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ABSTRACT: The use of dietary ingredients is gaining much significance as a practical approach to the reduction of the risk of a number of diseases. Epidemiological evidence has linked the habitual consumption of tea with reduced risk of cardiovascular disorders and cancer. Polyphenols appear to play an important role in the potential health benefits associated with tea. With growing interests on the positive health attributes of tea, the present review covers relevant findings on many therapeutic properties of tea. Types of tea, the polyphenols, and their nutraceutical implications, as well as adverse effects and course of action together with bioavailability form the essence of coverage in this review.
Tea (Camellia sinensis, family Theaceae) (Figure 1) is the most widely consumed plant-based beverage in the world (Zhu and others 2000). For many centuries, ancient Chinese medicine has been using tea infusions for their pharmacological properties (Sato and Miyata 2000). According to Chinese mythology, the Emperor Shen Nung discovered tea for the 1st time in 2737 B.C. (Harbowy and Balentine 1997). Since then the beverage has become popular, and currently the per capita worldwide consumption is approximately 120 mL brewed tea per day (Ahmad and others 1998). The composition of tea varies with the species, season, age of the leaves (plucking position), climate, and horticultural practices (Lin and others 1996, 1998).
Black tea represents about 76% to 78% of the tea produced and consumed worldwide. Green tea represents about 20% to 22%, while oolong tea accounts for only about 2% of the world production of tea (McKay and Blumberg 2002). Green tea is prepared from fresh tea leaves that are pan-fried or steamed and dried to inactivate enzymes. Chemically, the beverage is characterized by the presence of polyphenolic catechins. Black tea is prepared by crushing withered tea leaves and allowing enzyme-mediated oxidation, commonly referred to as fermentation, to occur, leading to the formation of oligomers such as theaflavins and polymers known as thearubigins. Oolong tea is a partially fermented product that contains considerable amounts of catechins and oligomerized catechins (Balentine and others 1997). The catechin content of tea may depend on the geographical location, growing conditions, and the way the leaves are processed prior to drying. The potential health benefits associated with tea consumption have been attributed to the antioxidative properties of tea polyphenols. The Chinese belief that drinking tea promotes good health and longevity is gaining scientific merit (Yang and Landau 2000).
Types of Tea and Their Polyphenols
Tea beverages are primarily manufactured as green, black, or oolong tea according to their degree of fermentation.
Green tea is consumed largely by the people of Japan and China. The tea leaves are usually heated with rolling immediately after harvest to inactivate the enzyme polyphenol oxidase (PPO) that is capable of oxidizing tea catechins to their oligomeric and polymeric derivatives such as the theaflavins and thearubigins. Leaves may be prepared by steaming fresh tea leaves and drying them at elevated temperatures to avoid oxidation and polymerization of the polyphenolic compounds (Katiyar and others 2001). The Chinese have a green tea called “gunpowder” so named because each leaf is rolled into a small round pellet resembling gunpowder. This is done to protect the leaves from damage and help them retain more flavor and aroma.
Green tea contains several groups of polyphenols that include flavonols (quercetin, kaempferol, and rutin) (Figure 2), caffeine, phenolic acids, theanine, flavor compounds, and leucoanthocyanins, accounting for up to 40% of the dry leaf weight (Graham and others 1992). Chemically, the beverage is characterized by the major polyphenolic catechins such as (–)–epigallocatechin-3-gallate (EGCG), (–)–epigallocatechin (EGC), (–)–epicatechin-3-gallate (ECG), and (–)–epicatechin (EC) (Figure 3); these are the most abundant water-soluble components of tea (Graham and others 1992; Balentine and others 1997). The constituents of green tea per kilogram of material comprise 191 g of the major catechins, 36- g caffeine, and 5.2- g flavonols on a dry mass basis (Perva-Uzunalic and others 2006). Bottled tea drinks contain not only the green tea epicatechins but also the 4 tea catechin epimers, namely, (–) gallocatechin gallate (GCG), (–)–catechin gallate (CG), (–)– gallocatechin (GC), and (+)–catechin (C). These catechin epimers are produced in the sterilization step during their manufacture (Murakami and others 2006). The bioactivity of geen tea is attributed to its high content of catechins, which exhibit a range of biological activities (Fujiki and others 1992; Yeng and Chen 1994, 1996; Balentine and others 1997; Dufresne and Farnworth 2000; Ohe and others 2001). EGCG is among the most effective chemopreventive and apoptosis-inducing agents present in the beverage (Azam and others 2004).
Polyphenols are present at 10% to 15% in green tea and 5% in black tea. The polyphenols constitute about 42% of the dry weight of green tea extract, of which 26.7% comprise catechin-gallate components such as EGCG (11.16%), ECG (2.25%), EGC (10.32%), epicatechin (2.45%), and catechin (0.53%). An infusion of green tea contains up to 200 mg of catechins (Lakenbrink and others 2000). Estimating the concentration in a cup of green tea at 3%, the expected concentration of EGCG would be 2.1 to 2.4 mg/mL. Green tea and EGCG (equivalent of 4 to 8 cups per day) have been tested in humans with no appreciable side effects (additivity and/or synergism with other possible compounds) (Pisters and others 2001; Chow and others 2003). Epidemiological studies have suggested tea consumption to have protective effects against human cancer. Animal studies have also demonstrated green tea to suppress the formation and growth of human cancers, including that of skin (Katiyar and others 2000), lung (Katiyar and others 1993), liver, esophagus (Wang and others 1995), and stomach (Katiyar and others 1993).
Black tea is quite popular in North America, Europe, and India. Manufactured from the young tender shoots of Camellia sinensis, it is the most widely consumed nonalcoholic beverage. The flavor quality and taste tend to change with variations in the geographical and climatic conditions (Howard 1978; Cloughley and others 1982; Takeo and Mahanta 1983). Black tea sells for its plain quality parameters, namely, theaflavins, thearubigins, and caffeine. Theaflavins contribute to the astringency (briskness) and brightness, while thearubigins contribute to the color and body (mouthfeel); and caffeine is responsible for the stimulatory effects of black tea. In the manufacture of black tea, the enzyme is allowed to act in a way that the leaves are fully fermented to give the characteristic aroma and color of black tea (Balentine and others 1997). Prepared by crushing withered tea leaves and allowing enzyme-mediated oxidation, the tea catechins oxidize to form oligomeric flavanols, including theaflavins, thearubigin, and other oligomers. Black tea is also smoked over wood to make smoked black tea.
Theaflavins include a mixture of theaflavin (TF-1), theaflavin-3-gallate (TF-2a), theaflavin-3′-gallate9TF-2b), and theaflavin-3, 3′-digallate (TF-3) (Figure 3) (Lin and Liang 2000). Black tea has a low tea catechin content (3% to 10%[w/w]), with theaflavins and thearubigins accounting for about 2% to 6% (w/w) and 10% to 20% (w/w) of the dry weight of the leaves, respectively. Theaflavins, which account for 2% to 6% of the dry weight of solids in brewed black tea, are orange or orange-red in color and possess a benzotropolone skeleton that is formed from co-oxidation of appropriate pairs of catechins, one with a vic-trihydroxy moiety and the other with an ortho-dihydroxy structure (Geissman 1962). They are produced by the oxidative dimerization of a simple (dihydroxy) catechin and a gallo (trihydroxy) catechin, catalyzed by PPO as follows (Owuor and others 2006):
EC + EGC → theaflavin
EC+ EGCG → theaflavin-3-gallate
ECG + EGC → theaflavin-3′-gallate
ECG + EGCG → theaflavin-3, 3′-digallate
During black tea processing, the tea shoots are macerated to initiate fermentation, during which the enzyme PPO catalyzes oxidation of catechins into quinones by molecular oxygen (Bendall 1959). The quinones from the oxidation of B-ring dihydroxylated catechins condense with quinones arising from the B-ring trihydroxylated catechins to give different theaflavins (Takino and others 1964; Brown and others 1969). The reaction involves the oxidation of the B-rings to quinones, followed by a “Michael” addition of the gallocatechin quinone to the catechin quinone, prior to carbonyl addition across the ring and subsequent decarboxylation (Balentine 1992).
DNA damage is the major cause of induction of cancer, and theaflavins may act as cancer suppressors by protecting DNA from damage. Theaflavins can inhibit the cleavage of DNA single strand and mutagenicity through scavenging of radicals (Wang and Li 2006). Oxidative stress-induced cytotoxicity, cellular DNA damage, and carcinogen-related DNA damage are inhibited by theaflavins through the suppression of elevated cytochrome P450 1A1 (CYP1A1) in cells (Feng and others 2002).
Kombucha tea Kombucha tea is sugared black tea fermented with a symbiotic association of acetic acid bacteria and yeasts for about 14 d (Jayabalan and others 2007). Made by placing a kombucha mushroom (actually a symbiotic colony of bacteria and yeasts, similar to kefir grains used to ferment milk) in sweetened black tea, it is considered a traditional medicinal food. The bacteria and yeasts of the mushroom ferment the tea. The kombucha mushroom can duplicate itself during fermentation and the new mushroom can be used to produce another brew of tea. The biodegradation of tea catechins, theaflavin, and thearubigen during kombucha fermentation might be due to some enzymes excreted by the yeasts and bacteria in the kombucha culture.
The tea is thought to have originated centuries ago in the Far East, making its way to Russia and Europe with time. Kombucha tea is an acidic, sharp-tasting beverage that tastes best on being refrigerated. It is composed of 2 portions: a floating cellulose pellicle layer and a sour liquid broth (Chen and Liu 2000). Kombucha tea has been shown to prevent paracetamol-induced hepatotoxicity and chromate (VI)-induced oxidative stress in albino rats (Sai Ram and others 2000; Pauline and others 2001).
Oolong tea, a semifermented tea, is allotted limited time of oxidation and is thus less fermented than black tea. The partially fermented oolong or paochong tea contains both green tea catechins, black tea theaflavins, and, possibly, thearubigins. Compared with green tea, oolong tea contains approximately half the EGCG, while polymerized polyphenols are double. The polymerized polyphenols of oolong tea such as procyanidins (condensed catechins) are produced by its unique fermentation (Balentine and others 1997; Lin and Liang 2000). The composition of oolong tea is shown in Table 1.
