Prevention of chronic diseases by tea: possible mechanisms and human relevance.
Yang CS, Hong J.
Annu Rev Nutr. 2013 Jul 17;33:161-81. doi: 10.1146/annurev-nutr-071811-150717. Epub 2013 Apr 29.
PMID: 23642203
ABSTRACT
Tea, made from leaves of the plant Camellia sinensis, Theaceae, has been used by humans for thousands of years, first as a medicinal herb and then as a beverage that is consumed widely. For the past 25 years, tea has been studied extensively for its beneficial health effects, including prevention of cancer, reduction of body weight, alleviation of metabolic syndrome, prevention of cardiovascular diseases, and protection against neurodegenerative diseases. Whether these effects can be produced by tea at the levels commonly consumed by humans is an open question. This review examines these topics and elucidates the common mechanisms for these beneficial health effects. It also discusses other health effects and possible side effects of tea consumption. This article provides a critical assessment of the health effects of tea consumption and suggests new directions for research in this area.
Tea is made of the leaves of the plant Camellia sinensis, Theaceae, a warm-weather evergreen. Tea leaves have been used for medicinal purposes since ancient days and later as a popular beverage. Cultivated in more than 30 countries, approximately 3.8 million tons of tea are produced annually. Depending on the processing of the tea leaves, tea is classified into three major types: green tea, black tea, and oolong tea. Green tea, which accounts for 20% of the world's tea production, is mainly produced and consumed in Asian countries such as China and Japan. Black tea, which accounts for 78% of the world's tea production, is produced in the warmer climate in south Asia, South America, and Africa and is consumed worldwide. Oolong tea, which accounts for 2% of the world's tea production, is mainly produced and consumed in southeast China, Taiwan, and Japan (5, 73).
For the past 25 years, tea has been studied for its potential beneficial health effects. These include the prevention of cancer, reduction of body weight, alleviation of metabolic syndrome (MetS), prevention of cardiovascular diseases (CVDs), and protection against neurodegenerative diseases. Most of these beneficial effects are believed to be due to the polyphenols in green tea, although caffeine also contributes. A unique amino acid, theanine (gamma-ethylamino-L-glutamic acid), has been shown to have neuroprotective effects. Many of the results of these studies have been published in different journals and were recently reviewed in a special issue of the journal Pharmacological Research (volume 64; 2011), edited by Chung S. Yang and Joshua D. Lambert.
Cancer and CVDs are the two most common diseases that lead to death. Overweight, obesity, and diabetes are emerging as major health issues, and the closely related MetS also predisposes individuals to CVDs. If tea could prevent or delay the development of these diseases, the public health implications would be substantial. Because of this, there is immense public interest on this topic. Unfortunately, some of the beneficial effects found in the laboratory may have been overextrapolated and propagated in the news media, in popular magazines, and even in review articles.
This review critically examines these topics to elucidate the possible common mechanisms involved and to evaluate the human relevance of the published health effects. It discusses other health effects of tea consumption as well as the possible side effects caused by consumption of excessive amounts of tea extracts, mainly from dietary supplements. Selected examples are used to illustrate relevant effects and elucidate mechanisms that are consistent with the biochemical activities of tea constituents. Because of the large number of publications on this topic, we use information from recently published meta-analyses and systematic reviews to help assess the relative strengths of the existing data. We cite recent review articles, when available, to cover the different topics, and we cite only selected original papers, particularly those published after completion of the major systematic reviews. Our goal is to explicate the health effects of tea consumption and suggest directions for future research in this area.
CHEMISTRY OF TEA CONSTITUENTS
In the manufacturing of green tea, tea leaves are steamed, rolled, and dried, which inactivates the enzymes with minimum oxidation of the constituents. The drying of tea leaves helps to stabilize tea constituents upon storage. Green tea possesses characteristic polyphenolic compounds known as catechins, which include (-)-epigallocatechin-3-gallate (EGCG), (-)-epigallocatechin (EGC), (-)-epicatechin-3-gallate (ECG), and (-)-epicatechin (EC). The structures of catechins together with L-theanine are shown in Figure 1. Catechins account for about 30% to 42% of the dry weight of brewed green tea, and EGCG is the major form of tea catechins. Tea leaves also contain lower quantities of other polyphenols, such as quercetin, kaempferol, and myricetin, as well as alkaloids, such as caffeine and theobromine. A typical brewed green tea beverage (e.g., 2.5 g tea leaves in 250 ml of hot water) contains 240 to 320 mg of catechins, of which 60% to 65% is EGCG, and 20 to 50 mg of caffeine (5, 73).
In the manufacturing of black tea, the tea leaves are withered, crushed, and allowed to undergo enzyme-mediated oxidation in a process commonly referred to as fermentation. During this process, most of the catechins are oxidized, dimerized, and polymerized to form theaflavins and thearubigins (5, 73). Theaflavins are produced from the dimerization of two catechin molecules. Theaflavins exist in four forms (theaflavin, theaflavin-3-gallate, theaflavin-3'-gallate, and theaflavin-3,3'-digallate) and contribute to the orange color and characteristic taste of black tea. Thearubigins are heterogeneous polymers of tea catechins with red-brown color, and their structures are poorly understood (73). In brewed black tea, catechins, theaflavins, and thearubigins account for 3% to 10%, 2% to 6%, and greater than 20% of the dry weight, respectively. The caffeine content in black tea is the same as in green tea. Oolong tea is manufactured by crushing only the rims of the leaves and limiting fermentation to a short period to produce a specific flavor and taste. Generally, oolong tea contains catechins, theaflavins, and thearubigins as well as some characteristic components such as epigallocatechin esters, theasinensins, dimeric catechins, and dimeric proanthocyanidins (73). The theanine content varies with the conditions of cultivation and manufacturing of tea.
