Green Tea

Scientific Name(s): Camellia sinensis (L.) Kuntze. Family: Theaceae

Common Name(s): Tea , green tea , black tea , oolong tea , Veregen

Uses

Tea is traditionally consumed as a beverage. Evidence from clinical trials suggests that green tea plays a role in metabolic syndrome because it may have an impact on body weight, glucose homeostasis, and other cardiovascular risk factors. It has yet to be determined whether green tea is an agent in cancer prevention; however, a role in the prevention of stroke has been suggested. Topical applications have been studied for protection from ultraviolet (UV) damage, and a commercial preparation has been approved for use in the treatment of anogenital warts.

Dosing

A daily intake of 3 to 5 cups/day (1,200 mL) of green tea will provide at least 250 mg/day of catechins. Green tea extract should not be taken on an empty stomach due to the potential for hepatotoxicity from excessive levels of epigallocatechin gallate. Anogenital warts : topical application of sinecatechins 3 times a day for a maximum of 6 weeks. Cardiovascular effect : 400 to 716 mg/day of catechins have been used in trials in divided dosages. Diabetes : Dosages of epigallocatechin gallate range from 84 to 386 mg/day in trials evaluating glucose homeostasis. Obesity : Dosage ranges used in trials include 270 to 800 mg/day of epigallocatechin gallate, or 125 to 625 mg/day of catechins.

Contraindications

Contraindications have not been identified; however, use caution when hepatic failure is present.

Pregnancy/Lactation

The US Food and Drug Administration (FDA) advises those who are or may become pregnant to avoid caffeine.

Interactions

Vitamin K present in green tea may antagonize the anticoagulant effect of warfarin. Green tea consumption reduces the bioavailability of folic acid and may interfere with the absorption of iron.

Adverse Reactions

There are no reports of clinical toxicity from daily tea consumption as a beverage. Adverse events include headache, dizziness, and GI symptoms. Hepatotoxicity, including 1 fatality, has been associated with high plasma levels of epigallocatechin gallate or its metabolites.

Toxicology

Multidose pharmacokinetic studies suggest a daily dosage of 800 mg/day of epigallocatechin gallate capsules for up to 4 weeks to be safe and well tolerated. High-dose oral green tea extract and catechins were hepatotoxic in rats.

Botany

Black, oolong, and green tea are produced from the leaves of C. sinensis , which is native to eastern Asia but also grown in other areas. This evergreen shrub or tree grows to over 9 m in height and is pruned from 60 cm to 1.5 m for cultivation. Its dark green, serrated-edged leaves are alternate and oval, while its white and fragrant blossoms appear singly or in clusters. 1 , 2 Green tea is the dried leaf component, while black tea is produced by a complex wilting and fermentation process. Oolong tea is produced by a process intermediate to that of green and black tea.

History

The dried, cured leaves of C. sinensis have been used medicinally for more than 5,000 years. Traditional Chinese medicine has recommended drinking green tea for the prevention of ill health, and in Asia, this is still regarded as a healthy practice. 2 , 3 , 4 , 5

Chemistry

The chemistry of tea is complex because of the numerous components that are formed during the curing and drying process, and variations aimed at producing various drinking teas, such as harvest season, climate, and horticultural and processing practices. 2 , 5 Quality control and analytical methods are improving, allowing for more confidence in recent clinical studies. 2 , 6

Tea leaves contain varying amounts of polyphenols (the majority of which are catechins) as well as smaller quantities of caffeine, theanine, theobromine, theophylline, and phenolic acids.

Other tea constituents include tannins, essential oils, riboflavin, niacin, folic acid, ascorbic acid (which is present in fresh leaf but destroyed in making black tea), pantothenic acid, malic and oxalic acids, manganese, potassium, magnesium, and fluoride. 2 , 4 , 7

The major polyphenol found in green tea is (-)-epigallocatechin gallate, with lesser amounts of catechin, epicatechin, gallocatechin, gallocatechin gallate, and epicatechin gallate. 6 , 7

The composition of green tea, prepared by drying and steaming (to inactivate the oxidase enzyme), is very similar to that of the fresh leaf, except for a few changes that occur extremely rapidly following plucking. The primary difference between green and black tea derives from the fermentation process required to produce black tea. The catechins are converted to the higher molecular weight theaflavins (absent in green tea). Less fermentation results in an intermediary, lighter tea known as oolong tea. 2

Decaffeination slightly reduces the catechin content of black tea, while herbal teas do not contain caffeine or catechins. The addition of milk to tea does not affect the bioavailability of catechins, but may alter the antioxidant potential, depending on the fat content. 5 , 7

