Can green tea do that? A literature review of the clinical evidence
Habitual green tea consumption has long been associated with health benefits including chemoprevention and cardiovascular protection. This non-systematic literature review presents the clinical evidence to date.
A literature review of peer-reviewed articles on observational and interventional studies was conducted to include green tea, its extract or its purified polyphenol (−)-epigallocatechin-3-gallate (EGCG). Electronic databases searched included PubMed (1966-2009) and the Cochrane Library (Issue 4, 2008).
Observational studies are inconclusive on the benefits of habitual consumption of green tea in the prevention of most cancers. However, there are trends towards prevention in breast and prostate cancers. Interventional studies have demonstrated reduction in relapses following surgical resection in colorectal adenomas and increased survival rates in epithelial ovarian cancer. Observational studies indicate that green tea may provide protection against hypertension and reduce the risk for stroke, and interventional studies are providing biochemical and physiological evidence.
Although the overall clinical evidence is inconclusive, habitual green tea consumption may be providing some level of chemoprevention in prostate and breast cancer. Green tea may also attenuate the risk factors association with the development of atherosclerosis thus reducing the incidence of cardiovascular events and stoke.
Green tea; Catechins; Epigallocatechin-3-gallate; Antioxidant; Chemoprevention; Cardiovascular
Green tea (Camellia sinensis) is one of the most popular beverages worldwide and its habitual consumption has long been associated with health benefits. In Asian countries, where tea drinking is a 4000 year-old cultural phenomenon, epidemiological studies show lower incidences of certain cancers and cardiovascular diseases. Many cancers and cardiovascular diseases are associated with Western lifestyle, especially related to diet on health outcomes ([Ziegler et al., 1993]and[Kolonel et al., 2004]). Most of the beneficial effects of green tea are attributed to its polyphenolic flavonoids, known as catechins, including epicatechin (EC), epigallocatechin (EGC), epicatechin-3-gallate (ECG) and the major flavonoid (−)-epigallocatechin-3-gallate (EGCG) (Graham, 1992). These polyphenols account for up to 40% of the dry weight of green tea, and purified EGCG has been the focus of research in recent years.
Extensive research on green tea has taken place over the last decade, especially on the isolated catechin EGCG; however, most are based onin vitroand animal experiments. This emerging body of research is providing the basic scientific evidence for the presumed chemopreventive and cardiovascular properties of green tea. Green tea polyphenols are known antioxidants and it is proposed that these phytochemicals modulate biochemical and physiological processes leading to the initiation and propagation of carcinogenesis and cardiovascular diseases. Although several systematic reviews and meta-analyses have been published most are restricted to the effect of green tea consumption on specific cancer types or cardiovascular diseases or their risk factors. This non-systematic review presents the clinical evidence globally of the effects of green tea in the context of prevention and therapeutic utility in all cancer types, and also in the prevention of cardiovascular and cerebrovascular diseases and the attenuation of associated risk factors.
Databases and search strategy
PubMed (1966-2009) and the Cochrane Library (Issue 4, 2008) were searched up to April 2009. The search terms used included green tea,C. sinensis, catechin, epigallocathechin-3-gallate, review, systematic review, meta-analysis, randomized controlled trial, controlled trial, clinical trial, case-control, cohort, cancer, stroke, obesity, hypercholesterolemia, antioxidant, cardiovascular, hypertension and LDL cholesterol.
Studies included clearly described the population, setting, intervention and comparison groups; and had appropriate measurement of outcomes, statistical and analytical methods, clear reporting of drop-outs and consideration and adjustment for potential confounders.
Interventional studies included randomized controlled trials and controlled trials. Observational studies included prospective cohort and case-control studies which provided risk ratios (relative risk, hazard ratio or odds ratio). Systematic and meta-analyses were also included. Case reports, case series, pilot studies,in vitrocell culture and animal studies were excluded. Studies using herbal mixtures (that included green tea), enriched green tea extracts or with other potential medicinal foods were not included. Studies with significant bias where potential confounders or where no adjustments were made for them were not considered.
Antioxidant effects of green tea
The accumulation of reactive oxygen species (ROS) is the hallmark of oxidative stress (Betteridge, 2000) and has long been associated with intracellular events leading to protein, DNA and lipid damage (Martindale and Holbrook, 2002). These oxidative stress-related intracellular events have also been shown to be strongly correlated to the increased incidence of diseases such as cancer (Oberley, 2002), cardiovascular diseases ([Dhalla et al., 2000]and[Berry et al., 2001]), neurodegenerative diseases (Andersen, 2004) and even in the aging process (Junqueira et al., 2004). It is hypothesized that the antioxidant effect of green tea is responsible for its chemoprevention and disease-modifying properties. Several interventional studies have demonstrated that habitual green tea consumption causes an increase in plasma antioxidant status and quantitative reduction of free radical-induced markers of lipid peroxidation (Rietveld and Wiseman, 2003).