Tea catechins and other tea polyphenols are strong antioxidants that efficiently scavenge free radicals. Several functional groups in their structures appear to be important in conferring their low reduction potentials (73). All catechins have two hydroxyl groups in ortho positions in the B-ring, which participate in electron delocalization. In EGCG and ECG, the hydroxyl group at the 3 position in the C-ring is esterified with gallic acid (D-ring), providing three additional hydroxyl groups. The hydroxyl groups in both the B-ring and D-ring contribute to the antioxidant activity. The 5- and 7-dihydroxy groups and 1-oxygen make the carbons at positions 6 and 8 in the A-ring strongly nucleophilic. During enzyme or nonenzyme oxidation, tea catechins may undergo condensation via either C-O or C-C bond formation in polymerization reactions. Tea polyphenols also have high affinity to bind metals, preventing metal ion–induced formation of reactive oxygen species (ROS) (5, 73).
The phenolic groups in catechins can be donors for hydrogen bonding. Hydrogen bonding of a catechin molecule to water forms a large hydration shell. This hydrogen bonding capacity also enables tea polyphenols to bind strongly to proteins, lipids, and nucleic acids. For example, EGCG is known to bind to serum proteins such as fibronectin, fibrinogen, and histidine-rich glycoproteins. In our studies on the inhibition of DNA methyltransferase 1 by EGCG, the formation of five hydrogen bonds between EGCG and the amino acids at the enzyme active site was proposed (23). More recently, EGCG has been shown to bind strongly to 67-kDa laminin receptor, Bcl-2 proteins, and vimentin, and these proteins have been proposed to be the targets of EGCG for anticancer activities (reviewed in 96). Black tea polyphenols may bind to biomolecules and biomembranes with affinity even higher than that of EGCG.
BIOAVAILABILITY AND BIOTRANSFORMATION OF TEA CONSTITUENTS
According to Lipinski's Rule of 5 (55), compounds that have 5 or more hydrogen bond donors, 10 or more hydrogen bond acceptors, a molecular weight greater than 500, and log P greater than 5 are usually poorly absorbed following oral administration. This poor absorption is due to their large actual size (high molecular weight), large apparent size (due to the formation of a large hydration shell), and high polarity (55). The bioavailabilities of tea polyphenols follow this prediction (reviewed in 17, 94). Both human and animal studies have shown that the bioavailabilities of EC and catechin (molecular weight 290 and 5 phenolic groups) are higher than EGCG (molecular weight 458 and 8 phenolic groups). In rats, following intragastric administration of decaffeinated green tea (200 mg/kg), the absolute plasma bioavailabilities of EGCG, EGC, and EC were 0.1%, 14%, and 31%, respectively. EGCG, EGC, and EC in plasma had elimination half-lives of 165, 66, and 67 min, respectively. However, the absolute plasma bioavailability of EGCG in mice following intragastric administration of EGCG (75 mg/kg) was much higher at 26.5%, with more than 50% of EGCG present as glucuronide conjugates. Levels of EGCG in the small intestine and colon were 20.6 and 3.6 ng/g, respectively. In humans, following oral administration of the equivalent of two or three cups of green tea, the peak plasma levels of tea catechins (including the conjugated forms) were usually 0.2–0.3 µM (94). With high pharmacological oral doses of EGCG, peak plasma concentrations of 2–9 µM and 7.5 µM were reported in mice and humans, respectively (94). Conversely, theaflavin and theaflavin-3,3'-digallate (molecular weights of 564 and 868, respectively, and containing 9 and 14 phenolic groups, respectively) have extremely low bioavailability when administered orally.
As illustrated in Figure 2, EGCG and other tea catechins undergo extensive biotransformation (reviewed in 94). Because of the catechol structure, EGCG and other catechins are readily methylated by catechol-O-methyltransferase. The preferred methylation sites of EGCG are the 4' and 4? phenolic groups. EGC is also readily methylated to form 4'-O-methyl-EGC. This metabolite as well as 4?-O-methyl-EGCG and 4',4?-dimethyl-EGCG have been detected in human and animal plasma and urine samples after the ingestion of tea. In addition to methylation, catechins are also glucuronidated by UDP-glucuronosyltransferases and sulfotransferases. Multiple methylation and conjugation reactions can occur on the same molecule. For example, we have observed methyl-EGCG-glucuronide, EGCG-glucuronide-sulfate, dimethyl-EGCG-diglucuronide, and methyl-EGCG-glucuronide-sulfate as urinary metabolites in mice (73).
Active efflux has been shown to limit the bioavailability of many polyphenolic compounds. The multidrug-resistance-associated protein 2 (MRP2), located on the apical surface of the intestine and liver, mediates the transport of some polyphenolic compounds to the lumen and bile, respectively (42). Therefore, EGCG and its metabolites are predominantly effluxed from the enterocytes into the intestinal lumen, or effluxed from the liver to the bile and excreted in the feces, with little or none of these compounds in the urine of humans and rats. However, low levels of urinary EGCG metabolites (in the conjugated forms) can be detected in mice (73). Tea catechins can be degraded in the intestinal tract by microorganisms. We have observed the formation of ring fission metabolites 5-(3',4',5'-trihydroxyphenyl)-gamma-valerolactone (M4), 5-(3',4'-dihydroxyphenyl)-gamma-valerolactone (M6), and 5-(3',5'-dihydroxyphenyl)-gamma-valerolactone (M6') in human urine and plasma samples several hours after the ingestion of tea (51). These compounds can undergo further degradation to phenylacetic and phenylpropionic acids.
