Green Tea
By David Tolson
Introduction
Next to water, tea is presently the most widely consumed beverage in the world [1]. The three forms of tea, which are differentiated by processing method, are green, oolong, and black tea. Of these, green tea undergoes the least amount of processing, and it has been used for medicinal purposes for thousands of years. Green tea has become well known for its antioxidant, antimutagenic and anticarcinogenic effects. Other possible benefits include treatment of cardiovascular disease, diabetes, dermatological problems, obesity, and oral health problems [2]. This article will examine the constituents of green tea and the various benefits they have to offer.
Constituents of green tea
* Catechins - The polyphenols are generally considered to be the most important elements of green tea, with the catechins being the most important polyphenols. Catechins found in green tea include EC, EGC, ECG, and EGCG. Of these, EGCG ((-)-epigallocatechin-3-gallate) is by far the most active by itself, but the combination of catechins can be especially effective for cancer protection [3], and EC appears to increase the incorporation of EGCG and ECG into lipid bilayers [4], emphasizing the importance of synergistic effects between the various components of green tea. Although the numbers vary, green tea is generally made up of about 10% polyphenols, 50% of which are EGCG. The green tea catechins have been studied extensively and will be the primary focus of this article.
* Pheophytins, chlorophylls, and carotenoids - Despite the importance of catechins, they are not the only constituents of green tea that offer health benefits. Some studies find that catechins depend on other components or are not even major players in some of the anti-genotoxic and antioxidant effects of green tea [5, 6]. The numerous other active compounds in green tea identified include chlorophylls a and b, pheophytins a and b, lutein, and beta-carotene. All of them have antioxidant properties [7], and the health benefits of beta-carotene and lutein (such as prevention of macular degeneration) are well known. Chorophylls and pheophytins from green tea are also anti-carcinogenic [8, 9], but a discussion of the many benefits these phytonutrients have to offer is beyond the scope of this article.
* Theanine - L-theanine is an amino acid found in high concentrations in tea, with a typical cup of tea containing 30 mg or more. Theanine decreases blood pressure [10, 11] and has been found effective in increasing the antitumor activity of cancer drugs [12, 13], but its most important properties are in the area of the brain. L-theanine bears structural similarity to glutamic acid and hence competes with it in binding to glutamate receptors, offering protection against glutamate neurotoxicity [11]. This glutamate receptor competition also provides a variety of differential effects on the brain. These include an increase in serotonin and/or dopamine in some areas of the brain, notably the striatum, hypothalamus and hippocampus [14], an increase in GABA [15], and an increase in brain alpha wave activity [15]. While beta wave activity is associated with periods of high stress, alpha waves are associated with a state of being awake, but relaxed (such as the period right before the onset of sleep). Theanine is said to promote a state of "alert relaxation" because of these differential effects [15], and it also antagonizes the stimulation and anxiogenic (anxiety promoting) effects of caffeine [11, 16] which may be responsible for the paradoxical calming effect of green tea despite the caffeine content.
* Caffeine - The amounts of caffeine in green tea are relatively low, with 20 mg in a typical cup (about half as much as a Coke). Surprisingly, caffeine can play a significant role in the anti-mutagenic effects of green tea in some cases, especially in the prevention of UV-induced skin cancer [17, 18]. The presence of caffeine in green tea will be of most importance in the upcoming discussion of thermogenesis.
Green tea and body composition
Recent research has confirmed that green tea can cause weight loss through multiple pathways. In addition to being a potent appetite supressant, green tea increases thermogenesis, preferentially burning fat over protein in a similar manner to many other thermogenics. Green tea has been demonstrated to be as or more effective than some prescription weight loss medications, and may rival the ECA stack in terms of fat loss. In addition, green tea is one of the few weight loss medications that has not been associated with negative effects on the cardiovascular system (such as increased heart rate and blood pressure) or CNS side effects (such as overstimulation and irritability). More research is needed before the level of effectiveness of green tea can be more conclusively determined, but the present data shows a clear benefit.
Green tea has been known to be a thermogenic agent for quite some time, but the thermogenesis was usually attributed to the caffeine content. It was then found in an in vitro experiment with brown adipose tissue that the thermogenic effect of green tea was "much greater than can be attributed to its caffeine content per se" [19]. Other in vitro experiments also demonstrate that green tea inhibits lipogenesis (the creation of fat) [20, 21]. In rodents, studies with both green tea and green tea powder have shown that it decreases body weight and food intake [22, 23] and inhibits lipogenesis [24].