Uses and Pharmacology

Many of the health benefits of tea drinking are attributed to the antioxidant capacity of the chemical constituents 4 , 8 and are largely borne out by in vitro experiments and epidemiological studies. 3 , 5 , 9 In vitro experiments show a direct effect of tea on reactive oxygen species and chelation of metal ions, such as iron and copper. 4 Green tea is considered to be more active than black tea 3 , 8 with epicatechin and catechins ranking most potent of 24 tested plant polyphenolic flavonoids. 3 , 8 The various methodologies of antioxidant experiments markedly affects the rankings. 10 , 11 , 12 , 13 , 14 , 15 Most clinical trials demonstrate that tea consumption improves plasma antioxidant capacity and biomarkers of oxidative stress. 3 , 4 , 8 , 15

Anogenital warts

In 2006, the FDA approved a green tea–based ointment containing sinecatechin (polyphenon E) for the treatment of anogenital warts. Randomized, double-blind clinical trials have demonstrated the efficacy of the ointment ( Veregen ), which is considered to act via antiviral, immunomodulatory, antioxidant, and antiangiogenesis mechanisms. 16

Cancer

Epidemiological studies and animal experiments have provided sufficient evidence of green tea's potential as an anticancer agent to warrant consideration, as demonstrated by the continued investigational interest in tea. Comprehensive reviews are available, but are limited in their findings because the studies included are too heterogeneous for meaningful comparisons. 3 , 5 , 9 Long-term and case-control studies suggest an inverse association between tea consumption and the risk of cancer of the colon, urinary bladder, stomach, esophagus, lung, pancreas, prostate, and squamous skin cells. 3 , 9 Increased risk of recurrence of breast cancer 9 and delayed onset of cancers in general have been described. 9 , 17 Results of epidemiological studies differ due to factors such as social class and lifestyle.

A Cochrane meta-analysis of the effects of green tea in cancer has found insufficient and conflicting evidence to support a preventative role. 7 The observed anticancer effects are largely attributed to the catechins found in tea, while action on tumors by theanine may be due to enhancement of the immune response. 18 A Cochrane review found no evidence suggesting the efficacy of green tea in preventing progression to malignancy in leukoplakia. 19

Mechanisms for anticancer activity of green tea have been investigated in animal models and laboratory experiments, but not yet demonstrated in vivo in humans. Doses used experimentally may not reflect usual tea consumption, and there may be a combination of effects or a combination of active compounds acting to produce the relationships reported in epidemiological studies. 3 , 9 , 20 The polyphenols in green tea inhibit cell proliferation. 7 The polyphenol epigallocatechin gallate increases the activity of antioxidants in specific organs in mice and thereby increases the overall chemoprotective effect of antioxidants in those organs. 3 , 7 , 9 , 17 Epigallocatechin gallate may also facilitate direct binding to certain carcinogens. 3 , 7

Polyphenols, especially catechins may protect cells from tumor development by enhancing gap junction communication between cells. 7 , 9 Tea has been shown to block tumor growth by sealing the receptors of affected cells. 9 , 17 , 20 Polyphenols may assist inhibition of tumorigenesis in a variety of organs including skin, lungs, oral cavity, esophagus, stomach, small intestine, colon, liver, pancreas, ovary, and mammary glands. 9 , 17 , 20 Green tea polyphenols induced apoptosis in a variety of cells, including human lymphoid leukemia and human prostate cells, 9 , 17 , 20 , 21 , 22 altered estradiol and sex-hormone binding globulin levels associated with the risk of breast cancer. 3 , 23 A risk of esophageal cancer from tea drinking has been suggested in epidemiological studies, but this has also been attributed to the scalding temperatures at which the beverage may be consumed. 3

Cardiovascular effects

Epidemiological studies and in vitro experiments show that tea consumption is inversely associated with cardiovascular disease, although a direct cause-effect relationship has not been conclusively demonstrated. 2 , 3 , 24 , 25 Mechanisms of action under investigation include reduced low-density lipoprotein (LDL) oxidation, enhanced endothelial cell functioning, hypotensive effects, effects on atherosclerosis, platelet aggregation, and improved cholesterol profiles. 25 , 26

Cholesterol-lowering effects of tea have been investigated in numerous clinical trials, including healthy volunteers, as well as obese children and adults. 26 , 27 , 28 , 29 , 30 A meta-analysis of trials up to June 2007 evaluated tea flavonoids for reducing the risk of cardiovascular events. A reduction in LDL cholesterol was found for green tea, but no effect on high-density lipoprotein (HDL) cholesterol was established. 27 These results are based on a limited number of clinical trials, because inclusion criteria for the individual trials and test compounds used are often too heterogeneous for meta-analysis. 25 , 27 Further trials evaluating effects on cholesterol and other cardiovascular markers showed decreases in total and LDL cholesterol for subgroups, 29 , 31 decreases in serum triglycerides, 31 , 32 and a decreased total:HDL cholesterol ratio. 30

