JR, Vadas MA. Angiogenesis: models
125. Kao YH, Hiipakka RA, Liao S. Modulation of endocrine sys-
and modulators. Int Rev Cytol 1995;159:113–160.
tems and food intake by green tea epigallocatechin gallate.
104. Hanahan D. Signaling vascular morphogenesis and mainte-
nance. Science 1997;277:48–50.
126. Sugiyama T, Sadzuka Y. Combination of theanine with doxo-
Vol. 202, No. 5, May 2006 Green Tea and Cardiovascular Disease rubicin inhibits hepatic metastasis of M5076 ovarian sarcoma.
inflammatory cell function. Adv Exp Med Biol 1998; Clin Cancer Res 1999;5:413–416.
127. Dreosti IE, Wargovich MJ, Yang CS. Inhibition of carcinogen-
138. Haqqi TM, Anthony DD, Gupta S, et al. Prevention of
esis by tea: the evidence from experimental studies. Crit Rev collagen-induced arthritis in mice by a polyphenolic fraction Food Sci Nutr 1997;37:761–770.
from green tea. Proc Natl Acad Sci 1999;96:4524–4529.
128. Yang CS, Wang Z-Y. Tea and cancer: review. J Natl Cancer Inst
139. Yokozawa T, Oura H, Sakanaka S, et al. Depressor effect of
tannin in green tea on rats with renal hypertension. Biosci 129. Cao J, Xu Y, Chen J, Klaunig JE. Chemopreventive effects of
Biotech Biochem 1994;58:855–858.
green and black tea on pulmonary and hepatic carcinogenesis.
140. Yokozawa T, Chung HY, He LQ, Oura H. Effectiveness of
Fundam Appl Toxicol 1996;29:244–250.
green tea tannin on rats with chronic renal failure. Biosci Bio- 130. Xu M, Baily AC, Hernaez JF, et al. Protection by green tea, black
tech Biochem 1996;60:1000–1005.
tea, and indole-3-carbinol against 2-amino-3-methylimidazo[4,5- 141. Diker KS, Hascelik G. The bactericidal activity of tea against
f]quinoline-induced DNA adducts and colonic aberrant crypts in the Helicobacter pylori. Lett Appl Microbiol 1994;19:299–300.
F344 rat. Carcinogenesis 1996;17:1429–1434.
142. Maity S, Vedasiromoni JR, Ganguly DK. Role of glutathione
in the antiulcer effect of hot water extract of black tea (Camellia 131. Landau JM, Wang Z-Y, Ding W, Yang CS. Inhibition of spon-
sinensis). Jpn J Pharmacol 1998;78:285–292.
taneous formation of lung tumors and rhabdomyosarcomas in 143. Toda M, Okubo S, Ikigai H, et al. The protective activity of tea
A/J mice by black and green tea. Carcinogenesis 1998;19:501– against infection by Vibrio cholerae 01. J Appl Bacteriol 1991; 132. Bushman JL. Green tea and cancer: a review of the literature.
144. Diker KS, Akan M, Hascelik G, Yurdakök M. The bactericidal
Nutr Cancer 1998;31:151–159.
activity of tea against Campylobacter jejuni and Campylobacter 133. Wu AH, Yu MC, Tseng CC, et al. Green tea and risk of breast
coli. Lett Appl Microbiol 1991;12:34–35.
cancer in Asian Americans. Int J Cancer 2003;106:574–579.
145. Yamamoto T, Juneja LR, Chu D-C, Kim M. Chemistry and ap-
134. Zeyuan D, Bingying TXL, Jinming H, Yifeng C. Effect of
plications of green tea. Boca Raton, FL: CRC Press LLC; 1997.
green tea and black tea on the blood glucose, the blood triglyc- 146. Fukuhara K, Miyata N. Resveratrol as a new type of DNA
erides, and antioxidation in aged rats. J Agric Food Chem cleaving agent. Bioorg Med Chem Lett 1998;8:3187–3192.
147. Cordova AC, Jackson LS, Berke-Schlessel DW, Sumpio BE.
135. Shimizu M. Modulation of the intestinal function by food
The cardiovascular protective effect of red wine. J Am Coll substances. Nahrung 1999;43:154–158.
136. Alexis AF, Jones VA, Stiller MJ. Potential therapeutic appli-
148. Hofmann CS, Sonenshein GE. Green tea polyphenol
cations of tea in dermatology. Int J Dermatol 1999;38:735– epigallocatechin-3 gallate induces apoptosis of proliferating vascular smooth muscle cells via activation of p53. FASEB J 137. Middleton E Jr. Effect of plant flavonoids on immune and

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