Two important studies have been done assessing the thermogenic effect of green tea in humans. The first was a preliminary study that compared the effects of green tea extract (containing 150 mg caffeine and 270 mg EGCG), caffeine (150 mg), and placebo on 24-hour energy expenditure. While caffeine alone increased energy expenditure by about .6% over placebo (which was not statistically significant in this study), the green tea extract increased it by 3.5%. Additionally, while the oxidation of fat contributed to 31.6% of energy expenditure in the placebo group, in contributed 41.5% in the green tea extract group, indicating that the increase in energy expenditure was due to the breakdown of fat, not protein. Measurements of urinary nitrogen excretion, which were significantly different between treatments, further supported this contention. It is also interesting to note that thermogenic response was not correlated with body mass index (BMI), implying that green tea may be equally as effective in relatively lean individuals. Finally, the increased thermogenesis was not accompanied by an increase in heart rate, which makes green tea distinct from other thermogenic drugs [25].
The second study was a three month open trial with 70 subjects using the same dosage of the same extract as in the above study (150 mg caffeine, 375 mg total catechins, 270 mg EGCG per day). Treatment with green tea was well tolerated and associated with a body weight reduction of 4.6% and a reduction of waist circumference of 4.5% [1]. Hopefully these promising results will be followed by larger placebo-controlled studies.
Green tea has many mechanisms of action in stimulating weight loss. The most important is probably the inhibition of catechol-O-methyl-transferase (COMT) by EGCG [1, 19, 25]. COMT is the enzyme that breaks down norepinephrine (NE), one of the body's most important lipolytic hormones. Caffeine also plays a synergistic role by inhibiting phosophdiesterases (enzymes that break down cAMP, which is further down the lipolytic pathway) [19, 25]. Although EGCG is the most responsible, some flavanoids found in small amounts in green tea such as quercetin and myricetin also inhibit COMT and may play a minor role [25].
Secondly, green tea decreases the digestibility of dietary fat [1, 26]. The proposed mechanism of action is inhibition of both gastric and pancreatic lipase, which has been demonstrated in vitro [1]. These enzymes both play major roles in the digestion of fat, so when they are inhibited a smaller proportion of fat is absorbed and a greater proportion excreted.
Green tea is also a potent appetite suppressant. This can be partly explained by the fact that it increases both NE and dopamine [14, 25], but further mechanisms of action have been hypothesized. Specifically, tea polyphenols have been known to elevate levels of cholecystokinin (CCK) [2], a hormone which depresses food intake [2, 22]. It is not yet known whether this plays a significant role in the action of green tea, and one of the effects of elevated CCK is an increase in pancreatic lipase, which is actually inhibited by green tea. It could be that green tea simultaneously elevates CCK and decreases pancreatic lipase, conferring the benefits of both appetite suppression and decreased fat digestibility.
Finally, the antioxidant properties of green tea may play a role in the lipolytic effect [20-22]. One cell culture study suggested that green tea inhibited lipogenesis by increasing superoxide dismutase activity and subsequently decreasing the formation of free radicals [20], while another suggests that vitamin C from green tea plays a role in its lipolytic activity [21]. Even if the antioxidant activity turns out to have little to do with the breakdown of fat, it leads to many health benefits that will be discussed in greater detail in following sections.
Green tea and cancer
Hundreds of studies have been done in recent years on the effect green tea has on both the prevention and treatment of cancer, as well as cardiovascular disease. Epidemiological studies tend to yield different results, with some finding no effect [27-28] and others finding that green tea drinkers have less incidence of certain types of cancer [29-30]. However, when a less specific variable such as total cancer deaths or lifespan is measured in a larger population it can be shown that green tea has a definite effect.