Benzie et al. (1999)demonstrated in an open-labeled randomized controlled study that green tea consumption caused an increase in plasma antioxidant power measured by the ferric reducing/antioxidant power (FRAP) assay. There was also evidence of catechin uptake by the increased urinary excretion of phenolic compounds compared with controls. In another open-labeled randomized controlled study the consumption of 2 cups of green tea (250mg total catechin) over 42days increased antioxidant status, caused a significant reduction in plasma peroxides and decreased the induction of DNA oxidative damage in isolated lymphocytes compared to controls (Erba et al., 2005). A study designed to assess the effect of green tea consumption on pump workers exposed to benzene (a chemical that induces oxidative stress-related toxicities) showed that drinking 6 cups of tea daily over a 6-month period caused significant improvement in antioxidant status and attenuated benzene-induced toxicity (Emara & El-Bahrawy, 2008). In this study green tea abrogated the benzene-induced decrease in plasma glutathione and erythrocyte antioxidant enzyme levels. Another open-labeled controlled study including 14 healthy men showed that the consumption of green tea (6g in 600mL water daily for 7days) increased plasma glutathione, increased FRAP and ameliorated post-exercise increase in lipid hydroperoxidase (Panza et al., 2008).
Anticancer effects of green tea
Numerousin vitrostudies using cancer cell lines and animals have shown that green tea extracts inhibit cell growth and induce apoptosis by the modulation of various intracellular signal transduction pathways. However, these results have not always translated into clinical evidence.
A large systematic review, which included 43 observational studies, 4 randomized trials and 1 meta-analysis of good to moderate overall quality, suggested that green tea consumption may provide some beneficial chemopreventive properties, but the results were inconclusive (Liu et al., 2008). Another systematic review and meta-analysis of observational studies conducted bySeely et al. (2005)demonstrated a non-statistically significant trend towards the prevention of breast cancer. A review of the epidemiological evidence byArts (2008)showed that high habitual intake of green tea significantly reduced the risk of lung cancer in only 4 out of the 20 observational studies.
Zhou et al. (2008)showed that there was no clear clinical evidence that green tea prevented the occurrence of gastric cancer in the meta-analysis of 14 epidemiological studies including 6123 cases and 134,006 controls. The meta-analyses of 13 epidemiological studies byMyung et al. (2009)showed that green tea consumption provided no preventive effect against the risk of development of gastric cancer. However, there was an 18% reduction in the risk for lung cancer with the consumption of least two cups of green tea per day was shown in the meta-analysis of 22 epidemiological studies (Tang et al., in press). Likewise, the meta-analysis of 3 cohort studies and 1 case-control study demonstrated that there was an approximate 20% reduction in the risk of breast cancer associated with high tea intake (Sun et al., 2006).
An early cohort study involving 8552 individuals over 40years of age followed over 9years showed that habitual consumption of green tea was associated with a significant reduction in the incidence of cancer, especially in women consuming more than 10 cups daily (Imai et al., 1997).
A cohort study including 18,244 Chinese men followed for up to 12years showed that tea catechins may prevent gastric and esophageal cancers (Sun et al., 2002). However, a prospective study following 30,370 men and 42,481 women followed for over 8years showed that habitual green tea consumption did not protect against stomach cancer death (Hoshiyama et al., 2002). A larger cohort including 72,943 individuals demonstrated a decreased risk for the development of gastric cancer among women, not men, drinking more than 5 cups daily (Sasazuki et al., 2004).Hoshiyama et al. (2004)showed that there was no risk reduction for the development of stomach cancer in a case-control study involving 157 cases and 285 age-matched controls. There was a trend towards reduced risk of oral cancers in women, not men, in a larger cohort study involving 50,221 individuals followed for over 10years in Japan (Ide et al., 2007).
A study evaluating two prospective cohort studies comprising of 26,311 and 39,604 subjects respectively showed that habitual consumption of green tea had no effect on the prevention of colorectal cancer (Suzuki et al., 2005). The regular intake of green tea was shown to provide protection against the development of colorectal cancer in a large cohort of 69,710 Chinese women followed for 2 to 3years (Yang et al., 2007).
Large cohorts of Japanese adults followed for up to 13years byLin et al. (2008)and up to 11years byLuo et al. (2008)did not demonstrate any protective effect of habitual green tea consumption in the risk for developing pancreatic cancer.