γ-Aminobutyric acid (GABA), an amino acid produced by the human body, is an antistress and an antianxiety component with a calming and relaxing effect. It is used clinically for patients with depressed sex drive and prostate problems, and as a nonaddictive tranquilizer substitute. GABA has been reported to reduce blood pressure in experimental animals (Stanton 1963; Omori and others 1987) and humans (Elliott and Hobbiger 1959). GABA tea may be produced on a commercial basis for patients with hypertension.
GABA accumulates in green, oolong, and black teas under anaerobic conditions (Tsushida and others 1987). GABA differs from green tea in the contents of GABA, glutamic acid, alanine, aspartic acid, EGCG, and EC, particularly the 1st two. The other compounds such as theanine, threonine, valine, methionine, tryptophan, crude fat, total free amino acids, total nitrogen, caffeine, and fatty acids do not differ significantly between the 2 kinds of tea (Wang and others 2005). Thus, GABA tea is almost the same as green tea in terms of the aforementioned bioactive compounds. In addition, GABA tea contains a high level of GABA that influences blood pressure, the nervous system, and the cardiovascular system. Overall, GABA tea is close to green tea in bioactivity (Wang and others 2005). Compared to the ester-type catechins (EGCG, ECG), more of the nonester type (free-type) catechins are present in GABA than in green tea (Table 2). The free-type catechins impart some brothy and smooth characteristics to the tea infusions, while the ester-type catechins exhibit astringency (Goto and others 1996; Wang and Helliwell 2000; Valentova and others 2002). It is postulated that GABA tea, high in GABA, valine, isoleucine, and leucine, may improve liver functions.
The catechin contents of 5 kinds of Chinese tea are listed in Table 3. Lung Chen tea and pu-erh tea are typical examples of Chinese green tea and black tea, respectively, while jasmine tea, iron Buddha tea, and oolong tea are semifermented Chinese teas. Oolong, pu-erh, and black teas contain lower amounts of catechins such as EGCG, EGC, ECG, and EC than green tea owing to the aerobic fermentation of tea-making that reduces the level of catechins significantly (Balentine and others 1997; Zuo and others 2002).
Like the other types of tea, white tea too comes from the Camellia sinensis plant. But the leaves are picked and harvested before the leaves open fully, when the buds are still covered with fine white hair and, hence, the name “white tea.” White tea is a very rare and expensive connoisseur's tea that is only produced in China, mainly in Fukien province. Once harvested, white tea is not oxidized or rolled, but simply withered and dried by steaming (http://www.stashteabusiness.com). White tea undergoes the least amount of processing and, hence, has the maximum amount of polyphenols, which are not oxidized or destroyed during processing. White tea is full of potent antioxidants and may be even more beneficial than green tea. It is shown to inhibit 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced colonic aberrant crypt foci (ACF) in rats (Carter and others 2007).
Biosynthetic Pathway of Tea Flavan-3-ols
The biosynthesis of flavonoids initiates from carbohydrate metabolism. The shikimate pathway is connected to carbohydrate metabolism through the pentose phosphate pathway. The shikimate pathway is responsible for the synthesis of phenylalanine, which serves as the precursor of the flavonoid pathway through the phenylpropanoid pathway. The shikimate pathway is also responsible for the formation of gallic acid, which presumably attaches to flavan-3-ol with an ester bond in the last stages of the biosynthesis process of the tea flavan-3-ols. However, malonyl-Co enzyme A (–CoA) is the precursor for flavonoid biosynthesis and synthesized from acetyl-CoA, which originates from the citric acid cycle (Figure 4) (Chu and Juneja 1997; Wright 2002).
The Antioxidant Capacity of Tea Polyphenols
Green tea extracts have higher antioxidant capacity than black tea, and the total antioxidant potential correlates strongly with the total phenolic content of tea (Benzie and Szeto 1999; Langley-Evans 2000). A number of in vitro studies have attributed the activity to quercetin and the major tea catechin, EGCG (Huang and others 1992; Koketsu 1997; Wiseman and others 1997; Yang and others 1998a, 1998b; Skibola and Smith 2000). Polyphenols are powerful antioxidants and free radical scavengers (Rice-Evans and others 1995). They are strong scavengers of superoxide, hydrogen peroxide, hydroxy radicals, and nitric oxide (NO) produced by various chemicals (Lin and Liang 2000). Shahidi and Alexander (1998) found green tea catechins to inhibit the oxidation of meat lipids better than α-tocopherol and gallates of catechins. They can also chelate metal ions, often decreasing the metal ion pro-oxidant activity. The radical-quenching ability of green tea is usually higher than that of black tea (Yang and others 2002). The 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging ability of tea polyphenols is of the order EGCG > ECG > EGC > EC = TF-2 > TF-1 > TF (Chen and Ho 1994). The theaflavins show lower lipid oxidation–inhibition activity compared to catechins. Heat-epimerized catechins show similar or greater antioxidative activities compared to tea catechins. Catechin and catechin-gallate esters of green tea are more effective antioxidants on a molar basis than vitamin C (Rice-Evans and others 1997). Catechins can reduce oxidative stress by their antioxidative properties (Murakami and others 2006).
Tea polyphenols scavenge the reactive oxygen species and chelate transition metal ions in a structure-dependent manner. The flavonoids are antioxidants by virtue of the number and arrangement of their phenolic hydroxyl groups (Rice-Evans and others 1996). The chemical structures contributing to the effective antioxidant activity of catechins include the vicinal dihydroxy or trihydroxy structure, which can chelate metal ions and prevent the generation of free radicals. The structure also allows for electron delocalization, conferring high reactivity to quench free radicals (Frenkel and others 1988; Wei and others 1993; Yang and others 2002) (Figure 5). The antioxidant effect of polyphenols depends on their structure and the position as well as number of hydroxyl groups. EGCG has the greatest potential in scavenging free radicals (Figure 6), followed by ECG and EC, with EGC being the weakest (Hu and others 2001).
Theaflavins possess in vitro antioxidative properties against lipid peroxidation in erythrocyte membranes and microsomes; and they suppress mutagenic effects induced by hydrogen peroxide. Oral administration of green or black tea leaf powder could inhibit the lipid peroxidation of liver induced by tert-butyl hydroperoxide in rats, while in the kidney, the antioxidant effect was observed only for the green tea-fed group (Sano and others 1995). Black tea and green tea offer protection against oxidative damage to red blood cells (Halder and Bhaduri 1998). EGCG of green tea suppresses the production of superoxide radicals and hydrogen peroxide by tumor promoter-activated human neutrophils.
Nutraceutical Implications of Tea Polyphenols
Cancer chemoprevention is defined as the prevention, inhibition, or reversal of carcinogenesis by administration of one or more chemical entities, either as individual drugs or as naturally occurring constituents of the diet (Lin and Liang 2000). Much of the cancer chemopreventive properties of green tea are mediated by EGCG (Katiyar and Mukhtar 1996; Ahmad and others 1998). The anticarcinogenic potential of tea polyphenols may be attributed to their ability to bind directly to carcinogens, induce Phase II enzymes such as UDP-glucuronosyltransferase (UDP-GT), and inhibit heterocyclic amine formation. Long-term ingestion of green tea increases UDP-GT activity, and the increased glucuronidation through UDP-GT induction is postulated to contribute to the anticarcinogenic effect of green tea. This facilitates the metabolism of chemical carcinogens into inactive products that are readily excreted (Donovan and others 2001).
Molecular mechanisms, including catechin-mediated induction of apoptosis and cell cycle arrest, inhibition of transcription factors NF-kB and AP-1 and reduction of protein tyrosine kinase activity and c-jun mRNA expression, are also relevant chemopreventive pathways for the polyphenols (Ahmad and Mukhtar 1999). Unique characteristics of green tea polyphenols include their ability to induce growth arrest and apoptosis in tumor cells, especially in epithelial-type cells, as well as protecting normal epithelial cells from carcinogens (Mukhtar and Ahmad 2000; Hsu and others 2002; Adhami and others 2003). The life span of both normal and cancer cells is significantly affected by the rate of apoptosis, a programmed type of cell death that differs from necrotic cell death and is regarded as a normal process of cell elimination. Chemopreventive agents that can modulate apoptosis and thereby affect the steady state cell population may be useful in the management and therapy of cancer (Mukhtar and Ahmad 2000). EGCG induces apoptosis and cell cycle arrest in human epidermoid carcinoma cells A431, and the apoptotic response of EGCG is specific to cancer cells. EGCG, in vitro, stimulates apoptosis and cell cycle arrest of various cancer cell lines, including prostate, lymphoma, colon, and lungs.
Intake of tea either as a liquid or as a tea extract may inhibit the development of cancers of the skin, lung, esophagus, stomach, liver, duodenum and small intestine, pancreas, colon, bladder, prostate, ovary, oral cavity, and mammary gland (Yang and Wang 1993; Conney and others 1999; Yang and others 2000; Hsu and others 2002; Su and Arab 2002; Zhang and others 2002). Among the 4 major polyphenols present in green tea, EGCG is the most abundant and extensively studied because of the strong epidemiological evidence for cancer prevention (Miyazawa 2000). EGCG is an inhibitor of the dihydrofolate reductase (DHFR) activity in vitro at concentrations found in the serum and tissues of green tea drinkers (0.1 to 1.0 μmol/L) (Navarro-Peran and others 2005). Thus, the prophylactic effect of green tea on certain forms of cancer is due to the inhibition of DHFR by EGCG. Hence, tea extracts are traditionally used as alternative medicines, particularly as anticarcinogenic/antibiotic agents and in the treatment of psoriasis. The anticancer activity of EGCG in green tea could also be due to inhibition of the enzyme urokinase (u-plasminogen activator), one of the most frequently expressed enzymes in human cancers. EGCG binds to urokinase, blocking His 57 and Ser 195 of the urokinase catalytic triad (Mukhtar and Ahmad 2000).
Inhibitors of procarcinogens and promutagens Most procarcinogens require metabolic activation by metabolite enzymes such as phase I and II enzymes in order to convert to electrophiles before they can exert any carcinogenic effects (Conney 1982). In limiting the formation of carcinogens, green tea and its catechins promote the elimination of procarcinogens such as polycyclic hydrocarbons and heterocyclic amines from the body by inducing phase I cytochromes P450 1A1, 1A2, and 2B1 enzymes and phase II detoxification enzymes, for example, GT (Sohn and others 1994) (Figure 7). The procarcinogen-activating enzyme cytochrome P450 3A4 is also suppressed (Lin and others 1999; Muto and others 2001).