Several investigators have reported the pharmacokinetics of tea polyphenols in human volunteers. For example, we found that with the oral administration of 20 mg green tea solids per kg body weight, it took 1.4 to 1.6 hours for the catechins to reach peak plasma concentrations (49). The resulting maximal plasma concentrations for EGCG, EGC, and EC were 77.9, 223, and 124 ng/ml, respectively. EGCG, EGC, and EC had terminal half-lives of 3.4, 1.7, and 2 hours, respectively. Plasma EGC and EC were present mainly in the conjugated forms, whereas 77% of the EGCG was in the free form. Methylated EGCG and EGC were also present in human plasma (49, 94). Chow et al. (16) demonstrated that following four weeks of oral administration of EGCG (800 mg once daily) there was an increase in the systemic bioavailability, but the molecular basis for this observation remains to be investigated.
In contrast to the limited bioavailabilities of catechins, caffeine has bioavailability close to 100% and is mainly metabolized by cytochrome P450 1A2 to dimethylxanthines and theophylline (4). Theanine is also almost 100% bioavailable and is metabolized to ethylamine and glutamic acid by phosphate-independent glutaminase (88). Both caffeine and theanine readily cross the blood-brain barrier and are neurologically active.
TEA AND CANCER PREVENTION
Inhibition of Carcinogenesis in Animal Models
Tea and its major constituents have been demonstrated to inhibit tumorigenesis in many animal models for different organ sites, including the lung, oral cavity, esophagus, stomach, small intestine, colon, skin, liver, pancreas, bladder, prostate, and mammary glands. Most of the studies were conducted with green tea, green tea polyphenol preparations, or pure EGCG administered through drinking water or the diet. Although EGCG and other catechins are thought to be the major cancer preventive agents in tea, effective inhibition of carcinogenesis by caffeine in the lung and skin, but not in the colon, has been demonstrated (95). Some of the results have been reviewed (95, 96).
At least 20 studies have demonstrated the inhibitory effect of tea or tea preparations on lung tumorigenesis (reviewed in 95). Most of the experiments were conducted in tobacco carcinogen-treated or transgenic mouse models, and a few studies were conducted in rat and hamster models. Inhibitory activities have been demonstrated when green tea preparations were administered during the initiation, promotion, or progression stages of carcinogenesis. The inhibitory activities of theaflavin and EGC have also been demonstrated. Treatment with green or black tea extracts for 60 weeks also inhibited the spontaneous formation of lung tumors as well as rhabdomyosarcomas in A/J mice. In addition, oral administration of green tea infusion reduced the number of lung colonies of mouse Lewis lung carcinoma cells in a metastasis model (95). These results demonstrate the broad activities of tea preparations in the inhibition of lung neoplasia at different stages of carcinogenesis.
Inhibitory effects of tea against tumorigenesis in the digestive tract, including the oral cavity, esophagus, stomach, small intestine, and colon, have been shown in more than 30 studies (95). For example, tea preparations were shown to inhibit chemically induced oral carcinogenesis in a hamster model and esophageal carcinogenesis in a rat model. EGCG also inhibited tumorigenesis in rat stomach and forestomach induced by N-methyl-N-nitro-N-nitrosoguanidine. The inhibitory effects of tea and tea polyphenols on intestinal tumorigenesis in mice have been consistently observed in different laboratories. For example, we showed that administration of EGCG at 0.02% to 0.32% in drinking fluid dose-dependently inhibited small intestinal tumorigenesis in ApcMin/+ mice (44). Shimizu et al. (81) also demonstrated the inhibition of azoxymethane (AOM)-induced colon aberrant crypt foci (ACF) formation in C57BL/KsJ-db/db mice by 0.01% and 0.1% of EGCG in drinking water. The effects of tea preparations on colon tumorigenesis in rats, however, have not been consistent (95). Our recent animal studies showed that in AOM-treated rats, administration of polyphenon E (a standardized tea polyphenol preparation that contains 65% EGCG, 25% other catechins, and 0.6% caffeine) at a dose of 0.24% in the diet decreased ACF formation, adenocarcinoma incidence, and adenocarcinoma multiplicity (95). In contrast to these beneficial effects, green tea polyphenol treatment of mice bearing colonic inflammation may produce deleterious effects. For example, we observed that 0.5% of EGCG in the diet or drinking water caused rectal bleeding, enhanced inflammation, and loss of body weight in mice treated with dextran sulfate sodium (28). In the mice treated with AOM and dextran sulfate sodium, rectal bleeding and enhanced carcinogenesis were observed with 0.3% EGCG in the diet (28). The possible extrapolation of these observations to humans and the mechanisms of such a proinflammatory effect need to be further studied.
Administration of a green tea polyphenol infusion (0.1% in drinking fluid) to TRAMP (transgenic adenocarcinoma of the mouse prostate) mice for 24 weeks markedly inhibited prostate cancer development and distant site metastases (1, 29). The inhibition was associated with decreased cell proliferation, increased apoptosis, decreased insulin-like growth factor (IGF) signaling, and decreased levels of angiogenic and metastatic markers. It is not clear whether tea polyphenols inhibit prostate carcinogenesis by a direct action of tea polyphenols present in the prostate or by an indirect action, such as by affecting circulating serum IGF-1 levels (29) or by affecting androgen levels.
As noted in previous reviews (95, 96), most of the reported studies have demonstrated the cancer preventive activities of tea catechins against carcinogenesis at different organ sites, and the evidence is strong. However, there are also some studies that did not observe cancer preventive effects. The reasons for the discrepancies may be complex. One possible factor is the dose and bioavailability of the tea catechins used. For example, in studies of the prevention of mammary carcinogenesis, the concentrations of EGCG in the mammary tissues may have been too low to be effective in some of the experiments (95).
Tea Consumption and Cancer Risk in Humans
In contrast to the strong evidence for the cancer preventive activities of tea constituents in animal models, results from epidemiological studies have not been consistent in demonstrating the cancer preventive effect of tea consumption in humans. Two systematic reviews on human studies, one by Boehm et al. (10) and the other by Sturgeon et al. (83), were published in 2009. A recent comprehensive review by Yuan et al. (100) concluded that consumption of green tea was frequently associated with a reduced risk of upper gastrointestinal tract cancer after adjusting for confounding factors, and limited data supported its protective effect for lung and hepatocellular carcinogenesis. However, intake of black tea in general was not associated with a lower risk of cancer (100). We agree with this general conclusion and add the following discussions.
