In this article, I review the current scientific evidence concerning green tea’s health effects and their responsible mechanisms of action. Tea is a beverage made from the leaves of the Camellia sinensis plant. Worldwide it is the second most consumed beverage, water being the first [1]. By far the most popular kinds of tea are black and green tea, respectively making up around 78% and 20% of all of the tea produced around the world [2]. Recently, there has been growing public and academic interest in green tea because of its purported health benefits. The research to date looks very promising; the diversity of health concerns which appear to benefit from green tea is both impressive and surprising. Nevertheless, there is a need for many large, well-designed, human experimental trials before its health effects can be conclusively determined. Thus, the effects discussed herein should not be taken as health claims, but rather a review of current scientific research. In addition to positive psychological effects, evidence supports a favorable effect of green tea towards the prevention and/or management of cardiovascular disease, cancer, obesity, type 2 diabetes, microbial infections, dental health, and kidney stones. There are comparatively few harmful effects of green tea consumption. Of greatest significance, green tea can reduce iron absorption and so care must be taken to this in individuals prone to deficiency in this mineral.
Bioactive phytochemicals of green tea
Green tea is rich in bioactive phytochemicals [3]. The most important of these are the polyphenols, which have diverse activities. Remarkably, polyphenols comprise around a third of the dry weight of green tea leaves' water extractable components. The most abundant polyphenols are catechins, including epigallocatechin gallate (EGCG), epicatechin gallate (ECG), epigallocatechin (EGC) and epicatechin (EC). Black tea differs from green tea in that it is permitted to oxidize, greatly reducing its catechin content. Other bioactive compounds in green tea include caffeine, the amino acid L-theanine, fluoride and trace minerals, including calcium and manganese.
Green tea has beneficial psychological effects
Green tea contains two principle psychoactive compounds: caffeine and L-theanine, both are highly bioavailable from tea [4].
Caffeine
Caffeine is a stimulant of the central nervous system. It affects neurotransmission in the brain by competitively blocking adenosine receptors [5] (particularly the A1 and A2a types). It thereby reduces the inhibitory action of adenosine on the brain, improving wakefulness, concentration, motor coordination, and reaction time [6]. However, it also modulates the dopaminergic system, which is known to be important in attentional processes. In humans, even low doses of caffeine (e.g. one cup of tea) improve subjective alertness and performance in attention tasks [7,8].
L-theanine
While there are several dietary sources of caffeine (such as coffee, chocolate, and soft drinks), L-theanine is unique to tea [4]. There is considerable evidence that L-theanine has both calming and anti-depressant effects [9]. These are achieved through action on the sympathetic nervous system and the central monoaminergic neurotransmitter system. The molecular basis of these effects is not fully understood, but L-theanine is known to have agonistic action on NMDA receptors and induces expression of BDNF in hippocampal neurons [10]. Furthermore, L-theanine affects cognition by changing the availability of certain neurotransmitters, through modulating the concentrations of amino acid precursors in the brain [11].
There is also evidence that L-theanine has anti-fatigue effects. That has been demonstrated in a mouse model [12]. Physiologically, it raised dopamine concentrations and increased hepatic glycogen, while it decreased serotonin and serum urea.
There is also evidence that L-theanine has anti-fatigue effects. That has been demonstrated in a mouse model [12]. Physiologically, it raised dopamine concentrations and increased hepatic glycogen, while it decreased serotonin and serum urea.
Synergy between caffeine and L-theanine
Since both caffeine and L-theanine are present in tea, their combined effect is most relevant to accessing the psychological effects of green tea consumption. In humans, a meta-analysis found that co-administration of these compounds synergistically improves alertness, attention, and multi-tasking (by improving the ability to switch attention between tasks) [13].
Green tea prevents cardiovascular disease
Animal and human studies have suggested that green tea may reduce the risk of cardiovascular disease. This has been shown in two animal models of antheroschlerosis, hypercholesterolemic hamsters and apoE-deficient mice [14,15]. In humans, numerous epidemiological studies and experimental trials have shown an inverse relationship between coronary heart disease and green tea consumption [16,17,18,19,20]. Several putative mechanisms contribute to this, including antioxidant activity, anti-atherosclerotic effects, hypolipedmic effects, and blood pressure-lowering effects.