Hypotensive effects of green tea have been evaluated, with the meta-analysis reporting no effect for green tea and black tea increasing blood pressure, 27 and other trials reporting a decrease in systolic pressure, 28 , 29 decreases in diastolic pressure, 33 , 34 or no effect. 30 Studies evaluating other markers of cardiovascular stress (inflammation and oxidative stress) include reported decreases in serum amyloid-alpha and malondialdehyde, 29 while others noted no effect on endothelial vascular reactivity. 30

CNS effects

A neuroprotective property has been suggested for green tea extracts, especially for epigallocatechin gallate and theanine. The pharmacological impacts are uncertain; however, several researchers have proposed a number of mechanisms by which it may act on the CNS that include free radical scavenging, iron-chelation, anti-inflammatory effects as well as modulation of enzymes involved in processing amyloid precursor protein. Animal experiments have shown positive findings for Alzheimer and Parkinson disease models. 35 , 36 , 37 , 38 , 39 Anxiolytic properties have been demonstrated for the theanine component of green tea. 40

Diabetes

Few clinical trials evaluate green tea extracts or catechins among diabetic populations, 25 , 41 , 42 , 43 , 44 with the majority of findings reported among obese adults or healthy volunteers. 33 , 34 , 45 Many studies report modest positive findings influencing glycosylated hemoglobin (HbA 1c ); however, a number of studies also report no effect on insulin sensitivity, fasting blood glucose, and glucose tolerance. 25 , 44 Dosages of epigallocatechin gallate range from 84 to 386 mg/day to support glucose homeostasis. 25

Obesity

Placebo-controlled clinical trials suggest that the thermogenic properties of green tea might contribute to weight control, 2 , 3 , 25 , 46 but there is debate regarding the role of caffeine in this effect. 46 , 47 Catechins may inhibit the enzyme responsible for the degradation of norepinephrine. 25 , 48 Most studies report positive findings for increased fat oxidation, changes in abdominal and subcutaneous fat, and decreased waist circumference. 28 , 31 , 32 , 34 , 41 , 45 , 48 , 49 Confounders include the quantity and possible adjuvant role of caffeine, as well as the intervention diets used. 25 Dosage ranges used in these trials include 270 to 800 mg/day of epigallocatechin gallate, 33 , 48 and 125 to 625 mg/day of catchins. 32 , 49

Osteoporosis

Animal experiments have demonstrated increased bone density with administration of green tea extract. Bone strength and fracture rates were not reported; therefore, extrapolation to a human application is difficult. 50 Mechanisms of action suggested an antioxidant and anti-inflammatory action, as well as direct action on osteoblasts (to increase survival) and osteoclasts (suppression), and an immunological action, including modulation of cytokines. Animal studies also suggest the tannin component of green tea may decrease the absorption of calcium to some extent 2 , 50 ; while the provision of fluoride is recognized as 3 cups (720 mL) of green tea per day, providing approximately 4 mg/day of fluoride. 50

Epidemiological and case control studies suggest tea consumption helps protect against osteoporosis in older women; however, not all find a positive association for increased bone density, and data for bone fractures are conflicting. 2 , 3 , 50 Differences in study populations makes a meta-analysis difficult. Long-term human studies are needed that include outcomes of bone fracture and examination of the bone micro-architecture before conclusive recommendations can be made.

Stroke (acute cerebrovascular episode)

Large epidemiological studies have shown an inverse association between green tea consumption and the incidence of stroke. Smaller case control studies, however, provide equivocal results. 51 , 52 A meta-analysis of 10 trials meeting the inclusion criteria for the analysis found support for 3 cups (720 mL) of green tea or more per day in reducing the incidence of stroke and reducing the mortality from stroke. 52 The meta-analysis included 3 trials from Japan and Finland that provided stronger support for this finding than the 3 trials included from US-based populations, which had wider confidence intervals. 52 Suggested mechanisms of action involve impacts on hypertension, atherosclerosis, and thrombogenesis. 51

UV protection

Green tea extracts (2% to 3%) have been evaluated for use as a topical photo-protective agent. Clinical studies have demonstrated a dose-independent protective effect via mechanisms other than a screening effect (the sun protection factor for the test materials was minimal). Erythema and inflammation consequent to solar-simulated UV exposure was reduced and was suggested to be related to protection against cutaneous immunosuppression and an antioxidant effect. 53 , 54 A 2-year clinical study, however, found no superiority of green tea polyphenols taken orally over placebo in photoaging by clinical and histological assessment. 55