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is the most toxic compound of dioxin congeners (Fukuda and others 2005). Exposure of experimental animals to dioxins causes adverse effects such as body weight loss, immunosuppression, endocrine disruption, cancer promotion, teratogenesis, and lethality. Dioxins bind to the cytosolic aryl hydrocarbon receptor (AhR), commonly called the dioxin receptor, resulting in its transformation. Since AhR transformation is the initial step in the expression of dioxin toxicity, inhibition of transformation would protect humans from toxic effects. Theaflavins inhibit the binding of the TCDD to the AhR and also the binding of the transformed AhR to the specific DNA-binding site as putative mechanisms. Tea extracts can inhibit the cytochrome P450-mediated metabolism of 2-amino-3-methylimidazo [4,5-f] quinoline (IQ) into its ultimate mutagenic metabolite forms, and interact with both the promutagens and their metabolites in a way that can reduce their mutagenic potential (Chen and Yen 1997). Benzopyrene (BaP)- and cyclophosphamide (CP)-induced genotoxicity in microbial and mammalian test systems are inhibited in a dose-dependent manner by theaflavins (Yogeshwer and others 2003). The polyphenols of black tea are more potent inhibitors of mutagenicity than those of green tea caused by the food mutagen PhIP (Apostolides and others 1996, 1997).
Cancer of the digestive and urinary tract organs Regular tea consumption among postmenopausal women may protect against cancers of the digestive and urinary tract organs. The associations are supported by the potential tumor-inhibitory effects of tea and tea polyphenols observed in most animal studies and epidemiological studies. The inhibitory effects of tea are on the endogenous formation of N-nitroso compounds that are potential carcinogens for the upper digestive tract, and the formation of heterocyclic aromatic amines that are potential carcinogens for the large bowel. With regard to urinary tract cancers, some anticancer tea constituents may exist in the urine and act directly on the renal and transitional cells during the secretion and storage process of urine. EGC and EC have been detected in urine among volunteers who ingested tea preparations (Zheng and others 1996). A population-based case-control study of 4000 human subjects indicated an intake of more than 5 cups of tea a day to be associated with a 30% reduction in the risk of bladder cancer; however, there is no evidence of a dose–response relationship (Bianchi and others 2000).
The risk of stomach cancer decreases with the quantity of tea consumed (Yu and others 1995a, 1995b; Ji and others 1996; Inoue and others 1998; Gao and others 2002). The mechanisms may involve the inhibition of the growth of Helicobacter pylori, a causative microorganism in gastric carcinogenesis and the development of gastric and duodenal ulcers (Graham and others 1992). Tea catechins, particularly EGCG, inactivate urease; urease converts urea to ammonia, which buffers the bacteria from digestion by gastric juice, and thereby suppresses the proliferation of the bacteria (Tsujii and others 1992; Yee and Koo 2000; Matsubara and others 2003). Tea consumption is also correlated to a lower incidence of pancreatic cancer in humans (Trevisanato and Kim 2000). Components from black and green tea extracts can modulate the expression of genes known to play a role in carcinogenesis, and therefore may be potential agents for chemoprevention against pancreatic cancer.
Cancer of the respiratory system Cigarette smoking is a known cause of lung cancer and other respiratory diseases. Cigarette smoke contains numerous compounds that generate reactive oxygen species which can damage DNA directly or indirectly via inflammatory processes (Frenkel and others 1988; Wei and others 1993; Hecht 1999). Regular drinking of green tea might protect smokers from oxidative damages and reduce cancer risk or other diseases caused by free radicals associated with smoking (Hakim and others 2003). Black tea extract offers protection against lung tumorigenesis (Chung and others 1998). A tea infusion fed to rats in drinking water during an N-nitroso-methylbenzylamine (NMBA) administration period inhibited esophageal tumorigenesis (Han and Xu 1990; Chen 1992).
Skin cancer The initiation of skin cancer is prevented by green tea and black tea and their polyphenols (Huang and others 1997). The promotion of skin cancer is also inhibited by green tea, black tea, and EGCG, and its progression is reduced by green tea, EGCG, black tea, and its polyphenols (Lu and others 1997).
The induction of inflammation in skin mediated by 12-O-tetradecanoylphorbol-13-acetate (TPA) is believed to be governed by cyclooxygenase (COX), lipooxygenase, and ornithine decarboxylase (ODC). These markers of inflammatory responses are important for skin-tumor promotion. Application of black tea polyphenols significantly inhibited the TPA-caused induction of epidermal ODC and of COX activities (Katiyar and Mukhtar 1997a). During infection and inflammation, the formation of NO increases, which could promote carcinogenesis (Moncada and others 1992). EGCG decreases the activity and protein levels of inducible nitric oxide synthase (iNOS) by reducing the expression of iNOS mRNA. The reduction occurs as a result of prevention of binding of the nuclear factor-kB to the iNOS promoter, thereby inhibiting the induction of iNOS transcription (Lin and Lin 1997). Excessive exposure to UV radiation overwhelms the body's natural antioxidant defense mechanisms leading to an increase in reactive oxygen intermediates and depletion in endogenous antioxidant enzymes. UVB induces skin cells to produce reactive oxygen species, eicosanoids, proteinases, and cytokines, and inhibition of these inhibitors is thought to reduce skin damage (Mukhtar and Ahmad 1999). EGCG has the potential to block the UVB-induced infiltration of leukocytes and the subsequent generation of ROS in human skin (Mukhtar and Ahmad 1999) (Figure 8). In an in vitro study using cultured human cells (lung fibroblasts, skin fibroblasts, and epidermal keratinocytes), EGCG resulted in a dose-dependent reduction in UV-induced DNA damage (Morley and others 2005). Green tea polyphenols also significantly inhibited the UVB-induced DNA damage when applied topically to the mouse epidermis, using a 32P postlabeling technique (Chatterjee and others 1996). With trolox, they can synergistically inhibit the oxidative damage of DNA with an activity sequence of EC = ECG > EGCG > EGC (Wei and others 2006).
Suppression of Wnt signaling by EGCG in invasive breast cancer cells Breast cancer afflicts 1 in 8 women over a lifetime. The effects of tea drinking on human cancers are not clear and appear to vary depending on a person's genotype, type of tea consumed (whether green or black), the socioeconomic and lifestyle factors associated with tea drinkers in different countries, and the specific type of cancer (McKay and Blumberg 2002; Adhami and others 2003). Green tea, but not black tea, consumption might be beneficial in reducing the relative risk of stage 1 or 2 (less severe stages) breast cancer recurrence (Seely and others 2005). Green tea consumption has been associated with the appearance of less aggressive breast cancer and an overall reduced rate of breast cancer recurrence in Japanese women. The oral delivery of EGCG reduced tumor progression in animal models of breast cancer (Kavanagh and others 2001).
Reductions in cell–cell adhesion and stromal and vascular invasion are essential steps in the progression from localized malignancy to metastatic disease for all cancers. Proteins involved in intercellular adhesion, such as E-cadherin and catenin, probably play an important role in metastatic processes and cellular differentiation (Muzio 2001). The Wingless-Type-1 (Wnt-1) pathway has emerged as a paradigm in breast cancer (Kim and others 2006). β-Catenin is a key downstream component of the Wnt signaling pathway, and studies of colorectal tumors have shown a functional link among β-catenin, adenomatous polyposis coli gene product (APC), and other components of the Wnt-1 pathway. Deregulated Wnt signaling by genetic or biochemical means triggers an oncogenic gene expression program that contributes to breast tumorigenesis. Wnt-1 pathway signaling is mediated through interactions between β-catenin and members of the lymphoid enhancer factor-1/T-cell factor (LEF-1/TCF) family of transcription factors. The Wnt signal stabilizes β-catenin protein and promotes its accumulation in the cytoplasm and the nucleus. In the nucleus, β-catenin associates with TCF to form a functional transcription factor that mediates the transactivation of target genes involved in the promotion of tumor progression, invasion, and metastasis, such as C-Myc, cyclin D1, c-jun, Fos-related antigen-1 (fra-1), and urokinase type plasminogen activator receptor (u-PAR). In numerous cancers, there are reports of loss-of-function mutations in APC and Axin, and gain-of-function mutations in β-catenin. HBP1 transcriptional repressor is a suppressor of Wnt signaling. HBP1 is a high-mobility group box containing transcription factor, like the LEF and TCF transcription factors in the Wnt pathway. HBP1 suppresses Wnt signaling at the level of the transcriptional activation, thereby preventing the expression of genes that would otherwise establish the oncogenic phenotype. In the context of Wnt signaling, HBP1 suppresses the expression of endogenous Cyclin D1 and c-MYC (Kim and others 2006). Epidemiological studies have associated green tea consumption with reduced recurrence of invasive and other types of breast cancer. The mechanism of EGCG-mediated suppression of the Wnt pathway is depicted in Figure 9. Reportedly, HBP1 function is abrogated in patients with invasive breast cancer, and HBP1 regulates the biological process associated with invasive breast cancer, including proliferation and invasion (Berasi and others 2004). Moreover, aberrant Wnt signaling is associated with proliferation and invasion. Wnt signaling is shown to be inhibited by EGCG in a dose-dependent manner in breast cancer cells (Kim and others 2006).
Colon cancer Polyphenols from tea are considered possible chemopreventive agents against colon cancer. EGCG selectively inhibits the activity of topoisomerase I but not topoisomerase II in human colon cancer cell lines (Dong 2000). EGCG and theaflavins have been shown to inhibit TPA and epidermal growth factor (EGF)-induced transformation of JB6 mouse epidermal cells in a dose-dependent manner (Yang and others 2000). In somatic colon cancer, APC mutations represent the earliest defined stage in the colon cancer pathway (Kinzler and Vogelstein 1996; Arends 2000). EGCG contributes to suppression of intestinal tumors in the Min mice, which arise through an APC mutation. Green tea inhibits the expression of COXs and iNOS in colonic tissues, which are constantly elevated in subjects with ulcerative colitis and colorectal cancers (Sano and others 1995; Kutchera and others 1996; Hendel and Nielsen 1997; Ohishi and others 2002). Since cancer-preventive agents like sulindac and tamoxifen are associated with adverse effects, a combination with EGCG could effectively inhibit intestinal tumors in multiple intestinal neoplasia.