Antioxidant effects
Green tea catechins have direct and indirect antioxidant activities in vitro and in vivo. These effects may be relevant towards the prevention of cardiovascular disease based on the oxidation hypothesis of atherosclerosis. Oxidation of LDL lipids may promote inflammatory and immune responses important for the pathogenesis of atherosclerosis. Interestingly, deposition of oxidized LDL on arterial walls is thought to precede plaque formation [21]. Furthermore, high serum oxidised LDL concentrations predicts future cardiovascular disease events in otherwise healthy men [22]. If the antioxidant activity of green tea catechins can reduce LDL oxidation, it may limit the development of atherosclerosis.
Consistent with this mechanism, these chemicals were found to scavenge reactive oxygen and reactive nitrogen species, preventing cholesterol and LDL oxidation in vitro [23]. In addition, green tea increases the activity of superoxide dismutase in the serum and catalase in the aorta, enzymes which decompose reactive oxygen species [24,25]. In vivo studies have also indicated green tea increases total plasma antioxidant capacity [24].
As counter-intuitive as this may seem, some of catechins' antioxidant effects may actually be mediated by pro-oxidant effects. Despite its direct chemical antioxidant activity, it appears that EGCG can generate reactive oxygen species when taken into cells through an as yet unknown mechanism [26]. It is postulated that this induces production of various detoxifying and antioxidant enzyme systems, affording a net gain of antioxidant defense.
Despite how encouraging the currently available data is, the extent to which the antioxidant effects of green tea are physiologically relevant in humans is yet to be clarified and remains controversial [27].
Consistent with this mechanism, these chemicals were found to scavenge reactive oxygen and reactive nitrogen species, preventing cholesterol and LDL oxidation in vitro [23]. In addition, green tea increases the activity of superoxide dismutase in the serum and catalase in the aorta, enzymes which decompose reactive oxygen species [24,25]. In vivo studies have also indicated green tea increases total plasma antioxidant capacity [24].
As counter-intuitive as this may seem, some of catechins' antioxidant effects may actually be mediated by pro-oxidant effects. Despite its direct chemical antioxidant activity, it appears that EGCG can generate reactive oxygen species when taken into cells through an as yet unknown mechanism [26]. It is postulated that this induces production of various detoxifying and antioxidant enzyme systems, affording a net gain of antioxidant defense.
Despite how encouraging the currently available data is, the extent to which the antioxidant effects of green tea are physiologically relevant in humans is yet to be clarified and remains controversial [27].
Inhibition of vascular smooth muscle proliferation
An important early event in vascular lesion formation is vascular smooth muscle proliferation. There is evidence that green tea may inhibit this process. Green tea polyphenols provide dose-dependent inhibition of proliferation of stimulated vascular smooth muscle cells in vitro [28]. Specifically, green tea catechins inhibit protein tyrosine kinase activity, which leads to lower JNK1 activation. They promote apoptosis of smooth muscle cells in via the NF-kappaB and p53-dependent pathways by inhibition of p44/42 MAP kinase expression. This is thought to principally occur through blocking MAP kinases’ Ang II-stimulated activation. Lastly, there is evidence that EGCG inhibit metalloproteinases in aortic smooth muscle cells [29]. Matrix metalloproteinases are important for tissue remodelling processes, including vascular smooth muscle proliferation. These effects have been observed in animal studies as well. In rabbits, green tea reduced the development of atherosclerotic lesions [30]. Contributions to this included inhibition of matrix metalloproteinases and decreased endothelial growth factor.
Hypolipidemic effects
A recent meta-analysis of human trials showed that green tea moderately reduces serum LDL cholesterol, total cholesterol and triglyceride levels [31]. Mechanistically, this is principally achieved by decreasing the absorption of dietary lipids and bile acids. In understanding its mechanism, it will be helpful to first review the steps involved with dietary fat digestion. Dietary fats cannot be absorbed as triglycerides; they must first be broken down to fatty acids by the action of lipase enzymes. Fats are insoluble in water, which is problematic since the lipases exist and function only in a water-solvated environment. This problem is solved through emulsification of the fats in the presence of bile acids. Large fat globules are separated into small droplets, providing high surface area for lipases to act on. The resulting products can be absorbed into the body by enterocytes.