In a meta-analysis of 25 epidemiological studies on tea consumption and colorectal cancer in 2006 (85), no association was found between black tea and colorectal cancer, and the results on green tea were mixed. Subsequently, a prospective study on women in Shanghai found a reduced risk of colorectal cancer in green tea drinkers (97). On the other hand, a cohort study in Singapore found that green tea consumption had a statistically nonsignificant increased risk for advanced-stage colon cancer only in men (84). The observed adverse effect in men may be related to smoking or the proinflammatory activities of tea catechins as were observed in animal models described above (28). The gender difference was also seen in other studies on the effect of tea consumption, and this is discussed in a section below.
The association between green tea consumption and breast cancer has been studied extensively. In a meta-analysis published in 2010, an inverse association was found in the four case-control studies but not in the three cohort studies (62). Two additional cohort studies in Japan and China also did not find an association. These results are consistent with the rather weak evidence from animal studies on the prevention of mammary cancer by tea. Similarly, an inverse association between green tea consumption and prostate cancer was found in two case-control studies but not in four prospective cohort studies (100).
Many intervention trials have been conducted with green tea, and some have found a beneficial effect of green tea polyphenols in preventing the development or progression of cancer. For example, in a double-blinded phase II trial in Italy, 30 men with high-grade prostate intraepithelial neoplasia (PIN) were given 600 mg of green tea catechins daily for 12 months (9). Only 1 patient developed prostate cancer, whereas 9 of the 30 patients with high-grade PIN in the placebo group developed prostate cancer (a statistically significant result). In a recent study in Japan in patients who had colorectal adenomas removed by polypectomy, supplementation with green tea extract (1.5 g per day) for 12 months was shown to reduce the development of metachronous colorectal adenomas compared to a group of patients who did not take green tea extract (80). These patients were regular tea drinkers (average of six cups per day); the dose-response relationship of this study is difficult to explain. The results of these studies are promising and would have a large impact if they could be reproduced in trials with larger numbers of subjects. More than 30 human trials with green tea polyphenol preparations are ongoing in the United States, China, and Japan (31; also see the NIH clinical trials Website,
http://cancer.gov/clinicaltrials). Some of these studies may yield clear conclusions concerning cancer preventive activities of green tea polyphenols.
The disparity in results between animal and human studies, observed not only in cancer prevention but also in the prevention of other diseases, is likely due to the lower quantities of human tea consumption as compared to the doses used in animal studies, as well as the many potential confounding factors involved in epidemiological studies. In animal studies, the doses of tea preparations and the experimental conditions are selected to maximize the opportunity to detect the hypothesized effect. In humans, many lifestyle factors, genetic polymorphisms, and other confounding factors may reduce the power of epidemiological studies for detecting a cancer preventive effect. Smoking appears to be a strong confounding factor. For example, in a case-control study on the effect of green tea consumption on esophageal cancer in Shanghai, a protective effect was observed only in women, who were mostly nonsmokers (27). Similarly, in the Shanghai Men's Health Study, green tea drinking was found to reduce the risk of colorectal cancer among nonsmoking men but not among men in general (98). In a recent large-scale, population-based case-control study in urban Shanghai, regular green tea drinking was associated with a 32% reduction of pancreatic cancer risk (compared to those who did not drink tea regularly) in women, who were mostly nonsmokers (91). Such a beneficial effect of tea drinking, however, was not observed in men, who were mostly smokers and former smokers; among men who never smoked, a trend of decreased risk was observed (91). A similar smoking pattern in Japan, where women were mostly nonsmokers and more men were smokers, may explain the gender difference in the effects of tea consumption on gastric cancer. A recent systematic review of epidemiological studies in Japan on green tea consumption and gastric cancer indicated no overall preventive effect of green tea in cohort studies. However, a small consistent risk reduction was found in women, and the result was confirmed by pooling data of six cohort studies (75).
The relationship between tea consumption and cancer risk may become more clear if the studies adjust for confounding factors, quantify tea consumption better, and consider genetic polymorphisms of the individuals. Objective measurements of biomarkers that reflect consumption of tea, such as urinary catechins, would be useful. For example, in a nested case-control study in a Shanghai cohort, we used urinary EGC as an indicator of tea consumption and found that urinary levels of EGC (or EGC plus its metabolite, 4'-O-methyl-EGC) were inversely associated with colon cancer risk (99).
Mechanistic Considerations
Many mechanisms have been proposed for cancer prevention by tea constituents, and this subject has been reviewed (95, 96). ROS have been shown to play key roles in carcinogenesis; the antioxidant actions of tea catechins could be an important mechanism for cancer prevention. Another possible mechanism is through the binding of EGCG to target proteins, leading to the inhibition of metabolic or signal-transduction pathways. As reviewed previously (96), the 67-kDa laminin receptor, Bcl-2 proteins, vimentin, and other proteins have been proposed as targets for EGCG. A recent study demonstrated the binding of EGCG to both the WW and PPIase domains of peptidyl-prolyl cis/trans isomerase (Pin 1), which is required for full activation of AP-1, NFkappaB, ß-catenin, and other signaling pathways (87). Biochemical studies showed a dissociation constant of 21.6 µM for the binding of EGCG to Pin 1, and this was proposed as a mechanism for the cancer preventive activities of EGCG (87). It is reasonable to assume that the high-affinity binding proteins reported in the literature could serve as initial targets, but this point remains to be substantiated in animal models. Some of the proposed mechanisms based on studies in cell lines, however, may not be relevant to cancer prevention.