One of the more comprehensive studies was conducted on a Japanese population over 13 years and the results were published this year in Ageing Research Reviews. It measured 90 lifestyle factors in a population of 8552 individuals over 40 years of age and determined the correlation of various factors with death from any cause. Consumption of over ten cups a day of green tea, when compared with less than three cups, was correlated with an increase in lifespan of 4.3 and 3.8 years in men and women respectively. Greater associations were seen in smokers (implying green tea had a protective effect) and those who died before age 80. Green tea was correlated with a 7.5 year longer lifespan in male smokers. Other large scale studies by this research group found that drinking green tea delayed cancer onset by 4.1 and 7.6 years in males and females respectively, cancer death by 3.9 and 5.9 years, and cardiovascular death by 1.9 and 1.4 years. Not surprisingly, these studies also found that smoking was correlated with earlier deaths from cancer and cardiovascular disease. The conclusion of this group was that green tea increases lifespan and decreases the risk of pre-mature death, particularly that caused by cancer [31].
Many animal and in vitro studies have also been conducted on the effect green tea has on specific types of cancer. In mice, both oral and topical administration of green tea significantly decreases the risk of UV-induced skin cancer [32]. However, it is possible that this is due to decreased tissue fat [33], and caffeine is a necessary constituent in this case [17, 33], so more research is needed in this area. Green tea selectively destroys breast cancer cells [34, 35] and epidemiologic data implies that it aids in the prevention of early stage breast cancer [30]. A case control study also found that green tea decreases the risk of developing ovarian cancer [36], while other in vitro data has found that green tea inhibits the proliferation of cervical cancer [37], prostate cancer [38], leukemia [39], head and neck carcinoma cells [35], and pancreatic carcinoma cells [40]. In the case of lung cancer, green tea has a definite and significant effect in smokers and nonsmokers alike. In vitro data [41] and epidemiologic data in both smokers [42] and nonsmokers [29] support this. Finally, green tea may have the ability to prevent cancer in the gastrointestinal tract. An epidemiologic study in China found that green tea drinkers had less incidence of gastrointestinal cancer [43], although a different study in Japan found no statistically significant difference [28]. In vitro and in rats, polyphenols also protect against colon cancer [44, 45].
As if this wasn't enough, green tea has also been tested against many carcinogens and almost always proves successful. Two toxins that humans are very commonly exposed to, tobacco and alcohol, are probably of most importance. An epidemiological study in China compared the incidence of various types of cancer among cigarette smokers and alcohol drinkers. In alcohol drinkers, those that regularly consumed green tea had 81%, 78%, and 39% decreased risk of gastric, liver and esophageal cancer, while smokers that drank green tea had 16%, 43%, and 31% decreased risk of these cancers [42]. In both mice and rats, green tea significantly protects against tumorgenesis induced by nitrosamines, which are found in tobacco as well as many food products [46, 47]. It also protects against the toxic effects of the environmental pollutant pentachlorphenol (PCP) and the chemotherapeutic drug cyclophosphamide (CP) in mice [48, 49] and the cancer induced by the carcinogens DMBA and DMH in other rodents [45, 50].
As with the thermogenic effect, there are multiple mechanisms for the proctive effect green tea has against cancer, and many of them are tissue specific. One of the more important ones is the protection against oxidative stress, which may play a primary role in certain types of cancer [48, 49-52]. The antioxidant properties of green tea and their importance will be discussed in more detail later on. Of more importance is that when it comes to cancer cells, green tea is actually a pro-oxidant which results in the death of these cells [53]. This condition-dependent antioxidant/pro-oxidant duality is a common feature of many antioxidants.
EGCG plays a fundamental role in cancer prevention as it inhibits many proteins and the activity of many protein kinases involved in tumor cell proliferation and survival. These include (but are by no means limited to) the large multi-catalytic protease and metaloproteionases involved in tumor survival and metastasis and the epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGF), platelet-derived growth factor receptor, mitogen-activated protein kinase, and IkB kinase [52]. The inhibition of EGFR and VEGF are of importance because they are known to play roles in angiogenesis [35, 28], which contributes to tumor formation in many cases [54]. The inhibition of metalloproteinases MMP-2 and MMP-9 are also known to play important roles in the anti-carcinogenic action of green tea [38, 41].
Other benefits of green tea
Many of the ingredients in green tea are potent antioxidants. In vitro, green tea and/or EGCG prevent the development of or directly quench a variety of reactive oxygen species (ROS) including superoxide [55], peroxynitrite [56, 57], and hydroxy radicals [57]. In preventing lipid peroxidation by hydrogen peroxide, it was superior to both lipoic acid and melatonin [58]. In humans, acute administration of green tea significantly improves plasma antioxidant capacity [59-61], with 450 mL (which would contain about 375 mg EGCG) causing an increase of 12.7% after two hours in one study [61]. In turn, this enhanced protection against oxidative stress offers a variety of health benefits.