In vitro studies have shown that green tea catechins, at concentrations achievable through regular tea consumption, disrupt emulsification, lipase activity, and solubilisation of dietary fat and cholesterol [27]. EGCG disrupts lipid emulsification by binding to and modulating the physicochemical properties of the lipid droplets, increasing their size. This reduces the surface area available for lipases to act on. In addition, green tea catechins directly inhibit the activity of both gastric and pancreatic lipases [32]. Both effects decrease the digestion of dietary fat and therefore attenuate its absorption. Lastly, solubilisation of cholesterol and other lipids in bile acid micelles is a critical step in facilitating transport and absorption by enterocytes. Green tea catechins have been shown to precipitate cholesterol from bile salt micelles, reducing its uptake [33]. In vivo animal studies further clarify this. In rats fed a cholesterol-rich diet, green tea has a hypocholesteolemic effect. This was shown to be mediated through increased fecal cholesterol and bile acid excretion, consistent with this mechanism [34]. Surprisingly, in addition to the catechins, L-theanine has hypercholesterolemic activity through increasing bile acid excretion [9]. The mechanism through which L-theanine alone can achieve this is currently unknown.
In vitro studies have shown that green tea catechins, at concentrations achievable through regular tea consumption, disrupt emulsification, lipase activity, and solubilisation of dietary fat and cholesterol [27]. EGCG disrupts lipid emulsification by binding to and modulating the physicochemical properties of the lipid droplets, increasing their size. This reduces the surface area available for lipases to act on. In addition, green tea catechins directly inhibit the activity of both gastric and pancreatic lipases [32]. Both effects decrease the digestion of dietary fat and therefore attenuate its absorption. Lastly, solubilisation of cholesterol and other lipids in bile acid micelles is a critical step in facilitating transport and absorption by enterocytes. Green tea catechins have been shown to precipitate cholesterol from bile salt micelles, reducing its uptake [33]. In vivo animal studies further clarify this. In rats fed a cholesterol-rich diet, green tea has a hypocholesteolemic effect. This was shown to be mediated through increased fecal cholesterol and bile acid excretion, consistent with this mechanism [34]. Surprisingly, in addition to the catechins, L-theanine has hypercholesterolemic activity through increasing bile acid excretion [9]. The mechanism through which L-theanine alone can achieve this is currently unknown.
Lowering blood pressure
Several meta-analyses have been performed recently on this topic, all finding that green tea consumption affords a small but statistically significant decrease blood in pressure in humans [31,35,36]. Interestingly, the most recent analysis found that the reduction was more dramatic in subjects that already had stage 1 hypertension [35]. Similarly, green tea consumption lowered blood pressure in a hypertensive rat model [36].
The most promising proposed mechanism of this is that green tea improves ventricular function. In particular, EGCG increases nitric oxide production in the endothelium, through the action on PI3 kinase-dependent pathways [37]. The ability of green tea catechins to directly neutralize reactive oxygen species, which may otherwise destroy nitric oxide, may also contribute to this [38].
The most promising proposed mechanism of this is that green tea improves ventricular function. In particular, EGCG increases nitric oxide production in the endothelium, through the action on PI3 kinase-dependent pathways [37]. The ability of green tea catechins to directly neutralize reactive oxygen species, which may otherwise destroy nitric oxide, may also contribute to this [38].
Anti-thrombotic effects
Platelet activation and aggregation are important components of cardiovascular disease pathophysiology [39]. Under normal physiology, platelets interact with the endothelial cell lining without strongly adhering to it. However, abnormalities in the endothelial layer (e.g. a fatty streak or a ruptured plaque) may initiate platelet aggregation, which can lead to cardiovascular events such as myocardial infarction. Consistent with this, therapeutic approaches which inhibit these processes reduce cardiovascular disease risk [40].
Green tea may prevent cardiovascular disease, in part, through anti-thrombotic effects [41]. There is significant evidence that green tea's catechins, in particular, exert a favorable effect on platelet aggregation. This has been observed in vivo through a rat model, where consumption of tea catechins decreased platelet aggregation and thrombosis [42]. In addition, catechins dose-dependently inhibit aggregation of human platelet cells in vitro [43]. Mechanistically, catechins suppress platelet activation by modulating its regulating signalling pathways in several ways. Intracellular calcium release is an important event in platelet activation. Catechins inhibit this step by activating a Ca2+-ATPase and inhibiting production of inositol 1,4,5-triphosphphate (a signalling intermediate) [44]. Interestingly, catechins may also block platelet aggregation by reducing production of plate-activating factor. This is a results from inhibition of a key enzyme in its biosynthesis (acetyl-CoA:1-alkyl-sn-glycero-3-phosphocholine acetyltransferase) [45]. Lastly, tea catechins may achieve their anti-platelet aggregation effects through modulation of the arachidonic acid pathway. Briefly, arachidonic acid is a signalling molecule secreted during inflammation. Platelets convert this compound into several mediators of platelet activation: thromboxane A2, endoperoxides, and prostaglandin. Catechins disrupt this pathway by both blocking arachidonic acid release and inhibiting the enzyme thromboxane A2 synthase [46,47].