Jian et al. (2004)demonstrated that green tea intake provided a protective effect against prostate cancer in Chinese men where a statistically significant difference was observed between controls and cases. In this study there was a positive association between frequency, quantity and duration of tea drinking. A prospective cohort study including 19,561 Japanese men indicated that green tea consumption provided no beneficial effects in the prevention of prostate cancer (Kikuchi et al., 2006). However, a larger cohort study including 49,920 Japanese men followed for up to 14years showed a demonstrable reduction in the risk of advanced prostate cancer with the habitual consumption of green tea; an additional dose-dependent risk reduction was observed (Kurahashi et al., 2008).
A case-control study including 649 cases of primary lung cancer and 675 controls showed a significant reduction in risk in women, controlled for smoking (Zhong et al., 2001). However, a large cohort study of 41,440 individuals followed over 7years provided no evidence that green tea consumption protected against lung cancer (Li et al., 2008).
A case-control study including 501 breast cancer cases and 594 controls showed that green tea consumption had a significant trend of decreasing risk in a dose-dependent manner, after adjusting for potential confounding factors (Wu et al., 2003).
A study involving 254 cases of epithelial ovarian cancer and 652 controls in China showed that habitual green tea intake was protective and the benefit was dose- and duration-dependent (Zhang et al., 2002). A recent prospective cohort study in 61,057 Swedish women followed for over 15years provided evidence that habitual green tea intake significantly reduced the risk for the development of epithelial ovarian cancer in a dose-dependent manner (Larsson and Wolk, 2005). In a small cohort study following 254 women with diagnosed epithelial ovarian cancer over 3years demonstrated that habitual green tea consumption caused a significant dose-dependent increase in survival rate (Zhang et al., 2004).
Kakuta et al. (2009) demonstrated a reduction in the risk of developing endometrial endometriod adenocarcinoma with habitual green tea consumption in a case-control study which included 437 women. A reduction in the risk for the development was observed for all subtypes of adult leukemia associated with the habitual high intake of green tea in a small case-control study involving 107 cases and 110 controls (Zhang et al., 2008).
Following colorectal adenomas removal a significant reduction in relapse was observed in a randomized placebo-controlled trial over 12months in 125 patients when green tea consumption was increased from 6 to 10 or more cups per day and supplemented with 1.5g green tea extract (Shimizu et al., 2008). The sizes of the relapsed adenomas were also significantly smaller in the treatment group.
A proof-of-principle randomized placebo-controlled clinical trial involving 60 men with confirmed high-grade prostate interstitial neoplasia demonstrated that consumption of 600mg green tea extract per day over 1year significantly reduced the development of tumor in the treated group (3%) compared with placebo group (30%), although total prostate-specific antigen did not differ significantly between groups (Bettuzzi et al., 2006).
Cardiovascular and cerebrovascular protective effects of green tea
Hypertension and hypercholesterolemia are major risk factors for the development of cardiovascular and cerebrovascular diseases and habitual consumption of green tea has been proposed to reduce blood pressure and prevent ischemic heart disease and stroke.
A recent meta-analysis of 5 randomized controlled trials including 343 volunteers (some were hypertensive) demonstrated that tea consumption (median duration of 4weeks) caused a significant reduction in blood pressure (Taubert et al., 2007). Another meta-analysis including 9 studies involving 4378 stroke incidents among 194,965 individuals demonstrated that drinking more than 3 cups of green tea daily significantly reduced the risk of stoke (Arab et al., 2009).
An observational study in 1507 newly diagnosed hypertensive patients (without a history hypertension over the last 10years) demonstrated a protective effect in habitual green tea drinkers (Yang et al., 2004). A large observational study including 40,530 persons in Japan followed for up to 11years also demonstrated a significant risk reduction in cardiovascular disease, including stroke, with habitual green tea consumption ([Kuriyama, 2008]and[Kuriyama et al., 2006]). A case-control study in 201 cases and 201 age and gender-matched controls demonstrated a significant reduction in the risk of subarachnoid hemorrhage in habitual green tea drinkers in a dose-dependent fashion (Okamoto, 2006). More recently, a 5-year follow-up observational study in 6358 individuals demonstrated that green tea consumption significantly reduced the risk of stroke in a dose-dependent manner (Tanabe et al., 2008).
A randomized controlled trial involving 110 healthy subjects given a standardized green tea extract twice daily demonstrated significant reductions in cardiovascular risk factors, including blood pressure, LDL cholesterol and oxidative stress over a 3-month period (Nantz et al., 2009). A small open-labeled randomized crossover study in 20 healthy male smokers showed that the consumption of 400mL of green tea induced immediate reversal of endothelial dysfunction as measured by forearm blood flow (Nagaya et al., 2004). Persistent endothelial dysfunction, caused by oxidative stress, is crucial in the pathogenesis of atherosclerotic plaques which progress to cardiovascular events such as stroke and myocardial infarction.