As discussed earlier, drinking green tea may delay death from cardiovascular disease by 1-2 years with a greater increase seen in men [31]. A study on 14,000 Japanese workers adjusted for dietary factors, age, BMI, alcohol consumption, tobacco use, coffee intake, and type of work found that green tea drinkers had significantly lower cholesterol levels [62] while a smaller study on 500 Japenese subjects found a statistically significant reduced risk of atherosclerosis in men, but not in women [63]. Although the present epidemiologic data does not support the idea that green tea increases HDL ("good") cholesterol in humans [62], it has been demonstrated that it does so in rats [64]. The data in this regard is still relatively preliminary so it is hard to draw too many conclusions, but the proposed mechanism of action for the delay in cardiovascular death is prevention of oxidative damage [57].
Due to its ability to increase superoxide dismutase and glutathione levels, green tea also may aid in the prevention of insulin resistance and type II diabetes [65], which is often closely interrelated with other cardiovascular conditions. In normal rats, green tea significantly increases glucose tolerance, while in diabetic rats it significantly reduces serum glucose [65]. Another study also found that green tea improved kidney function in diabetic rats [66].
Another area in which the activity of green tea is particularly important is in the brain. It goes without saying that green may protect against the development of brain tumors [67]. It also protects against oxidative damage in the brain [57] and improves brain recovery from ischemia/reperfusion injury in rats [68]. Green tea may also be useful in preventing Parkinson's disease through a fairly specific mechanism, and this has been an area of much study as of late [69].
Green tea also exert a protective effect in the liver, acting in a synergistic fashion with vitamin E [70], as well as the digestive organs. It protects against or lessens liver damage caused by alcohol and carbon tetrachloride in rats [71, 72] and protects liver cells from a variety of toxins in vitro [73]. In the gastrointestinal tract, it reverses intestinal damage induced by fasting in rats [74] and inhibits the production of a toxin (produced by Helicobacter pyroli) associated with some gastric diseases [75]. Other preliminary studies indicate that green tea may be useful in the treatment of arthritis [76] and cataracts [77].
Finally, recent cell culture studies have found that green tea may have strong antiviral activity. It has been tested sucessfully against influenza A and B and has been found to inhibit their growth [78], and it may also decrease the chance of HIV infection [79]. As of yet, it is unknown whether these observations are relevant in humans, in which the concentrations of the active ingredients wwould be much smaller.
Possible side effects and precautions
Green tea, even in large amounts, is associated with very few side effects. In mice, signs of toxicity were only observed when doses reached 2 g/kg daily of an 80% polyphenol abstract (this is about the equivalent of 8 cups per pound of body weight, per day 1200 cups of tea in a 150 lb. individual) [80].
It is possible that large amounts of polyphenols could impair mineral absorption, making extra mineral supplements a wise course of action. Of primary importance is a significant inhibition of nonheme iron absorption, which is relevant if most of your iron comes from sources other than meat [81, 82]. It is possible that there is also mild inhibition of calcium, manganese, and zinc [83, 84], although there is a study that disputes the finding of impaired zinc absorption [84]. The only place where the phenomenon of significant mineral blockage by green tea has even been of worry is in Tunisia, where there is high tea intake and non-meat products are the primary source of dietay iron [81]. However, it may be prudent to take a multivitamin supplement that provides adequate amounts of these minerals at a separate time or a low-dose slow release iron supplement if one decides to consume large amounts of polyphenols.
A concern that is commonly brought up about green tea is the idea that it decreases levels of androgens such as testosterone and DHT. One study reported that after administered to rats, EGCG "significantly reduced food intake; body weight; blood levels of testosterone, estradiol, leptin, insulin, insulin-like growth factor I, LH, glucose, cholesterol, and triglyceride" [22]. However, a different study with green tea catechins in rats found decreased body weight but increased thyroid stimulating hormone (TSH), LH, and testosterone levels [85]. A final study in mice with green tea indicated drastic increases in both testosterone and DHT from green tea treatment, but levels of both were synergistically inhibited when it was adminstered along with soy phytochemicals [86]. In vitro, EGCG inhibits type I 5AR [2, 87], which is partially responsible for the conversion of testosterone to DHT (for this reason, it has been proposed in the topical treatment of acne and hair loss [2]), while in rats, green tea is an aromatase inhibitor, which (in theory) would be responsible for an increase in tesotsterone levels [85].