Green tea may prevent cardiovascular disease, in part, through anti-thrombotic effects [41]. There is significant evidence that green tea's catechins, in particular, exert a favorable effect on platelet aggregation. This has been observed in vivo through a rat model, where consumption of tea catechins decreased platelet aggregation and thrombosis [42]. In addition, catechins dose-dependently inhibit aggregation of human platelet cells in vitro [43]. Mechanistically, catechins suppress platelet activation by modulating its regulating signalling pathways in several ways. Intracellular calcium release is an important event in platelet activation. Catechins inhibit this step by activating a Ca2+-ATPase and inhibiting production of inositol 1,4,5-triphosphphate (a signalling intermediate) [44]. Interestingly, catechins may also block platelet aggregation by reducing production of plate-activating factor. This is a results from inhibition of a key enzyme in its biosynthesis (acetyl-CoA:1-alkyl-sn-glycero-3-phosphocholine acetyltransferase) [45]. Lastly, tea catechins may achieve their anti-platelet aggregation effects through modulation of the arachidonic acid pathway. Briefly, arachidonic acid is a signalling molecule secreted during inflammation. Platelets convert this compound into several mediators of platelet activation: thromboxane A2, endoperoxides, and prostaglandin. Catechins disrupt this pathway by both blocking arachidonic acid release and inhibiting the enzyme thromboxane A2 synthase [46,47].
Green tea may prevent cancer
An overwhelming number of animal studies have found inhibitory effects of green tea consumption on carcinogenesis. This has been demonstrated in various animal models and diverse tissue types, including skin, breast, prostate, lung, liver, bladder, stomach, mouth, esophagus, stomach, small intestine, and liver [48]. Tea polyphenols, particularly EGCG, have been shown to be principally responsible for these effects. Despite the consistent inhibitory effects seen in animal models and in vitro experiments, results from human studies have been more ambiguous. Furthermore, the evidence available is limited, especially the number of experimental trials.
Over the past three decades, epidemiological studied have accessed the effects of green tea consumption on the risk of developing various cancers, mostly among Chinese and Japanese populations. While many studies reported favorable, statistically significant effects of green tea consumption, others found no effect [49]. This inconsistency has, in part, been attributed to confounding variables, such as how tea drinkers are more likely to consume alcohol and smoke than non-tea drinkers in most of the populations studied. The temperature of the beverage is also an uncontrolled variable. Importantly, drinking overly hot beverages, regardless of type, may increase the risk of esophageal cancer [50]. Overall, there is currently insufficient evidence to conclude whether or not green tea consumption affects the risk of developing cancer in humans. Hopefully this will be clarified in the years to come through large, well-designed, experimental trials.
Nonetheless, the results from in vitro studies have corroborated the cancer-preventing effects of green tea seen in animal studies. Putative mechanisms for these effects have been thoroughly examined and are discussed in the sections which follow.
Over the past three decades, epidemiological studied have accessed the effects of green tea consumption on the risk of developing various cancers, mostly among Chinese and Japanese populations. While many studies reported favorable, statistically significant effects of green tea consumption, others found no effect [49]. This inconsistency has, in part, been attributed to confounding variables, such as how tea drinkers are more likely to consume alcohol and smoke than non-tea drinkers in most of the populations studied. The temperature of the beverage is also an uncontrolled variable. Importantly, drinking overly hot beverages, regardless of type, may increase the risk of esophageal cancer [50]. Overall, there is currently insufficient evidence to conclude whether or not green tea consumption affects the risk of developing cancer in humans. Hopefully this will be clarified in the years to come through large, well-designed, experimental trials.
Nonetheless, the results from in vitro studies have corroborated the cancer-preventing effects of green tea seen in animal studies. Putative mechanisms for these effects have been thoroughly examined and are discussed in the sections which follow.
Antioxidant effects
The antioxidant activity of green tea catechins discussed previously, if physiologically relevant, could help prevent cancer. Through many mechanisms, reactive oxygen species (ROS) contribute to cancer's development and progression. Most obviously, they can cause oxidative DNA damage which leads to mutations. Evidence suggests green tea catechins can reduce oxidative DNA damage in humans [51,52].