Other uses
Antimicrobial

Tea has been demonstrated to have in vitro activity against a number of pathogenic bacteria 56 , 57 , 58 and fungi. 59 Activity by epigallocatechin gallate against HIV has been demonstrated in vitro, with direct binding to CD4. 2

Orodental

Evidence for protection against dental caries comes from kinetic and animal models, with few human trials published. Green tea exhibits antimicrobial actions against oral bacteria 2 , 3 , 60 , 61 and provides a natural source of fluoride. 3 , 7 , 50 Oolong and green tea inhibited bacterial adherence to tooth surfaces and inhibited the rate of acid production in animal studies. Black and green tea have been shown to inhibit amylase activity. 3 , 60

Dosage

Pharmacokinetic studies of tea have been conducted in humans, with measurable levels of various chemical compounds found in the plasma, feces, and urine. Chemical constituents are able to cross the blood-brain barrier. 61 , 62 , 63 , 64 , 65 , 66 , 67 Bioavailability of active compounds appears unaffected by the addition of milk to tea, and can be enhanced in a fasted state. 3 , 5 , 14 , 67 , 68 Plasma levels of epigallocatechin gallate are increased 5-fold when green tea extracts are taken in the fasted state and may lead to potentially toxic doses. Extracts must, therefore, be taken with meals. 69

A daily intake of 3 to 5 cups/day (720 to 1,200 mL) of green tea will provide at least 250 mg/day of catechins. 7

Anogenital warts

Topical application of sinecatechins 3 times a day for a maximum of 6 weeks. 16

Cardiovascular effect

400 to 716 mg/day of catechins have been used in trials in divided dosages. 29 , 30

Diabetes

Dosages of epigallocatechin gallate range from 84 to 386 mg/day to support glucose homeostasis. 25

Obesity

Dosage ranges used in trials include 270 to 800 mg/day of epigallocatechin gallate 33 , 48 and 125 to 625 mg/day of catchins. 32 , 49

Pregnancy/Lactation

Safety for use in pregnancy has not been established. Due to the caffeine content of tea, use during pregnancy should be limited. Caffeine crosses the placenta and reaches fetal blood and tissue levels similar to maternal concentrations. Excessive caffeine intake (greater than 600 mg/day) has been weakly associated with increased fetal loss, low birth weight, premature deliveries, an increase in the incidence of fetal breathing activity, and a fall in baseline fetal heart rate. 70 Caffeine appears in the milk of breast-feeding mothers.

Interactions

Case reports suggest probable antagonism of warfarin by green tea. 71 Concomitant consumption of green tea with folic acid is not recommended in pregnant women, megaloblastic anemia, or when a reduction in folic acid may have clinical consequences. A folate transporter interaction has been described, leading to decreases in bioavailability of folic acid. 72 Epidemiological studies suggest a detrimental effect of tea drinking on iron status, but the data are inconsistent with multiple confounding influences. 73 Dose-dependent inhibition of intestinal nonheme iron absorption was demonstrated in a controlled clinical trial using epigallocatechin gallate. 62 Other published studies report that black tea reduces iron absorption most and green tea least, suggesting the type of polyphenol in tea is an important factor. 62

Coadministration of tea extracts and iron products is not advised, and patients with poor iron status should avoid drinking tea with meals, because iron absorption may be impaired. 3 , 73 Conversely a beneficial effect of drinking tea with meals was suggested in a trial of patients with genetic hemochromatosis. 3

Adverse Reactions

There are no reports of clinical toxicity from daily tea consumption. Adverse events recorded in pharmacokinetic studies in humans using tea extracts include headache, dizziness, and GI symptoms. 64

Hepatotoxicity has been reported, leading to the withdrawal of a particular green tea product ( Exolise ) in France and Spain. A review of 34 case studies of hepatotoxicity, including 1 fatality, found possible causality due to epigallocatechin gallate or its metabolites. Onset of toxicity occurred within 3 months in 70% of cases, with increased transaminases and bilirubin evident. 74 Plasma levels of epigallocatechin gallate are increased 5-fold when green tea extracts are taken in the fasted state and may lead to potentially toxic doses. Green tea extract must not be taken on an empty stomach. 69

Toxicology

Multidose pharmacokinetic studies suggest a daily dosage of 800 mg/day of epigallocatechin gallate capsules (approximately equivalent to 16 Japanese-style cups of green tea) for up to 4 weeks, to be safe and well tolerated. 66 , 69

High-dose green tea extract and catechins were hepatotoxic in rats upon oral administration. Similarly, low-dose intraperitoneal administration lead to severe hepatic necrosis and mortality. 74

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