Apparently, mechanisms derived from cancer prevention studies in animal models are likely to be more relevant. These include the induction of apoptosis in different animal models; inhibition of the phosphorylation of c-Jun and Erk1/2 in a lung tumorigenesis model; suppression of phospho-Akt and nuclear ß-catenin levels in colon cancer models; inhibition of the IGF/IGF-1R axis in colon, prostate, and other cancer models; and suppression of vascular endothelial growth factor–dependent angiogenesis in lung and prostate cancer models (95). It is still unclear whether these molecules are direct targets for EGCG or are downstream events of the primary action. Based on the limited human data, actions of tea polyphenols in reducing oxidative stress and enhancing the elimination of carcinogens may be considered as important mechanisms.
WEIGHT CONTROL AND ALLEVIATION OF METABOLIC SYNDROME BY TEA
Laboratory Studies
Overweight, obesity, and type 2 diabetes are emerging as major health issues in the United States and many other countries. MetS is a complex of symptoms that includes elevated waist circumference and two or more of the following: elevated serum triglyceride, dys-glycemia, elevated blood pressure, and reduced high-density lipoprotein cholesterol (25). MetS is an early manifestation of type 2 diabetes and a key risk factor for CVDs. Therefore, beneficial effects of tea consumption on weight reduction and MetS could have a huge public health implication.
The effects of green tea consumption on body weight and MetS have been studied extensively in animal models, and this topic was reviewed recently by Sae-tan et al. (72). In the 12 publications reviewed concerning body weight reduction, 10 studies showed that consumption of green tea extracts or EGCG significantly reduced the gaining of body weight and/or adipose tissue weight (72). Of the 11 papers reviewed concerning the effects of tea catechin consumption on blood glucose and insulin, all demonstrated a beneficial effect in the reduction of blood glucose or insulin levels as well as in the increase of insulin sensitivity or glucose tolerance (72). These studies used rodents on high-fat diets or genetically obese/diabetic animal models. For example, in mice fed a high-fat (60% of calories) diet, we found that dietary EGCG treatment (3.2 g/kg diet) for 16 weeks significantly reduced body weight gain, percent body fat, and visceral fat weight compared to mice without EGCG treatment (11). EGCG treatment also attenuated insulin resistance, plasma cholesterol, and monocyte chemoattractant protein concentrations in mice on the high-fat diet.
As for the mechanisms for weight reduction, there is strong evidence to suggest that tea catechins decrease lipid absorption as reflected in the increased level of fecal lipids (11, 72). This could be a result of direct binding to lipids or changing the physicochemical properties of the lipid emulsion and decreasing their absorption. There are also reports indicating that dietary supplementation of catechins in rats reduced activities of enzymes of fatty acid synthesis, such as fatty acid synthase. Treatment of mice with dietary tea catechins has also been suggested to increase AMP-kinase alpha activity as well as ß-oxidation and other fatty acid degradation enzymes in the liver. Modulation of gene exp
ression, such as peroxisome proliferator-activated receptor (PPAR)gamma, fatty acid synthase, lipases, and uncoupling protein 2 in liver and white adipose tissue by tea catechins has also been reported (reviewed in 72).
An example of the beneficial effect of green tea in alleviating MetS is the studies on obese and insulin-resistant beagle dogs. When the dogs were treated with oral doses of green tea extract (80 mg/kg daily) just before the daily meal for 12 weeks, the insulin sensitivity index was markedly increased, and the homeostasis model for insulin resistance was decreased by 20% (76). Tea consumption also upregulated mRNA levels of PPARgamma, lipoprotein lipase, adiponectin, or glucose transporter (GLUT)4 in visceral and subcutaneous adipose tissues. It also upregulated PPARalpha and lipoprotein lipase in the skeletal muscle and induced GLUT4 translocation into the plasma membrane in muscle cells (76). In studies with rats on a high-fructose diet, green tea administration for six weeks increased GLUT4 and increased insulin receptor substrate (IRS) mRNA levels in the liver and muscle (13). In insulin-resistant rats, treatment with green tea polyphenols significantly decreased blood glucose, insulin, triglycerides, total cholesterol, low-density lipoprotein (LDL) cholesterol, and free fatty acids (68). Treatment with green tea polyphenols also increased the cardiac mRNA levels of IRS1, IRS2, GLUT1, GLUT4, and glycogen synthase 1 as well as decreased proinflammatory cytokines (68).
Several studies have reported the beneficial effects of tea catechins in preventing hypertension and improving endothelial functions. Treatment of rats with green tea extracts (0.6% in water) for 14 days reduced angiotensin II–induced systolic and diastolic blood pressure; this activity may be associated with the inhibition of angiotensin II–induced cardiac NAD(P)H oxidase, which is known to play a key role in the induction of endothelial oxidative stress (63). In spontaneously hypertensive rats, EGCG treatment significantly decreased systolic blood pressure, decreased myocardial infarct size, and enhanced nitric oxide signaling (67).
Tea catechins have been shown to reduce hepatic steatosis and liver toxicity in rodents treated with ethanol, tamoxifen, endotoxins, and liver ischemia/reperfusion injury (reviewed in 72). For example, we demonstrated that administration of 0.32% dietary EGCG for 16 weeks ameliorated high-fat-diet-induced hepatic steatosis in mice (11). EGCG treatment reduced the incidence of hepatic steatosis, liver size (22% decrease), liver triglycerides (69% decrease), and plasma alanine aminotransferase concentration (67% decrease) compared to high-fat-diet-fed control mice. Histological analyses of liver samples revealed decreased lipid accumulation in hepatocytes in mice treated with EGCG compared to high-fat-diet-fed mice without EGCG treatment.
Overall, these studies in animal models are very impressive. The modulation of the activities of specific enzymes and the exp
ression of specific genes by tea polyphenols are intriguing. Some of the effects were produced by rather high doses of green tea polyphenols. It is not known whether these activities are exerted by tea catechins directly or indirectly through body weight reduction or other actions caused by the administration of tea polyphenols.