Under normal conditions, the intestinal epithelium serves as a highly selective barrier that permits absorption of water, electrolytes, and various nutrients from the lumen, simultaneously restricting the passage of larger and potentially toxic compounds of microbial origin (Madara and Stafford 1989). Increased permeability of this barrier has been implicated in the pathogenesis of several gastrointestinal disorders, including inflammatory bowel disease (Farhadi and others 2003). In a model for murine colitis, protective effects of green tea have been demonstrated (Varilek and others 2001). EGCG prevents the increase of epithelial permeability induced by interferon-γ (IFNγ) (Watson and others 2004).
Liver cancer Oxidative stress plays a major role in several liver diseases. Green tea has an antiproliferative activity on hepatoma cells, suppresses hepatoma-induced hyperlipidemia (hypercholesterolemia and hypertriglyceridemia), and also prevents hepatotoxicity (Crespy and Williamson 2004). Green tea may be a chemopreventive agent for hepatocarcinogenesis in the absence of chronic hepatocyte damage. It suppresses D-galactosamine-induced liver injury in rats, which could be through inhibition of tumor necrosis factor-induced apoptosis (He and others 2001). Daily ingestion of green tea prevented hepatotoxicity (increase in serum glutamic-oxaloacetic transaminase and glutamic-pyruvic transaminase; decrease in hepatic glycogen, serum triglyceride, and lactate dehydrogenase) and cell proliferation in the liver of rats on administration of 2-nitropropane (Sai and others 1998).
Prostate cancer Prostate cancer is one of the most common types of cancer among men in Europe, North America, and Australia (Coleman and others 1993). In contrast, Japanese and Chinese men who consume several cups of green tea have one of the lowest incidences of prostate cancer in the world. Many in vitro and in vivo experiments have suggested a potential anticarcinogenic effect of green tea in the prostate (Gupta and others 1999). In vitro, tea inhibits the 5-α-reductase-mediated conversion of testosterone to 5-α-dihydrotestosterone, a potential mechanism of action in prostate cancer (Liao and Hiisakka 1995). The cytotoxic effect of EGCG on prostate cancer cells correlates with its ability to inhibit fatty acid synthase (FAS), a lipogenic enzyme overexpressed in many human cancers (Brusselmans and others 2005). FAS is a key metabolic enzyme that catalyzes the synthesis of long-chain fatty acids. In contrast to most normal tissues that show low FAS expression, expression of FAS is markedly increased in various human cancers, including cancer of the prostate, breast, ovary, endometrium, colon, and lung.
Figure 10 shows quercetin, luteolin, and kaempferol to efficiently inhibit lipogenesis and induce marked morphological changes of LNCaP cells, including loss of cell–cell contacts and formation of astrocyte-like extrusions. Similar changes of LNCaP cell phenotype were observed on specific RNAi-mediated FAS inhibition, which caused a reduction of lipogenesis to 34% of the normal levels, such as a FAS inhibitory effect comparable with that of 6 to 12 μM luteolin or 25 to 50 μM quercetin or kaempferol, suggesting that the changes in cell morphology induced by them are direct results of FAS inhibition (Brusselmans and others 2005).
Mucosa leukoplakia In a double-blind, placebo-controlled trial on human subjects with oral mucosa leukoplakia, a precancerous lesion, oral and topical administration with a mixture of black and green tea resulted in a partial regression of the lesion in 37.9% of the treated patients (Li and others 1999). High concentration of EC, EGCG, and EGC is achieved in the oral mucosa on drinking tea slowly. The saliva levels are 2 orders of magnitude higher than plasma levels within minutes of consuming 2 to 3 cups of green tea. However, the half-life of catechins in the saliva is much shorter than in the plasma, and encapsulated tea solids have no effect on the salivary catechin level.
Tea inhibits the growth of Vibrio cholerae, Salmonella typhi, Campylobacter jejuni, Campylobacter coli, Helicobacter pylori, Shigella, Salmonella, Clostridium pseudomonas, Candida, Mycoplasma, and Cryptococcus (Diker and others 1991; Toda and others 1991; Sugita and others 1999). Subinhibitory concentrations of EGCG and ECG can suppress the expression of bacterial virulence factors and reverse the resistance of the opportunistic pathogen Staphylococcus aureus to β-lactam antibiotics. In fact, relatively low concentrations of ECG can sensitize methicillin-resistant S. aureus (MRSA) clinical isolates to levels of oxacillin that can be readily achieved in clinical practice (Taylor and others 2005).
Chlamydia trachomatis and Chlamydophila pneumoniae are ubiquitous pathogens that cause various types of infections in humans. Chl. pneumoniae is a common organism that causes respiratory tract and other infections (Kuo and others 1995). Inhalation therapy using a nebulizer containing tea polyphenols is effective for respiratory tract infections caused by Chl. pneumoniae (Yamazaki and others 2003). C. trachomatis is the frequent cause of sexually transmitted diseases (Centers for Disease Control and Prevention 1995). Since C. trachomatis causes endocervicitis, urethritis, conjunctivitis, and afebrile pneumonia in infants and is a respiratory pathogen that causes pneumonia and bronchitis, topical use of the polyphenols is beneficial. Tea polyphenols also have in vitro antimicrobial effects on the influenza virus, Vibrio cholerae, Staphylococcus aureus, Campylobacter jejuni, Campylobacter coli, and others (Nakayama and others 1990, 1993; Toda and others 1991; Yam and others 1998).
Reports indicate oral administration of tea extracts for the prevention of food poisoning (Hara 2001a). Polyphenols and polyphenol derivatives are effective in the prevention and cure of Helicobacter pylori-associated gastric diseases. Infection by the stomach-dwelling bacterium H. pylori constitutes a major risk factor for gastritis, peptic ulcer, gastric cancer, and mucosa-associated lymphoid tissue lymphoma (Montecucco and Rappuoli 2001). Epidemiological studies indicate a correlation between H. pylori seropositivity and environmental factors, including diet. A lower incidence of the infection has been associated with the consumption of vegetables, wine, and green tea (Suadicani and others 1999). VacA, a major virulence factor of the widespread stomach-dwelling bacterium, causes cell vacuolation and tissue damage by forming anion-selective, urea-permeable channels in plasma and endosomal membranes. Green tea polyphenols are able to inhibit ion and urea conduction and cell vacuolation by VacA. Stenotrophomonas maltophilia has emerged as an important nosocomial pathogen, especially for patients whose immune systems are compromised by debilitating diseases (Navarro-Martinez and others 2005). S. maltophilia infection can cause bacteremia, endocarditis, pneumonia, mastoiditis, peritonitis, meningitis, or infections of the eyes, bones, joints, urinary tract, soft tissues, and wounds. EGCG shows strong antibiotic activity against S. maltophilia, the mechanism of action being related to its antifolate activity.
Aids weight loss and obese people
A long-term feeding of tea catechins is beneficial in the suppression of diet-induced obesity by modulating lipid metabolism (Crespy and Williamson 2004). An inverse relationship may exist among habitual tea consumption, body fat percent, and body fat distribution for subjects who have maintained tea consumption for more than 10 y (Wu and others 2003). Dietary supplementation with EGCG could be considered a natural treatment for obesity, which is partly mediated via a direct influence on the adipose tissue. On an EGCG-supplemented diet, FAS and acetyl-CoA carboxylase-1 mRNA levels are markedly reduced in the adipose tissues (Wolfram and others 2005). A green tea extract rich in EGCG is able to inhibit gastric lipase (GL) and pancreatic lipase (PL), the enzymes involved in in vitro lipid digestion (Juhel and others 2000). This reduces the solubility of cholesterol in the biliary micelles, which may be responsible for the lowering of intestinal cholesterol absorption, total fat absorption, and serum triglyceride and cholesterol levels.
The consumption of tea elevates metabolic rate and increases fat oxidation (Figure 11). Green tea may have thermogenic properties not attributable to its caffeine content alone. EGCG and caffeine from the tea act synergistically to produce the thermogenic response and increase in fat oxidation. Thermogenesis and fat oxidation are under the control of the sympathetic nervous system and its neurotransmitter norepinephrine. A clinical study demonstrated that an intake of green tea extract (containing 90- mg EGCG and 50- mg caffeine) by 10 healthy men resulted in a significant increase (4%) in energy expenditure (EE), a decrease in respiratory quotient, and an increase in urinary excretion of norepinephrine. Neither caffeine nor a placebo had any effect on the expenditure or excretion of norepinephrine (Dulloo and others 1999). Thus, green tea polyphenols may play a role in weight control and be beneficial in treating obesity.
Oolong tea has an inhibitory effect on fat absorption (Murakami and others 2006). The polymerized phenols present therein increase EE (Komatsu and others 2003). A study on human subjects who took 4 cups of oolong tea per day (the brew from four 2-g tea bags) showed a loss of over 1 kg of body weight during a 6-wk period, suggesting it to promote weight loss by increasing EE by 10% to 20% (Chen and others 1998). Oolong tea contains caffeine, and the human subjects received 125 mg/d caffeine. Caffeine reportedly increases EE for several hours following ingestion depending on the level of intake. The amount of caffeine consumed during the study would be indicative of a 16% increase in resting EE.
Green tea catechins may be considerd for the treatment of neurodegenerative disorders such as Parkinson's and Alzheimer's (Mandel and others 2006). Alzheimer's disease is a progressive neurodegenerative disorder pathologically characterized by the deposition of β-amyloid (Aβ) peptides as senile plaques in the brain (Rezai-Zadeh and others 2005). Neuroprotection is due to the potent antioxidant and iron-chelating action of the polyphenolic constituents of black tea extracts, preventing nuclear translocation and activation of the cell-death-promoting NF-κB (Levites and others 2002). Tea catechins are able to penetrate the brain barrier and protect neuronal death in a wide array of cellular and animal models of neurological diseases. EGCG has been shown to modulate the amyloid precursor protein cleavage and reduce cerebral amyloidosis in Alzheimer transgenic mice (Rezai-Zadeh and others 2005).