So, how does one make sense of this mess of contadictory data? It should first be noted that 5AR inhibition has only been shown in vitro [87], while it has not been observed in live animals in fact, drastic increases in DHT have been found - and it seems that other constituents of green tea counteract the 5AR inhibition [88]. The conclusions of the first study, which found drastic decreases in body weight, testosterone, and other hormones, are very misleading. A drastic reduction in levels of all of the
substances mentioned can unfortunately be expected from weight loss in any situation (which is one of the reasons losing weight without losing muscle mass is so difficult). Indeed, when the authors of the same study restricted the food intake of the rats to cause a similar weight loss to that induced by EGCG, similar effects were seen, implying that the changes were not due to EGCG but due to drastic body weight loss [22]. The effect green tea has on levels of androgens and other hormones is complex and depends on various factors, but no detrimental effects have as of yet been seen in human populations.
Green tea pharmacokinetics
This last section will examine the optimal dosage and dosing schedule for green tea. For cancer prevention, the present data indicate that relatively high amounts are required to achieve a significant effect 10 cups or more per day [55, 88]. Luckily for those of us that do not have time to brew and drink ten cups of tea per day, there are supplements. (It has even been suggested that 10 cups a day in addition to supplements would be ideal for cancer prevention [89]). Ten cups is about 20 grams of tea leaves, which would contain about 2 grams of polyphenols, 1 gram of which would be EGCG. In comparison, 270 mg EGCG is all that is needed for significant fat loss [1], and this would still have positive health benefits. When we look at the pharmacokinetics of green tea, we can see that there may be ways to maximize the effect of a given amount. The most important thing to note is that green tea polyphenols undergo saturable presystemic elimination. This means that low doses only increase plasma EGCG levels marginally, but once the point of saturation is reached, the same amount of tea will have much greater effects.
The amount required to achieve saturation in humans varies from study to study. Using tea leaves, one study found 3.0 grams to increase plasma EGCG levels by 2.7-3.4 times as much as 1.5 grams, while the difference between 3.0 grams and 4.5 grams was not statistically significant [90]. However, a study measuring antioxidant potential of green tea leaves found that 2.5, 5.0, and 7.5 increased plasma antioxidant potential by 2.1%, 6.2%, and 12.7% respectively at the 120 minute mark, indicating that 7.5 grams was over twice as effective as 5.0 grams [61]. 7.5 grams equates to about 375 mg of EGCG (note that this is only an approximation), and a pharmacokinetic study with green tea extract yielded a similar result. Amounts containing 225, 375, and 525 mg EGCG raised plamsa concentrations by 657, 4300, 4410 pmol/mL, respectively [91]. However, in a last study, despite the fact that 400 mg EGCG (from an extract) overcame saturation as opposed to 200 mg (the AUC, in this case a measure of total bioavailability, was 23.0 and 64.9 respectively), 600 mg and 800 mg amounts kept getting significantly more effective, with AUCs of 111.1 and 258.2 respectively [92]. The maximum plasma concentrations similarly increased. It is also noteworthy that this study found that it took 600, not 400 mg of pure EGCG (without other catechins) to overcome saturation, once again emphasizing that the other catechins operate synergistically with EGCG.
With this data in mind, we could safetly say, for example, that taking an extract containing 400 mg EGCG once daily would be considerably more effective than 200 mg twice daily. Increasing this amount to 600 mg may or may not have a significant effect, depending on the study we look at. Either way, a minumum of 400 mg EGCG should be taken at a time to overcome saturation. An ideal dosing schedule would be 400 mg 2-3 times daily, while a more economical (but still very effective) one would be 400 mg once daily (preferably in the pre-workout period).
Here are some of the best supplements containing green tea:
* Now Green Tea Extract is the most economical option, with each capsule containing 400 mg of green tea and providing about 100 mg of EGCG.
* Now L-Theanine contains 100 mg of unstandardized decaffeinated green tea per capsule, as well as 100 mg of L-theanine, the benefits of which are discussed above.
* Syntrax
Radox and Now Super Antioxidants are two of the best antioxidant supplements available, and both contain green tea in moderate quantities.
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