Human Studies
During the past decade, the effects of tea consumption on body weight have been studied in many small, randomized controlled trials (RCTs). Systematic reviews and meta-analyses were conducted by Hursel et al. in 2009 (covering 11 RCTs; 39) and by Phung et al. in 2010 (covering 15 RCTs; 66). Most of these studies used green tea or green tea extracts with caffeine for 8 to 12 weeks in subjects with normal weight or who were overweight. As compared with caffeine-free controls, most studies observed a lowering of body weight but not waist circumference or waist-to-hip ratio. Several intervention studies have also indicated that green tea drinking has beneficial effects on body composition (reviewed in 69). A randomized placebo-controlled trial with moderately overweight Chinese subjects showed that daily consumption of 458 to 886 mg of green tea catechins (with less than 200 mg caffeine) for 90 days reduced total body fat and percent body fat (90). The role of caffeine was inconsistent among the different studies: Some studies suggested that the weight reduction effect was due to caffeine purely, whereas others suggested the effect was due to a combined effect of caffeine and tea catechins. A meta-analysis of metabolic studies showed that both the catechins-caffeine mixture and caffeine alone dose dependently stimulated daily energy expenditure, but only the catechins-caffeine combination significantly increased fat oxidation (38). Several human studies have also provided evidence that tea drinking could ameliorate features of MetS and the subsequent risk for type 2 diabetes. An age- and gender-matched study of 35 subjects with obesity and MetS indicated that the consumption of green tea beverage (four cups per day) or green tea extracts for eight weeks significantly decreased body weight, body mass index, and LDL cholesterol as well as markers of oxidative stress (8). The treatments, however, did not significantly alter features of MetS or biomarkers of inflammation (7). Two recent epidemiological studies also support the beneficial effects of green tea consumption on MetS. A cross-sectional study of US adults showed that hot tea (but not iced tea) intake was inversely associated with obesity and decreased biomarkers of MetS and CVDs (89). A study of elderly male Taiwanese dwelling in a rural community also indicated that tea drinking, particularly for individuals who consumed 240 ml or more of tea daily, was inversely associated with MetS (14).
There is evidence from some, but not all, human studies that tea consumption is associated with a reduced risk of type 2 diabetes. A meta-analysis based on seven studies (N = 286,701 total participants) reported that individuals who drank more than three to four cups of tea per day had lower risk of type 2 diabetes than those consuming no tea (40). A retrospective cohort study of 17,413 Japanese adults aged 40 to 65 years indicated that consumption of more than six cups of green tea daily (but not oolong or black teas) lowered the risk of diabetes by 33% (41). A prospective cross-sectional study with US women aged 45 years and older also showed that consumption of more than four cups of tea per day was associated with a 30% lower risk of developing type 2 diabetes, whereas the intake of total flavonoids or flavonoid-rich foods was not associated with reduced risk (82). The effect of caffeine in these epidemiological studies is unclear. Several clinical intervention studies have yielded inconclusive results on insulin resistance and blood glucose control but have reported changes in certain biomarkers such as an increase in the level of ghrelin (a hunger-stimulating peptide), a reduction of hemoglobin A1C, an increase in satiety, and a decrease in diastolic blood pressure (12, 26, 37, 43).
TEA AND CARDIOVASCULAR DISEASE PREVENTION
Epidemiological Studies
There have been many human studies about tea and CVDs, and this topic has been reviewed recently (19, 21). The strongest evidence for the reduction of CVD risk by the consumption of green tea (5 to 10 cups daily) is provided by large cohort studies in Japan. For example, in the most recent study with 76,979 Japanese adults, consumption of green tea (>6 cups daily) was associated with decreased CVD mortality (60). A case-control study in China also showed a correlation between consumption of green or oolong tea and a decreased risk of ischemic stroke (54). Many, but not all, studies in the United States and Europe demonstrated an inverse association between black tea consumption and CVD risk (19). For example, in the Determinants of Myocardial Infarction Onset Study, black tea consumption (>2 cups daily) was associated with reduced CVD mortality and lower prevalence of ventricular arrhythmia for myocardial infarction during a follow-up for 3.8 years (61). In the Dutch cohort study, with 37,514 healthy men and women followed for 13 years, consumption of black tea (3 to 6 cups daily) was associated with the decreased risk for CVD mortality (18). In this study, however, tea consumption was also associated with a healthy lifestyle. Apparently, lifestyle and socioeconomic status may have confounded the results of many studies (19). The quantity and types of tea consumed are also key factors for prevention of CVDs. For example, in the Women's Health Study (77), the level of tea consumption was rather low (only a small percentage of women drank more than four cups of black tea per day), and only a trend in the prevention of CVD was observed. In previous meta-analyses, green and black tea drinkers were shown to have lower incidence of myocardial infarction and ischemic stroke (3, 65). However, in a recent meta-analysis of 13 articles on the effects of green tea and black tea on the risk of coronary artery diseases, consumption of green tea, but not black tea, was found to be beneficial (92).
Mechanistic Considerations
The actions of tea catechins in the prevention of CVDs may be attributed to the attenuation of their risk factors as follows.
Lipid-lowering effects. The cholesterol-lowering effect of green and black tea consumption was found in many observational studies and intervention studies (19). In a meta-analysis of 133 intervention studies on the effects of flavonoid-containing foods, it was concluded that green tea consumption has a significant LDL-cholesterol-lowering effect (35). The action could be mainly due to the lowering of the absorption of cholesterol and other lipids by tea catechins and black tea polyphenols, as has been demonstrated in animal models. Specific actions on the inhibition of cholesterol synthesis by EGCG have been proposed. Black tea polyphenols have very low or no bioavailability, and therefore binding of lipids may be the most important mechanism of their lipid-lowering effects.