Epidemiological studies suggest polyphenols from black and green tea to protect against cardiovascular diseases (Riemersma and others 2001). Any possible production of peroxynitrite is eliminated by black tea theaflavins, by simply preventing the induction of inducible NOS synthesis (Sarkar and Bhaduri 2001). Regular ingestion of black tea improves brachial artery vasodilation by significantly increasing endothelium-dependent and -independent dilatation. Black tea may reduce cardiovascular risk via improved vasodilator function of conduit arteries (Hodgson and others 2002). In patients with coronary artery disease, short- and long-term consumption of black tea reversed endothelial vasomotor dysfunction (Duffy and others 2001). Atherogenesis may be slowed by reducing the oxidative modification of low-density lipoprotein (LDL) cholesterol and associated events such as foam cell formation, endothelial cytotoxicity, and induction of proinflammatory cytokines. The susceptibility of LDL to oxidative modification is readily inhibited in vitro by extracts of black and green tea (McAnlis and others 1998; Cherubini and others 1999). Some human studies have not shown protective effects of tea consumption on serum lipid profiles and coronary heart disease morbidity and mortality. Nevertheless, the overall picture emerging from published studies is that tea confers protective effects on the cardiovascular system. This is supported by the observations that tea drinking significantly reduces the risk of ischemic heart disease and stroke as well as serum or plasma concentrations of cholesterol and homocysteine (Trevisanato and Kim 2000).
Endothelial cell function Normal endothelial functions include regulating vasomotor tone, platelet activity, leukocyte adhesion, vascular smooth muscle proliferation via the release of NO, and other hormone-like substances (Duffy and others 2001). NO plays an ambiguous role in physiology. The acetylcholine-induced relaxation in aorta is NO-mediated. Upon stimulation of the acetylcholine-receptor, the constitutive NOS produces NO. NO activates guanylate cyclase to produce cyclic GMP and, ultimately, vasorelaxation. On the other hand, NO is toxic, predominantly due to the formation of peroxynitrite with superoxide radicals (Radi and others 1991). Endothelial dysfunction, particularly endothelium-derived NO activity, contributes to the development and progression of atherosclerosis and impaired blood flow through arteries. Endothelial dysfunction is associated with increased oxidative stress and may be reversed by antioxidant interventions. Both acute and chronic consumption of tea improve the flow-mediated dilation and increase plasma catechin concentration (McKay and Blumberg 2002). Green tea is a better NO and peroxynitrite scavenger than black tea, with EGCG being the major contributor to both the peroxynitrite- and NO-scavenging ability (Heijnen and others 2000).
Hypocholesterolemic effect The hypocholesterolemic activity of tea could offer protection against heart diseases. In animals fed diets high in fat and cholesterol, green tea, black tea, and tea polyphenols prevented elevations in serum and liver lipids, decreased serum total cholesterol or atherogenic index, and increased fecal excretion of total lipids and cholesterol. Chinese green tea and jasmine tea, both with a minimum degree of fermentation, have significant serum and liver cholesterol-lowering effects. In rats with diet-induced hypercholesterolemia, Chinese tea with various degrees of fermentation was found to reduce the increase in liver weight due to lipid deposition, lower the atherogenic index, and increase the HDL: total cholesterol ratio (Yang and Koo 1997). The hypocholesterolemic effect could be attributed to the ECG and EGCG in the tea extracts. Thus, inclusion of tea in a diet moderately low in fat could reduce the total and LDL cholesterol significantly and may, therefore, reduce the risk of coronary heart disease (Davies and others 2003). However, the effect of tea drinking may vary with respect to individual differences in colonic microflora and genetic differences in enzymes involved in polyphenol metabolism (McKay and Blumberg 2002).
Squalene epoxidase (SE) is a nonmetallic flavoprotein monooxygenase that catalyzes the conversion of squalene to (3S) 2,3-oxidosqualene. SE is considered to be a rate-limiting enzyme in cholesterol biogenesis (Abe and others 2000). SE and HMG CoA reductase are the only 2 genes involved in cholesterol biosynthesis. The green tea gallocatechins and theasinensin A are potent and selective inhibitors of SE. However, the flavan-3-ols without the galloyl group at C-3 do not show significant enzyme inhibition. The cholesterol-lowering effect of green tea may be attributed to their potent SE-inhibition activities. The inhibition could be due to specific binding to the enzyme and scavenging of reactive oxygen species required for the monooxygenase reaction.
Inhibition of LDL oxidation The oxidative modification of LDL by free radicals is a key event in the pathogenesis of atherosclerosis (Steinberg and others 1989). One of the proposed mechanisms for the possible protective effect of tea against cardiovascular diseases is the inhibition of the oxidation of LDL (Wiseman and others 1997). In vitro studies have shown LDL oxidation to be inhibited by extracts of green and black tea (Princen and others 1998; Cherubini and others 1999; McKay and Blumberg 2002); however, such an antioxidative effect was not demonstrated in human studies (van het Hof and others 1999). One study indicated the consumption of black tea to slightly protect LDL against oxidation ex vivo. Tea polyphenols were accumulated in LDL particles within 3 d of green or black tea consumption, but their levels were not sufficient to enhance resistance to LDL oxidation (van het Hof and others 1999). It is proposed that a daily intake of 7 to 8 cups of tea is not sufficient to promote catechin concentrations high enough to inhibit LDL oxidation (Miura and others 2000; McKay and Blumberg 2002). Higher plasma concentrations of catechins, similar to concentrations attained in in vitro studies, can be achieved by repeated intake of tea over a period of time, for instance, 1 cup of tea in every 2 h.
Estrogen-like activity Tea flavonols with antioxidative activity include quercetin, kaempferol, and myricetin, which account for the favorable effects on cardiovascular health. Kaempferol is shown to exhibit estrogenic activity in vitro (Miksicek 1995). The daily kaempferol intake doubles in regular tea drinkers compared with nondrinkers. Tea also contains lignan polyphenols such as secoisolaracinol, which are phytoestrogens. Phytoestrogens in tea may account for part of the benefits of tea against coronary heart disease.
Blood pressure Hypertension is a common disease among the aged, with high blood sodium level as one of the causative factors. The physiological effects of tea and its components on cardiovascular disease risk factors such as hypertension are of interest. The potassium in tea can induce the excretion of sodium and, hence, tea could have a preventive effect against hypertension. Tea catechins can inhibit the angiotensin-converting enzyme activity and thus lower blood pressure. Both black and green tea polyphenols attenuate blood pressure increases through their antioxidant properties (Negishi and others 2004). Elevated blood pressure can accelerate the atherosclerotic process, and evidence linking reduced blood pressure with tea consumption is reported for green tea polyphenols in hypertensive animals and among black tea drinkers (Stensvold and others 1992; Hara 2001b). Thus, tea consumption has been inversely associated with the development and progression of atherosclerosis. Black-tea consumption helps reduce blood pressure by reducing the risk of atherosclerosis, which interferes with the ability of the blood vessels to relax.
Tyrosine kinase inhibitor Enhanced activity of tyrosine kinase receptors (RTKs) is implicated as a contributing factor in the development of malignant and nonmalignant proliferative diseases such as cancer and atherosclerosis (Sachinidis and Hescheler 2002). Several growth factors transducing mitogenic signals through RTKs are implicated in the development of tumor and cardiovascular diseases. Catechins of green tea are potent natural inhibitors of several RTKs. Animal and cell culture studies suggest catechins as potential candidates for the clinical therapy of cancer and cardiovascular diseases (Sachinidis and Hescheler 2002).
Contrary to the findings of some studies, tea consumption may protect and not contribute to the development of kidney stones, as indicated by a large prospective cohort study. It is postulated that tea affects the absorption of oxalates resulting in kidney stone formation (Massey 2000). In the Nurses' Health Study, a prospective cohort study of more than 81000 women, aged between 40 and 65 y of age, tea drinking was inversely correlated with kidney-stone development (Curhan and others 1998).
A daily intake of black or green tea for 3- mo was shown to inhibit diabetic cataracts and also have a blood glucose-lowering effect (Vinson and Zhang 2005). Oolong tea may be an effective adjunct to oral hypoglycemic agents in the treatment of type 2 diabetes (Hosoda and others 2003). Figure 12 shows the mechanism of tea polyphenols on diabetes.
Diabetes is generally accompanied by nephropathy due to microvascular dysfunction or impairment (Crespy and Williamson 2004). In normal kidney tissue, the production of thromboxane A2 (TXA2) and prostacyclin I2 (PGI2) is controlled, and the balance between them is important to maintain homeostasis in vivo. A modification of the PGI2:TXA2 ratio accelerates thrombogenesis in the renal tubules, increasing the risk of impaired function and atherosclerosis. The production of these compounds depends on the activity of phospholipase A2 (which is higher in the case of kidney disorders) and the fatty acid composition. Administration of green tea catechins decreases the synthesis of TXA2 and increases that of PGI2 and brings the ratio to the normal level. Kidney function is thus improved by green tea catechin supplementation as a result of its antithrombogenic action, which in turns controls the arachidonic acid cascade system.
The catechins and theaflavins have a wide range of biological activities, including prevention of tooth decay and oral cancer (Lee and others 2004). Compounds in tea may play a role in the prevention of plaque build-up on teeth and dental caries (Jones and others 1999). Tea contains natural fluoride, and tea extracts are able to inhibit the potential cariogenicity of oral bacteria such as Escherichia coli, Streptococcus salivarius, and Streptococcus mutans (Rasheed and Haider 1998; McKay and Blumberg 2002). Black tea components prevent cavities by inhibiting salivary amylase and glucosyl transferase, and also prevent the adherence of Str. mutans. Also, rinsing the mouth with tea inhibits the breakdown of starch in the food particles trapped in the mouth, producing an antiplaque effect (Hamilton-Miller 2001).
EGCG may play an important role in the development of new HIV-drug therapies that would protect against HIV by preventing its progression. EGCG has been proposed to have an anti-HIV-1 effect by preventing the binding of HIV-1 glycoprotein (gp) 120 to the CD4 molecule on T cells (Williamson and others 2006). CD4 is a cell surface gp expressed on T cells and plays an important role in the recognition of antigens by T cells and their activation (Williamson and others 2006). It also acts as a receptor for HIV-1, because the viral envelope protein gp 120 binds to it via its D1 domain and uses this interaction to infect CD4+ T cells. Therefore, there has been interest in finding molecules that block the binding of gp120 to CD4 (entry inhibitors) as a way of reducing HIV-1 infectivity. To achieve the effective concentrations, it would be necessary to take therapeutic doses of EGCG. Theaflavin derivatives have more potent anti-HIV-1 activity than catechin derivatives (Liu and others 2005). The tea polyphenols inhibit HIV-1 entry into target cells by blocking HIV-1 envelope gp-mediated membrane fusion.