Another important role of ROS in is as secondary messengers in various cellular signalling pathways. Many of the affected pathways regulate processes important in cancer progression, like growth, differentiation, protein synthesis, and cell survival [53]. It is hypothesized that the ability of catechins to directly and indirectly quench ROS could modulate these cellular pathways favorably towards inhibiting carcinogenesis [54].
Another important role of ROS in is as secondary messengers in various cellular signalling pathways. Many of the affected pathways regulate processes important in cancer progression, like growth, differentiation, protein synthesis, and cell survival [53]. It is hypothesized that the ability of catechins to directly and indirectly quench ROS could modulate these cellular pathways favorably towards inhibiting carcinogenesis [54].
Enzyme inhibition and modulation of signalling pathways
The tea catechin EGCG has been shown in vitro to bind with high affinity to many biologically important proteins, including receptors and enzymes. For instance, EGCG binds and inhibits the anti-apoptotic Bcl-2 family proteins [55]. This activity favors induction of apoptosis, a process which prevents cancer cell survival. In addition, EGCG binds and inhibits the insulin-like growth factor 1 receptor [56]. Activation of this receptor promotes cellular proliferation and survival. In fact, in various cancer types activation of this receptor promotes angiogenesis and metastasis [57]. EGCG also has been shown to bind and inhibit enzymes whose activities are relevant to carcinogensis, such as matrix metalloproteinases [58]. The activity of these enzymes are important for metastasis and the invasion of surrounding tissue. Consistent with this mechanism, EGCG reduced cancer invasion and metastasis in a mouse model [59]. As a final example, EGCG potently inhibits the enzyme epidermal growth factor receptor kinase [60]. This enzyme is a key mediator of another signalling pathway important in cancer proliferation. Importantly, in many cases described here the in vitro interaction affinities are sufficiently strong to be relevant under physiologically reasonable EGCG concentrations.
Though less studied, other tea constituents may exert relevant biological effects. For instance, metabolic derivatives of L-theanine may directly mitigate cancer growth by effecting epidermal growth factor and NF-kappa B signalling pathways, which are important in cell survival and proliferation [61].
It is currently unclear which, if any, of these mechanisms would be relevant in humans [54]. Provided that green tea does have cancer-preventing effects, it seems likely that this would be achieved through a synergistic combination of multiple mechanisms.
Though less studied, other tea constituents may exert relevant biological effects. For instance, metabolic derivatives of L-theanine may directly mitigate cancer growth by effecting epidermal growth factor and NF-kappa B signalling pathways, which are important in cell survival and proliferation [61].
It is currently unclear which, if any, of these mechanisms would be relevant in humans [54]. Provided that green tea does have cancer-preventing effects, it seems likely that this would be achieved through a synergistic combination of multiple mechanisms.
Clearance of carcinogens by drug-metabolizing enzyme induction
Long-term green tea consumption may lower cancer risk by inducing drug-metabolizing enzymes, facilitating the clearance of carcinogens. Two instances of this effect are discussed below.
The enzyme UDP-glucuronsyl transferase plays a critical role in the metabolism of many drugs, toxins, and other exogenous chemicals. Glucuronidation is a chemical modification which greatly improves the water-solubility of these compounds and facilitates their rapid clearance from the body. Various green tea phytochemicals are also metabolized and cleared through this pathway. Interestingly, as a long-term adaption to persistent green tea consumption higher levels of the enzyme is expressed. Serendipitously, this not only provides more efficient clearance of the green tea phytochemicals, but also of carcinogens which happen to be eliminated from the body by the same mechanism. In other words, while the green tea phytochemicals themselves are not harmful, they induce changes that protect us against chemicals which are. This mechanism has been experimentally demonstrated in animal models [62,63].
Another important enzyme class towards drug/toxin metabolism is the cytochrome P450 enzymes. These mono-oxygenases oxidize the drug/toxin, making a more soluble derivative which can be eliminated from the body more readily. The effect of green tea on this enzyme system is somewhat more complex, as it depends on the P450 isoform. Various cytochrome P450 isoforms exist and have different substrate specificities. In rats, green tea has been found to increase activities of the 1A1 and 1A2 isoforms, but have not effect on 2B1 and 2E1 activities [64]. While this makes it more complex to generalize the importance of this effect, it could be a mechanism by which green tea protects against certain carcinogens.