Beneficial effects on endothelial function. As reviewed by Deka & Vita (19), a large number of studies showed that black tea and green tea consumption improves endothelium-dependent vasodilation in individuals with or without atherosclerosis. These beneficial effects may prevent the development or decrease the progression of atherosclerosis, which is a strong risk factor for CVD. Tea catechins may exhibit these beneficial functions by suppressing caveolin-1 [a negative regulator of endothelial nitric oxide synthase (eNOS)] (53) and activating AMP-kinase, which leads to activation of PI3K/Akt and eNOS phosphorylation (101).
Antioxidant and anti-inflammatory effects. The antioxidant activities of tea and tea polyphenols have been studied extensively both in vitro and in vivo. Many studies have shown that tea consumption increased the ability of plasma to scavenge ROS. In human studies, consumption of green tea, but not black tea, decreased the urinary levels of 8-hydroxy-deoxyguanosine in smokers (30). A recent meta-analysis of 31 intervention studies on this topic, however, concluded that there was limited evidence that regular consumption of green tea increased plasma antioxidant capacity and reduced LDL oxidation (22). The anti-inflammatory effects of tea and tea polyphenols have been shown in vitro and in animal models, but epidemiological and intervention studies have yielded mixed results (19).
Antiproliferative and antiplatelet effects. Similar to studies in cancer cells, antiproliferative and antimigratory effects of EGCG on vascular smooth muscle cells have been demonstrated in vitro and in vivo (19). However, evidence for such actions in humans is lacking. Several studies suggest that tea catechins have antiplatelet effects that may decrease CVD risk (19). Lowering of plasma levels of p-selectin (a marker of in vivo platelet aggregation) has been shown by black tea consumption in healthy volunteers (34) and by green tea consumption in male smokers (50).
NEUROPROTECTIVE EFFECTS OF TEA
The loss of cognitive function due to the loss of structure and function of neuronal cells is a common process in neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease. Vascular dementia caused by stroke is also common in elderly people. Several epidemiological studies have suggested that tea drinking was associated with the improvement of cognitive function. For example, green tea consumption was associated with a lower prevalence of cognitive impairment among elderly Japanese (47) and with better cognitive performance in community-living elderly Chinese (24). Recently, green tea drinking was shown to be associated with lower risks for stroke and cognitive impairment in elderly Japanese (86). Interestingly, the protection against cognitive decline in the elderly by tea consumption was shown in aged women but not in men, according to one report (2).
Although there is no clear epidemiological result of the beneficial effect of green tea on AD, several studies have described a moderate risk reduction of PD in tea drinkers. A meta-analysis covering 11 case-control studies and 1 cohort study concluded that tea consumption could protect against PD, especially in Chinese populations (6). A recent meta-analysis also supported the conclusion that tea drinking can lower the risk of PD; however, there was no apparent dose-response relationship or dependence on the types of tea consumed (52). Tea drinking was also associated with lowering risks of depressive symptoms (33) and psychological distress (36).
On the basis of animal and cell culture studies, catechins and theanine are believed to be mainly responsible for the neuroprotective action of green tea. The proposed mechanisms of action of EGCG and catechins include their antioxidant and iron-chelating activities as well as anti-inflammatory and signal-modulating activities related to neuronal cell growth (reviewed in 93). Because neuronal cells are sensitive to oxidative damage, antioxidant actions of catechins are important for their protective effect. Iron accumulation in the brain is a common feature of neurodegeneration, and iron is also involved in the production of amyloid precursor protein and ß-amyloid formation (71). EGCG is known to reverse the iron-dependent events in many in vitro models. Involvement of the protein kinase C signaling pathway in protection against neuronal cell death and in inhibiting progression of neurodegenerative diseases by tea catechins has been suggested (reviewed in 57). Although several reports indicated that EGCG can pass the blood-brain barrier and exert a neuroprotective action, it is unclear whether EGCG can reach the brain at levels high enough for neuroprotection in humans.
The characteristic amino acid theanine, which can cross the blood-brain barrier, is considered to be an important compound for the neuroprotective actions of tea. Theanine has been investigated for the treatment of anxiety, depression, stress, insomnia, sleep disturbance, and some schizophrenic symptoms. Several studies indicated that theanine relieved anxiety symptoms in patients with schizophrenic and schizoaffective disorders (70), and a combination of green tea extract and theanine improved memory and attention in subjects with mild cognitive impairments (64). Theanine was also effective in improving sleep quality in boys diagnosed with attention deficit/hyperactivity disorder (56). Several mechanisms of theanine in neuroprotective action have been proposed. As an analogue of glutamate, a neuroexcitatory transmitter, theanine may act as an antagonist against glutamate receptors and prevent glutamate-induced excitatory neuronal toxicity. Because the affinity of theanine to the receptors is low, interference in glutamine transporter and modulation of levels of other neurotransmitters, such as dopamine and gamma-aminobutyric acid, have also been suggested to be neuroprotective mechanisms of theanine (45).
In summary, tea drinking appears to have protective effects on several types of cognitive dysfunctions in humans, and the mechanisms of these associations need to be further investigated.
OTHER HEALTH EFFECTS AND POSSIBLE SIDE EFFECTS OF TEA
Tea polyphenols have strong affinities for proteins and minerals and thus may affect nutritional status. Decreased iron absorption by tea drinking has been reported previously, but this effect is mainly on nonheme iron, particularly when tea and iron are taken simultaneously. The absorption of heme iron was not affected by tea consumption. In the National Health and Nutrition Examination Survey II study, with 11,684 participants, anemia was not associated with the consumption of tea or coffee (59). Black tea extracts have been shown to reduce calcium absorption in rats (15). However, tea consumption was associated with higher bone mineral density measurements among women 65 to 76 years of age (32), which is consistent with the later report that tea was protective against bone fractures (20). The epidemiological data and animal studies on tea and bone health have been reviewed by Shen et al. (78, 79). The antioxidant and anti-inflammatory actions of tea catechins have been proposed as the mechanisms for the increase in bone formation and suppression of bone absorption (78). Tea constituents other than polyphenols, such as fluoride, may influence bone mineral density. Fluoride in tea may also be related to dental health. Green tea consumption may reduce the occurrence of periodontal disease (48) and the chance of tooth loss (46). The inhibition of oral bacterial growth and adherence by tea polyphenols could be the major factors that contribute to oral health.