Trypanosoma cruzi is the causative agent of Chagas disease, which is a major endemic disease in South and Central America (Paveto and others 2004). Human hosts are infected either by the triatomide insect vector bite, by blood transfusion, or by congenital transmission. The chronic phase of the disease occurs several years after infection, with cardiac and gastrointestinal pathologies being the typical clinical manifestations. GCG and EGCG from green tea could serve as therapeutic agents for Chagas disease.
Osteoarthritis and rheumatoid arthritis
Osteoarthritis (OA) of the knee and hip is a debilitating disease affecting more women than men, and the risk of developing OA increases sharply with age. The severity of OA varies from person to person, and the consonant clinical signs include joint pain, tenderness, limited movement, crepitus, occasional effusion, and variable degrees of inflammation without systemic effects. Although not a traditional inflammatory disease, symptoms of local inflammation and synovitis are evident in many patients with OA and also seen in animal models (Goldring 1999). Inflammatory joint diseases, of which rheumatoid arthritis (RA) represents the most common form, is a chronic and systemic inflammatory disease of unknown etiology, and is marked by synovial hyperplasia with local invasion of bone and cartilage leading to joint destruction. RA affects about 1% of the adult population, with more women being afflicted than men. An animal study that involved collagen-induced arthritic mice brought out the ability of green tea polyphenols in significantly reducing the risk and severity of arthritis. The expression of the inflammatory mediators in arthritic joints was lower in the mice fed with green tea. Theaflavins from tea impact expression of multiple genes involved in arthritis. When mice were fed a theaflavin-enriched tea plant extract, inflammatory cytokines were greatly reduced, and the mice had reduced symptoms of induced arthritis (Hirsch and Evans 2005). The study could stimulate interest in conducting human trials to investigate the possible role of tea in the prevention and treatment of arthritis.
The consumption of tea lowers the risk of osteoporosis, with green tea catechins accumulating at appreciable levels in bones. Tea consumption is identified as an independent factor protecting against the risk of hip fractures in human subjects over the age of 50 in a Mediterranean osteoporosis study (Kanis and others 1999). Studies on women aged between 65 and 76 y showed the influence of tea on greater bone mineral density (Hegarty and others 2000).
Hindmarch and others (2000) demonstrated that day-long consumption of tea improved the cognitive and psychomotor performance of healthy adults in a manner similar to coffee, but tea (which contains less caffeine) is less likely than coffee to disrupt the quality of sleep at night.
Possible probiotic effects
Regular intake of tea improves the metabolic function of the bacteria in the intestinal tract, an important contributor to health promotion (Weisburger 2003). Green tea flavonoids alter colonic bacteria to favor “friendly” bacteria and reduce fecal odor (Goto and others 1998, 1999). This was demonstrated in 2 studies on elderly patients administered green tea flavonoids in capsules.
Besides various health benefits, tea polyphenols also act as antiaging agents. The polyphenols neutralize free radicals that are responsible for the aging effect (http://www.stopagingnow.com). Due to the antiaging properties, tea is now finding its way into topical preparations.
Oolong tea is useful in the prevention of diseases related to stress without adversely affecting appetite or physical fitness. The effects of oolong tea on plasma lipid peroxide levels arise from the antistress and antioxidant effects of the polyphenols, caffeine, and other active components that are abundant in tea (Kurihara and others 2003). Investigations on the anxiolytic activity of EGCG on acute administration in mice using behavioral tests and by electrophysiology on cultured hippocampal neurons showed EGCG to consistently inhibit spontaneous excitatory synaptic transmission (Vignes and others 2006).
Hepatic fibrosis is characterized by excessive production of extracellular matrix (ECM), which is a characteristic of activated hepatic stellate cells (HSC). EGCG may be used as an antifibrogenic candidate in the prevention and treatment of liver fibrosis (Yumei and others 2006).
Multiple organ dysfunction syndrome (MODS)
MODS is a progressive deterioration in the function of several organs or systems of patients with septic shock, multiple trauma, severe burns, or pancreatitis. Regardless of the cause, MODS typically consists of the sequential dysfunction of several organ systems, beginning with the lungs, followed by hepatic, intestinal, renal, hematological, and, eventually, cardial dysfunction; the exact order may vary because of pre-existing diseases or the nature of the precipitating cause. Green tea polyphenols are able to attenuate the lung, liver, and pancreatic injury, and renal dysfunction, as well as the increase in myeloperoxidase (MPO) activity in the lung and intestine (Paola and others 2006).
Absorption and Metabolism
Knowledge on the absorption and metabolism of flavonoids is crucial to the understanding of whether the compounds or their metabolites have the potential to exert the biological activity in vivo that the in vitro studies suggest. Polyphenols are so extensively altered during the 1st-pass metabolism that, typically, the molecular forms reaching the peripheral circulation and tissues are different from those present in the original food (Zhang and others 2003). EGCG is quite stable in the stomach and small intestine. The content of EGCG in the intestine increases sharply within a few hours and is detectable within 8 h of a single dose of EGCG (50 mg) in rats (Nakagawa and others 1997). Absorbed tea catechins are biotransformed in the liver to conjugated metabolites, namely, glucuronidated, methylated, and sulfated derivatives. While EGC and EC are mainly conjugated, EGCG is usually present in free form in the human plasma (Chow and others 2001). Piperine is reported to enhance the bioavailability of EGCG (Lambert and others 2004). Some of the catechins delivered to the gut can be glucuronidated by the glucuronosyl transferase in the mucosa of the intestine (Piskula and Terao 1998). The metabolism to a glucuronide does not interfere with their antioxidant properties as assessed by their ability to scavenge superoxide radicals. In the gut tissue, β glucuronidases and microflora convert the conjugated products to aglycones. Some of them may be reabsorbed, while others are metabolized to form valerolactones, phenylacetic acid, and phenylpropionoic acids (Meselhy and others 1989; Li and others 2000).
The low bioavailability of theaflavins is not due to pH or temperature-dependent degradation in the gastrointestinal tract, but due to the high molecular weight and large polar surface area of these compounds. Compounds with a molecular weight above 500 Da, more than 5 hydrogen-bond donors, or 10 hydrogen-bond acceptors have poor bioavailability due to their large actual size (high molecular weight) or large apparent size (due to the formation of a large hydration shell) (Lipinski and others 2001). The hydroxyl groups on theaflavins are likely to form a large hydration shell that gives the compounds greater apparent surface area, thus preventing their movement through the plasma membrane (Lee and others 2004). The hydroxyl groups not only serve as functional handles for Phase II enzymes but may also reduce the absorption of the compounds from the intestinal lumen.
A schematic representation of the possible mechanisms of absorption and metabolism of catechin in rats is shown in Figure 13. The absorbed catechin enters intestinal epithelial cells where it is always glucuronidated and sometimes methylated. Apparently, some of the glucuronides are able to enter the hepatocytes. In the cytosol of hepatocytes, catechin glucuronides are sulfated and/or methylated and eliminated extensively by bile. The circulating forms are then exclusively glucuronide conjugates of catechin and O-methyl catechin (OMC) (Donovan and others 2001). Meng and others (2002) demonstrated EGCG to be methylated into 4′,4″-di-O-methyl-EGCG. The concentration of the metabolite was about 15% of that of EGCG in the human plasma. The major circulating metabolites of epicatechin have been elucidated to be epicatechin-3′-O-glucuronide, 4′-O-methylepicatechin-3′-O-glucuronide, 4′-O-methylepicatechin-5- or 7-O-glucuronide, and the aglycones epicatechin and 4′-O-methylepicatechin (Natsume and others 2003) (Figure 14) .
On absorption, the catechins are distributed in all body tissues, particularly in the esophagus, small intestine, and colon (Yang and others 2000; Lambert and Yang 2003). The plasma concentration of the catechin peaks at 1.5 to 2.6 h in human subjects and returns to baseline at 24 h. Less than 10% of EGC and EC was found to be excreted 3 to 6 h after ingestion of 1.2- g tea solids by healthy volunteers. However, the CGs were not detected in the urine (Lee and others 1995). Lee and others indicated that plasma concentration of EGCG on ingestion of 1.2 g of decaffeinated green tea was only 46 to 268 ng/mL (Lee and others 1995). Microbial metabolites, namely, 5-(3′,4′,5′-trihydroxyphenyl) valerolactone, 5-(3′,4′-dihydroxyphenyl)valerolactone, and 5-(3′,5′-dihydroxyphenyl)valerolactone, mostly in conjugated forms, were identified in the plasma and urine of volunteers after ingestion of green tea (Meng and others 2002) (Figure 15). These metabolites, accounting for 6% to 39% of the ingested EGC and EC, could exert some interesting antioxidant activity because of their di-/trihydroxyphenyl groups (Li and others 2000; Lee and others 2002).
Maintenance of high plasma concentrations of flavonoid metabolites could be achieved with regular and frequent consumption of plant products. Due to rapid absorption and a short half-life, repeated intake of catechin is necessary to obtain an accumulation of metabolites in the plasma (van het Hof and others 1999; Warden and others 2001). A transdermal system would provide an alternative delivery mechanism for catechins, thus giving consumers an option to formalize dosing (Batchelder and others 2004). Transdermal delivery from patches is highly popular among consumers and administration of tea catechins via the skin would have numerous distinct advantages, including elimination of the 1st-pass liver metabolism and food interactions, and easy, controlled dosing with constant plasma concentrations. The highest percent permeation of EGCG was found to be from the drug-in-adhesive patches containing green tea extract.
Isolation of Tea Polyphenols
The isolation of active components from tea has received considerable attention owing to their antioxidant properties. The commonly applied techniques include high-speed counter-current chromatography, supercritical carbon dioxide extraction, Sephadex-based chromatography, and other liquid chromatographic techniques (Xu and others 2006). High-peformance media (Sepharose HP) may be employed for the purification of EGCG from crude green tea extracts. Poly(N-methyl-N-p-vinylbenzylacetamide) (PMVBA), poly(N-methyl-N-p-vinylbenzylurea) (PMVBU), and poly(N-methylacrylamide) (PMA) can adsorb tea polyphenols in aqueous solution efficiently, and PMVBU has the largest equilibrium adsorption capacity and adsorption enthalpy for tea polyphenols (Huang and others 2007). The extraction and analysis of tea catechins from complex food matrices is complicated due to the strong association of tea catechins with macronutrients such as proteins (Ferruzzi and Green 2006). Effective extraction methods are required to accurately assess and validate the levels of bioactive tea catechins in new products. The usefulness of pepsin treatment for enhancing the recovery of tea catechins is demonstrated in the analysis of commercial soy and milk-tea beverages.