Antihypercholestolemic effects of green tea
The oxidation of low-density lipoprotein (LDL) cholesterol is critical for the initiation and progression of atherosclerosis. Theoretically, antioxidant green tea catechins should reduce LDL cholesterol oxidation and attenuate atherosclerotic plaque formation to thwart long-term cardiovascular and cerebrovascular events such as myocardial infarction and stroke.
A meta-analysis of 4 interventional studies showed that green tea flavonoids caused a reduction in LDL cholesterol (Hooper et al., 2008).
An open-labeled randomized controlled study over 42days in subjects consuming 2 cups of tea (250mg catechins) demonstrated a modest but significant reduction in LDL cholesterol (Erba et al., 2005). A 24-week stratified randomized placebo-controlled trial in 40 overweight Japanese children showed a significant reduction in LDL cholesterol with consumption of green tea (576mg catechin) (Matsuyama et al., 2008). The randomized controlled trial including 111 subjects a standardized green tea extract produced significant decreases in total and LDL cholesterol in volunteers with initial elevated LDL cholesterol (Nantz et al., 2009).
A randomized controlled study in 40 healthy volunteers showed that the daily intake of 400mg catechin (equivalent to 6-7 cups of green tea) caused a significant reduction in oxidized LDL, although there were no effects on the overall lipid profile (Inami et al., 2007). Subsequently, a small open-labeled crossover study in 5 healthy females showed that the consumption of 4.5g daily of ground green tea over 2weeks significantly reduced the susceptibility of LDL oxidationex vivo(Gomikawa et al., 2008).
Anti-obesity effects of green tea
Obesity is another major risk factor for the initiation and progression of cardiovascular disease and green tea has been proposed to possess multiple properties including its ability to reduce adipocyte differentiation and proliferation, lipogenesis and fat absorption which contribute to weight loss (Wolfram et al., 2006).
In a small randomized double-blind controlled trial, including 17 treated and 18 controls, the daily consumption of green tea (with 690mg catechin) over 12weeks caused a significant reduction in body weight and other anthropometric measurements including waist circumference, body fat mass and subcutaneous fat area (Nagao et al., 2005).Nagao et al. (2007)later confirmed these findings in a larger stratified randomized, double-blind, placebo-controlled trial including 240 volunteers. This study demonstrated that consumption of green tea high in catechin content over 12weeks produced significant reduction in body weight and anthropometric parameters, systolic blood pressure and LDL cholesterol. Another randomized controlled trial in 34 obese women (diagnosed with polycystic ovary syndrome) investigated the weight-reducing effect of green tea over 3months; although there was no significant reduction in body weight, green tea intake attenuated the weight gain that was observed in the control group (Chan et al., 2006). A randomized controlled trial including 132 overweight or obese women over 12weeks demonstrated a significant reduction in abdominal fat and subcutaneous abdominal fat area in the group that consumed green tea compared with the control group (Maki et al., 2009). Green tea consumption over 13weeks following a 4-week very-low energy diet intervention in 104 male and female participants did not significantly affect weight regain compared with placebo (Kovacs et al., 2004).
A recent randomized controlled study showed that the daily consumption of 1200mg of green tea extract over 12weeks in 78 otherwise healthy obese women produced a non-significant weight loss of just 0.15kg, and there were no significant effects on other anthropometric measurements (Hsu et al., 2008). However, another randomized controlled trial in 60 otherwise healthy obese volunteers demonstrated that the daily consumption of 750mg of green tea over a 12-week period produced a significant 3.3kg reduction in body weight which was induced by increased resting energy expenditure and fat metabolism (Auvichayapat et al., 2008).
Although laboratory-based results demonstrate the chemopreventive effects of green tea extracts these must be tempered with the findings from epidemiological and interventional studies which show that habitual green tea consumption may not provide the anticipated protection against most malignancies. Overall, systematic reviews seem to be generally inconclusive regarding the protective effect of green tea for most types of cancers. Large cohort studies show that green tea consumption provides no protection against gastric and pancreatic cancers. However, there appears to be some protective effect in specific types including lung, breast, ovarian and prostate cancer. Intervention studies show that green tea consumption may prevent relapse after surgical removal of colorectal adenomas and enhance survival rates in epithelial ovarian cancer.
Observational studies indicate that habitual green tea consumption may be providing protective effects in the cardiovascular and cerebrovascular systems with a significant reduction in the incidences of hypertension and stroke. Habitual green tea consumption also decreases LDL cholesterol and total cholesterol, and reduces LDL oxidation. There also appears to be an immediate effect to improve endothelial function and enhance blood flow. These combined biochemical and physiological effects may be important factors in the amelioration of initiation and progression of atherosclerosis which support the epidemiological findings. Green tea increases metabolism and energy expenditure and may have utility in weight reduction in obese patients.