The above-discussed studies are on humans taking moderate amounts of tea. When tea extracts or tea polyphenols are used as supplements for the purpose of weight reduction, the doses are usually high enough to reduce the absorption of lipids. The possibility that these tea-based supplements adversely affect the nutritional status of micronutrients needs to be carefully investigated.
Green tea extracts are the principal ingredients in many dietary supplements for weight reduction. Some of the recommended daily doses can reach 1,000 mg or higher. Many cases of hepatotoxicity due to the consumption of green tea extract–based dietary supplements have been reported (reviewed in 58). Because of the hepatotoxicity concern, French and Spanish regulatory agencies suspended market authorization of a weight-reduction product containing green tea extracts (74). The US Pharmacopeia reviewed 216 green tea extract case reports, including 34 reports of liver damage (74). As a beverage, tea is considered safe, and there are no reports of toxicity from tea beverage consumption. However, tea drinking may cause stomach irritation to occur in some individuals, especially those who drink it on an empty stomach.
CONCLUDING REMARKS
As discussed above, the possible beneficial health effects of tea consumption in the prevention of chronic diseases have been suggested by many laboratory and epidemiological studies. Whereas many of the laboratory results are strong and consistent, human studies have not yielded consistent results on some of the beneficial effects. EGCG has only limited bioavailability, and black tea polyphenols have very low or no bioavailability. Therefore, caution needs to be applied in the interpretation of data from studies in vitro; some of these results may not be relevant in vivo. In animal studies, conditions are usually optimized to demonstrate the hypothesized effects, and the doses of tea preparations used are usually higher than the levels of human consumption. Effects of confounding factors related to lifestyle, such as smoking, physical activity, and dietary intake of coffee, calories, fat, and fiber, make it difficult to interpret human data. After taking these factors into consideration, a clearer pattern may emerge, as was shown in our discussions on smoking as a confounding factor in evaluating the effects of tea consumption on the risks for esophagus, stomach, and colon cancer. Without consideration of these factors or the type and dose of tea consumption, meta-analyses may yield inconclusive results.
As for the common mechanisms for the prevention of many diseases discussed herein, the antioxidant actions of tea polyphenols are likely to be important in the prevention of cancer, CVDs, and neurodegenerative diseases as well as in the alleviation of inflammation in obesity and MetS (Figure 3). The binding of tea polyphenols to lipids appears to be a major mechanism for body weight reduction, which also provides beneficial effects for MetS, diabetes, and CVDs. The binding of catechins, such as EGCG, to specific enzymes, receptors, and signaling molecules provides exciting insights for further investigations on the mechanisms of prevention of many diseases. How a molecule such as EGCG could specifically affect the exp
ression of many genes as discussed in the present review is intriguing and requires further investigation.
Figure 3. The proposed mechanisms by which tea constituents (polyphenols, caffeine, and theanine) prevent chronic diseases. Abbreviations: CVDs, cardiovascular diseases; MetS, metabolic syndrome; NDDs, neurodegenerative diseases; ROS, reactive oxygen species.
Bioavailability is an important issue in determining the biological effects of tea polyphenols in internal organs. This factor could explain why many of the beneficial effects were observed with green tea but not with black tea. Tea polyphenols that are not absorbed into the blood, however, may exert their effects in the gastrointestinal tract; for example, in decreasing lipid absorption. This is probably why black tea is also effective in lowering body weight, body fat, and cholesterol levels. The intestinal microbiota may degrade tea polyphenols, as has been shown for tea catechins (51). Some of the metabolites may have interesting biological activities. The microbial degradation of black tea polyphenols has not been sufficiently characterized, and more research is needed. The effects of tea consumption on intestinal microorganisms have been studied in the past, and more comprehensive research on the microbiota using newer approaches would provide additional information.
In human studies, the lack of beneficial effects of green tea consumption observed in some studies could be due to the relatively low quantities of tea consumed. However, caution should be applied in the use of high doses of tea for disease prevention. In addition to the risk of hepatotoxicity as discussed above, ingestion of large amounts of tea may cause nutritional and other problems because of the strong binding activities of tea polyphenols to minerals and biomolecules.
The possible health benefits of tea consumption as discussed in the present review are important public health issues. For protection against certain diseases, the effects of lower levels of tea consumption (one to three cups per day) may be subtle. However, in comparison to other beverages, such as sugared or nonsugared soft drinks or ready-made iced tea drinks, freshly brewed green or black tea, consumed without added sugar and cream, appears to be a healthier beverage. In order to obtain a better understanding of the health effects of tea consumption, more research is needed. We suggest the following: 1. More prospective cohort studies are needed, and special attention needs to be paid to the quantity and types of tea consumption, smoking status, diet, physical activities, genetic polymorphisms, and other confounding factors.
2. Additional well-designed intervention studies, based on strong laboratory data and with adequate duration, are needed.
3. More laboratory studies relevant to human dosing and bioavailability issues are needed.
4. The doses that are required to produce a beneficial effect, such as four cups or more of tea daily for body weight reduction and alleviation of MetS, may not be easily achieved. Approaches of incorporating green tea powder to food items may be explored to increase the intake of tea polyphenols and fiber.
5. Additional studies are needed to investigate the effects of tea consumption on intestinal microbiota and the role of intestinal microbial metabolism of tea constituents in affecting human health.
coffee, tea, caffeine