The schematic diagram for the isolation of tea polyphenols is shown in Figure 16 (An and others 2004). Dried green tea is repeatedly extracted with 60% acetone for 24 h at room temperature. The upper layer is evaporated and filtered to remove chlorophyll, and the remnant is loaded onto a Sephadex LH-20 column and separated by a methanol:acetone ratio of 0:1 through 1:0. Each fraction of polyphenol could be developed using silica gel thin-layer chromatography (TLC) and lyophilized. AlCl3 is also able to efficiently extract green tea flavanols from green tea (Chen and others 2001). A yield of 9.6- g extract per 100- g dry tea leaves with green tea flavanols of more than 94% could be obtained with AlCl3 at a pH of 5.5 and 30 °C. The fractionation of Lung Chen tea is depicted in Figure 17.
A maximum extraction effciency of green tea catechins with water is obtained at 80 °C for 20 min (97%) and 95 °C for 10 min (90%) (Perva-Uzunalic and others 2006). Dried and pulverized green tea leaves may be extracted with 40% ethanol for 30 min at RT and filtered to give a flavan-3-ol extract as demonstrated by Wright (2002). A process for the isolation of tea polyphenols and caffeine from green tea leaves by extraction with water, followed by ultrafiltration with a CA–Ti composite ultrafiltration membrane, adsorption by a resin, and finally elution by a mixed solvent system has been developed by Li and others (2005).
In the isolation of EGCG, unfermented or half-fermented tea leaves are treated with hot water (80 to 100 °C), a 40% to 75% aqueous solution of alcohol, or a 30% to 80% aqueous solution of acetone; the extract is washed with chloroform and transferred into an organic solvent such as ethyl acetate, n-butanol, methyl isobutyl ketone, or acetone. The organic solvent is removed by distillation and the residual component is freeze-dried or spray-dried. The tea catechins are separated by reverse-phase high-performance liquid chromatography (HPLC) using an eluting solution containing 0% to 25% acetone, 0% to 35% tetrahydrofuran, and 65% to 85% water (by volume). The resulting EGCG product may be concentrated, dried, and powdered, or purified by recrystallization from water (Hara 1986).
High-speed countercurrent chromatography (HSCCC) could be applied to the separation of polyphenols from tea leaves (Degenhardt and others 2000). The capability of HSCCC to isolate pure tea polyphenols from complex mixtures on a preparative scale is demonstrated for catechins, flavonol glycosides, proanthocyanidins, and strictinin from green and black tea. The purity and identity of isolated compounds is reportedly confirmed by (1)H NMR and HPLC-ESI-MS/MS. HSCCC has been applied for the separation of theaflavins from a black tea infusion. Pure theaflavin and theaflavin-3,3′-O-digallate (TFDG) were obtained by using a solvent system composed of hexane-ethyl acetate-methanol-water (1.25:5:1.25:5 [v/v/v/v]) by gradient elution (Cao and others 2004).
Microwave-assisted extraction (MAE) is another technique employed for the extraction of phenolic compounds from tea leaves. The methodology includes mixing the sample with an appropriate solvent (20:1, mL/g), the extraction rate improving proportionately with the degree of grinding (http://www.rsc.org). A preleaching time of 90 min at room temperature before MAE (4 to 12 min) increases the efficiency of extraction. A 4-min MAE results in a higher extraction yield compared to an extraction at room temperature for 20 h, an ultrasonic extraction for 90 min, or a heat-reflux extraction for 45 min, respectively (Pan and others 2003). Shu and others (2003) demonstrated extraction yield of ginsenosides from ginseng root by a 15-min MAE (ethanol–water) to be higher than that obtained by a 10-h conventional solvent extraction (ethanol–water).
The process of obtaining theaflavins is shown in Figure 18. Black tea leaves are extracted with boiling water to produce a concentrated tea extract (Balentine and Harbowy 1995), which is further concentrated under vacuum to produce an extract of higher concentration. The extract is allowed to “cream” by holding at 15 °C for more than 30 min, followed by centrifugation to remove the cream from the supernatent. The cream is solubilized to regenerate a concentrated solution of about 20% solids with boiling water, followed by addition of an approximately equal weight of a water-soluble solvent such as acetone or alcohol. The solution is cooled to below room temperature and allowed to precipitate, followed by centrifugation to remove the insoluble materials. The extract so obtained is suitable as a concentrated source of tea polyphenols upon drying; or it may be used directly as a starting material for extraction and/or chromatography to prepare purified polyphenols. The process of extraction and fractionation of black tea adopted by Fukuda and others (2005) is shown in Figure 19.
Stability of Polyphenols
The chemical instability of tea polyphenols can be a major drawback for its clinical applications. When tea polyphenols are exposed to factors such as light, heat, and oxidants, they are rapidly oxidized. The green tea catechins, as a whole, are more stable than the theaflavins of black tea. Heating at 100 °C for 3 h led to 25% degradation of green tea catechins, while the theaflavins were completely degraded (Su and others 2003). In soft drinks, both green tea catechins and theaflavins have poor long-term stability and decay by at least 50% during the 1st month of storage at room temperature. It is desirable to get a chemically stable dosage form of tea polyphenols for the quality control of drug products. Incorporation in solid lipid-based carriers such as solid lipid nanoparticles (SLN) can overcome the chemical instability. SLN are generally produced by homogenization or microemulsion technique. An improved microemulsion method of preparing tea polyphenols-loaded SLN (TP-SLN) has been developed by Ma and others (2007).
The considerable antioxidant potential is dependent on a number of factors involved in the preparation of tea. The tea epicatechins are remarkably stable when exposed to heat as long as the pH is acidic; only about 15% degrades after 7 h in boiling water at pH 5 (Clifford 1999). Maximum antioxidant capacity is associated with the drinking of green tea prepared at high temperatures (90 °C) and with long infusion times. Black tea should ideally be prepared between 70 and 90 °C and from leaves rather than tea bags, and infusion times should not exceed 1 to 2 min to produce maximum antioxidant potential (Langley-Evans 2000). Moreover, due to the flavonoid-binding capacity of milk proteins, the addition of milk can decrease the antioxidant potential of black tea preparations (Robinson and others 1997; Langley-Evans 2000). Milk/polyphenol complexes may resist gastric breakdown, rendering the polyphenols unavailable for absorption (Serafini and others 1996). An increase of plasma antioxidant capacity was observed in humans following tea consumption without milk. More recent findings indicate that adding milk to black tea does not influence the absorption of tea catechins and the antioxidant capacity in human plasma (van het Hof and others 1998; Leenen and others 2000). Ascorbic acid, in vitro, protects flavonoids against oxidative degradation during processing and storage (Kaack and Austed 1998).
The stability of theaflavins in the oral cavity and gastrointestinal tract may affect the bioavailability of these compounds. Holding pure theaflavins (0.18 mg/mL) in the mouth results in a 10- to 20-fold higher salivary levels of the compounds than does holding black tea extract that has a similar concentration of theaflavins, indicating that other components in black tea interfere with the transfer of theaflavins from the solution into the saliva and the oral mucosa (Lee and others 2004). The theaflavins are stable under acidic conditions (pH 6.5), but degrade at neutral and basic pH (pH > 7.0). The pH of the oral cavity is usually 7.0 to 7.4, and it is expected that under physiological conditions, some degradation of the theaflavins could occur. Once the compounds enter the gastric environment, they are probably stable. Theaflavins are stable in simulated gastric juice (pH 1.7) at 37 °C for more than 4 h. Likewise, the slightly acidic pH of 6.4 and largely anaerobic environment of the small intestine disfavor theaflavin degradation. In the colon, however, the pH becomes more basic (pH about 8.0) and the potential for degradation may arise, but the low oxygen tension disfavors oxidative degradation of theaflavins.
Tea Polyphenols as Functional Ingredients in Foods
The antioxidative activity of catechins makes them a potential candidate as functional ingredients for a number of foods and beverages (Yilmaz 2006). Catechins are able to inhibit lipid oxidation in red meat, poultry, and fish (He and Shahidi 1997; Tang and others 2001). For the effective inhibition of lipid oxidation by tea catechins, concentrations higher than 0.3% are required. Tea catechins along with rosemary and sage beow 0.5% could be used as natural antioxidants to reduce lipid oxidation in raw and cooked pork patties produced from frozen pork meat (McCarthy and others 2001a, 2001b). Tea catechins were found to be the most effective antioxidants against lipid oxidation of cooked pork patties among ginseng, mustard, rosemary, sage, butylated hydroxyanisole/butylated hydroxytoluene (BHA/BHT) and vitamin E. Mitsumoto and others (2005) used tea catechins (200 to 400 ppm) to inhibit the lipid oxidation in cooked or raw beef patties. The inhibitory effect of tea catechins against lipid oxidation in raw beef was higher than that of sodium ascorbate at the same concentration. Direct addition of 1000- ppm tea catechins to longissimus dorsi steaks was found to improve the color and lipid stability of beef patties significantly (Kerry 2005).
Green tea, tea extracts, and tea catechins such as epicatechin, EGC, ECG, and EGCG could be used as antioxidative agents in fish meat model systems instead of artificial antioxidants such as α-tocopherol, BHT, BHA, or tertiary butyl hydroquinone (TBHQ). Using hot water extracts of green, oolong, and black teas, Seto and others (2005) found extracts of tea to inhibit the oxidation of blue sprat tissues, with inhibition being positively correlated with the total catechin content of the tea extracts. Green and oolong teas were also effective in the suppression of lipid peroxidation in dark meat and skin of blue sprat. O'Sullivan and others (2005) have demonstrated tea catechins to inhibit the lipid oxidation of cod liver oil and white pollock liver oil. Catechin and epicatechin also serve as natural antioxidants in peanut oil and canola oil (Chen and Chan 1996; Chu and Hsu 1999). The use of green tea extracts in foods such as cereals, cakes, biscuits, dairy products, instant noodles, confectionery, ice cream, and fried snacks gives a healthier appeal to consumers, and, hence, the market potential for these foods may be improved by the presence of catechins (Wang and others 2000).
Foods and beverages rich in phenolic compounds have been associated with a reduced risk of several diseases. Thus, dietary polyphenols have the potential to be developed as effective food supplements as well as drugs for the prevention and treatment of cancer and other disease conditions. Chewing or holding green or black tea leaves is the most convenient and economical sustained-delivery system, resulting in the most effective delivery of the compounds to the oral cavity. Development of sustained release products such as chewing gums may aid in the esthetic acceptance and standardization of tea-polyphenol delivery (Lee and others 2004). Hangzhou Tearrow Foodstuff Co., Ltd., manufactures black tea sugarless chewing gum. The therapeutic properties of black tea in the chewing gum are maintained to produce the beneficial antibacterial and stomach-protecting effects. The product is available in various flavors, including oolong tea flavor, mint tea flavor, green tea flavor, and lemon tea flavor.
The tea used in nutritional supplements is either in extract form or as powdered leaves. Stability and interaction with food constituents should be taken into consideration for commercial applications of tea polyphenols as a functional ingredient. Green tea catechins are unstable at high temperatures and pH values, and their stability is poor when stored at room temperature for a long time (Su and others 2003).
Popular nonprescription weight-loss products and multivitamin supplements contain extracts of green tea owing to its efficiency in promoting weight loss (Dulloo and others 1999; Wang and Tian 2001). Quantum-Rx Nano-Green Tea™ (Quantum Nutrition Labs, LLC, Round Rock, Tex., U.S.A.) is a nutraceutical preparation designed to assure the absorption of the full spectrum of green tea polyphenols (http://www.gnlabs.com). The organic green tea is “nanized” (predigested into extremely small particles) so that it is rapidly absorbed into the blood stream. CardioTea™ with Policosanol, from Cardio Tabs (Kansas City, Mo., U.S.A.), is a unique blend of theaflavin-enriched tea extract with the added benefit of policosanol. Both theaflavin and policosanol have been clinically proven for their ability to significantly reduce cholesterol levels (http://www.cardiotabs.com).
Because of the various health attributes of tea polyphenols, tea extracts could be used as nutraceuticals in food preparations. In Japan, green tea is used in cakes, sweets, biscuits, bread, and ready-to-drink beverages. Scientists from the Univ. of Singapore have found the threshold level of green tea extract to be at 1.5 g/kg flour for brightness, hardness, and stickiness, and 5.0 g/kg flour for astringency and sweetness in bread (Wang and others 2007). Tea extracts could be used in jelly candies as a source of polyphenols (Gramza-Michalowska and Regula 2007). Sunphenon (Taiyo International, Minneapolis, Minn., U.S.A.) is a commercial product containing highly purified polyphenols rich in natural green tea catechins. It is approved by the Japanese Foundation for Health and Nutrition as a food for specified health use (FOSHU). Sunphenon contains more than 90% EGCG and less than 1% caffeine, suitable for use in supplements, foods, or beverages without imparting the characteristic taste or color of tea. Teavigo™ (DSM Nutritional Products, Switzerland) is natural EGCG, isolated from green tea and available as a very fine powder with a purity of 94% (Wolfram and others 2005). Green tea extract has received generally recognized as safe (GRAS) affirmation, allowing the food and beverage industries a free hand in its use for novel food products. The health care market is increasing its use of green tea in tablets, capsules, and health drinks.
For the cosmetic industry, green tea acts as an antioxidant within the product itself while on the skin surface it helps to reduce sun damage with the perceived benefits of antiaging and reduced wrinkling of the skin (http://www.rirdc.gov.ac). Cosmetic products that use green tea are sunscreens, moisturizers, foundations, toothpastes, and hair-care products. Owing to their antimicrobial activity, tea extracts have good potential as a complementary mouthwash (Esimone and others 2001). Green olive shower gel contains soapwort, green olive oil, and green tea extract as its ingredients. An antishine product for use under foundation or as an alternative to foundation, designed to prevent the skin's natural oils from becoming evident through the facial make-up, uses green tea extract (http://www.int.the-body-shop.com).
There is an increasing worldwide market for canned and bottled ready-to-drink tea. In bottle-packed beverages such as tea and coffee, hydrogen peroxide (H2O2) is gradually produced through exposure to air, although only a small amount is detected in the beverage immediately after the bottle is opened. Since H2O2 is toxic, it is necessary to develop safe and simple ways of reducing its production in bottled beverages. The addition of an aqueous extract of citrus peel reduces the concentration of H2O2 in green tea. The vitamin C from lemon has antioxidative properties and can positively influence the antioxidant potential of tea. The addition of L-cysteine or glutathione (GSH) (reduced form) with a thiol residue can also reduce the H2O2 concentration (Aoshima and Ayabe 2007). In Japan, vending machines are used to sell hot drinks (50 to 60 °C) (Sakanaka and others 2000). Thermophilic spoilage bacteria, both gas forming and flat sours, proliferate well at these temperatures. Flat sour spoilage has been observed in some canned drinks, such as milk-coffee, cocoa, shiruko (sweet red bean drink), and zenzai. On the other hand, canned tea rarely suffers spoilage in vending machines even in the absence of any antibacterial substances, presumably due to the antimicrobial properties of tea polyphenols in commercial green tea. In China and the United States, tons of tea are consumed annually, with 80% of them processed into “iced tea” (Wang and others 2004).
There could be a reduction in the digestibility of carbohydrates, proteins, and lipids whose hydrolysis reactions in the gut are enzyme-mediated (He and others 2007). Four digestive enzymes, including α-amylase, pepsin, trypsin, and lipase, were used to investigate the TP-enzyme interaction and the potential antinutritional property of tea polyphenols. The inhibition ratios of α-amylase, pepsin, trypsin, and lipase were 61%, 32%, 38%, and 54%, respectively, at a tea polyphenol concentration of 0.05 mg/mL. The effect of milk in altering the antioxidant activity of teas has produced mixed results, with some in vitro tests indicating that phenolics interact with the lipid fraction or with casein proteins or that milk lowers the antioxidant activity or produce no change at all (Luck and others 1994; Robinson and others 1997; Langley-Evans 2000; Richelle and others 2001; Arts and others 2002). The effects of tea consumption in increasing the phenolic antioxidant levels in human plasma have also been reported to be either inhibited (Serafini and others 1996) or unaffected (van het Hof and others 1998; Leenen and others 2000; Hollman and others 2001) by the addition of milk to tea. Serafini and others (1996) demonstrated that the addition of milk to black tea abolished the increase in the antioxidant potential that was observed when tea was consumed without milk. However, subsequent studies showed that addition of milk to black or green tea had no effect on the bioavailability of catechins, quercetin, or kaempferol in humans (van het Hof and others 1998; Hollman and others 2001).
Increased consumption of green tea is associated with a decreased hemoglobin concentration (Imai and Nakachi 1995). Black tea appears to inhibit the bioavailability of nonheme iron by 79% to 94% when both are consumed concomitantly (McKay and Blumberg 2002). Polyphenols in tea form insoluble complexes with iron within the gastrointestinal tract and render the iron unavailable for absorption. On the positive side, this effect may benefit patients with genetic hemochromatosis; Kaltwasser and others (1999) observed a significant reduction in iron absorption when some hemochromatosis patients included tea in their diet instead of water. The interaction between tea and iron could be mitigated by the addition of lemon or by consuming tea between meals (McKay and Blumberg 2002).
EGCG might induce amnesic activity
Behavioral tests indicate EGCG to exert amnesic effects just like the benzodiazepine drug, chlordiazepoxide. Moreover, EGCG and chlordiazepoxide induce indistinguishable chemical states for the brain (Vignes and others 2006).
Prooxidative effects of tea polyphenols on G6PD-deficient erythrocytes
Tea polyphenols have prooxidative effects on glucose-6-phosphate dehydrogenase (G6PD)-deficient erythrocytes with no similar change on normal erythrocytes (Hay and others 2005). G6PD deficiency is a genetic disorder, and the G6PD-deficient subjects are vulnerable to oxidative stress, predisposing them to chemical-induced hemolysis if exposed to prooxidative agents. Reduced GSH is a major antioxidant in human tissues that provides reducing equivalents for the glutathione peroxidase (GPx)-catalyzed reduction of hydrogen peroxide and lipid hydroperoxides to water and the respective alcohol. EGCG causes significant depletion of reduced GSH and in the presence of Fe2+ ions results in lipid peroxidation. Green tea and EGCG also cause oxidative damage to DNA, particularly in the presence of transition metals, and Fe2+ or Cu2+ ions.
Animal and epidemiological studies suggest promising health benefits of tea against several diseases, including cardiovascular disorders and some forms of cancer, as well as the promotion of oral health and other physiological functions. Tea polyphenols act as antioxidants and prevent tissues from damage by free radicals. They appear to protect genes from the mutagenic effects of environmental factors. Tea may be used as a therapeutic agent against premalignant lesions in the mouth. The polyphenols eliminate active forms of carcinogens and other toxicants, accounting for lower risk of cancer. Apparently, current evidence for the nutraceutical properties of polyphenols has stimulated the food and supplement industries to develop and promote polyphenol-rich products. Future research needs to define the actual magnitude of the health benefits of tea polyphenols and establish the safe range of tea consumption associated with the benefits. More promising studies are required to elucidate the therapeutic effects of tea.
Aberrant crypt foci
Adenomatous polyposis coli gene product
The cellular counterpart of the transforming protein that mediates transcriptional regulation in response to a variety of stimulants.
Myc (cMyc) is a proto-oncogene, which is overexpressed in a wide range of human cancers.
Cyclooxygenase is a protein encoded by the bcl-1
gene, which plays a critical role in regulating the cell cycle. Cyclin D1 acts primarily as a regulatory subunit of cyclin dependent kinases (CDKs) such as CDK4 and CDK6.
Epidermal growth factor
Fatty acid synthase
Food for Specified Health Use
(−) Gallocatechin gallate
Generally recognized as safe Glutathione
HMG (high mobility group)-box protein 1
High-performance liquid chromatography
Hepatic stellate cells
High-speed countercurrent chromatography
Inducible nitric oxide synthase
2-Amino-3-methylimidazo [4,5-f] quinoline
lymphoid enhancer factor / T-cell factor. Transcription factors play an important role in Wnt/Wg signal transduction pathway directing cell differentiation.