The enzyme UDP-glucuronsyl transferase plays a critical role in the metabolism of many drugs, toxins, and other exogenous chemicals. Glucuronidation is a chemical modification which greatly improves the water-solubility of these compounds and facilitates their rapid clearance from the body. Various green tea phytochemicals are also metabolized and cleared through this pathway. Interestingly, as a long-term adaption to persistent green tea consumption higher levels of the enzyme is expressed. Serendipitously, this not only provides more efficient clearance of the green tea phytochemicals, but also of carcinogens which happen to be eliminated from the body by the same mechanism. In other words, while the green tea phytochemicals themselves are not harmful, they induce changes that protect us against chemicals which are. This mechanism has been experimentally demonstrated in animal models [62,63].
Another important enzyme class towards drug/toxin metabolism is the cytochrome P450 enzymes. These mono-oxygenases oxidize the drug/toxin, making a more soluble derivative which can be eliminated from the body more readily. The effect of green tea on this enzyme system is somewhat more complex, as it depends on the P450 isoform. Various cytochrome P450 isoforms exist and have different substrate specificities. In rats, green tea has been found to increase activities of the 1A1 and 1A2 isoforms, but have not effect on 2B1 and 2E1 activities [64]. While this makes it more complex to generalize the importance of this effect, it could be a mechanism by which green tea protects against certain carcinogens.
Synergy with chemotherapy agents
There is beneficial, synergistic effects from co-administration of L-theanine and certain anti-cancer drugs in combination therapy [61]. For instance, L-theanine reduces biosynthesis of intracellular glutathione and glutamate transport protein. This is beneficial when given with the anti-cancer drug doxorubicin, as it reduces the amount of drug-glutathione conjugate and decreases its intracellular transport. This improves its anti-tumor efficacy. Furthermore, L-theanine attenuates the toxicity of doxorubicin by inhibiting glutathione peroxidase. This reduces the oxidative stress generated by the drug. Synergistic effects between L-theainine and other anti-cancer drugs have also been described, like cisplatin and irinotecan hydrochloride.
Green tea has anti-obesity effects
Consumption of green tea offers protective effects against weight gain, this has been shown in mice fed a high-fat diet [65]. These effects have also been examined in many human trials and studies. While more large and optimally designed studies are still required, the balance of evidence convincingly shows green tea has anti-obesity effects in humans [66,67].
This activity is achieved, in part, through modulation of lipid metabolism by catechins and caffeine. Tea catechins act by simultaneously promoting fat utilization while reducing fatty acid biosynthesis. In mice, they increased the level of liver enzymes involved with breaking down fat (acyl-CoA oxidase and medium-chain acyl-CoA dehydrogenase) [68]. In contrast, hepatic triacylglycerol and the liver enzyme fatty acid synthase were reduced [69]. Mechanistically, inhibition of the enzyme catechol-O-methyltransferase, an enzyme which degrades catecholamines, is thought to contribute to these effects [70]. Interestingly, EGCG has also been found to to block adipocyte proliferation and differentiation in vitro [71]. However, this effect is unlikely to be relevant in humans because the required plasma concentration is unfeasible [72].
Caffeine participates by increasing energy expenditure. It accomplishes this particularly by enhancing thermogenesis. This has been shown in humans, with 100 mg of caffeine increasing resting energy expenditure by around 10% over 12 hours [73]. Caffeine also promotes the lipolysis of fat, mediated by catecholamine signalling [74]. Though both catechins and caffeine contribute to green tea's anti-obesity activity, their combination provides synergistic effects greater than either alone [75,76].
Another likely mechanism is through decreasing nutrient absorption, leading to lower energy excess. Green tea's catechins are responsible for this. Firstly, they block the intestinal absorption of lipids as described earlier, by disrupting emulsification, lipase activity, and solubilisation of dietary fat and cholesterol. Furthermore, catechins also reduce carbohydrate absorption. Complex carbohydrates must be broken down into monosaccharides for intestinal absorption. Tea catechins inhibit various digestive glycosidase enzymes involved in this process [77,78,79]. In addition, the intestinal absorption of these products, principally glucose, is also disrupted. Glucose is imported into intestinal epithelial cells through specific transporters including the sodium-dependent glucose transporter (SGLT1) and others (GLUT2 and GLUT5). Green tea catechins inhibit glucose uptake by these proteins [80,81]. Consistent with these mechanisms, tea catechins decreased and slowed the glycemic response of mice fed starch [82].
This activity is achieved, in part, through modulation of lipid metabolism by catechins and caffeine. Tea catechins act by simultaneously promoting fat utilization while reducing fatty acid biosynthesis. In mice, they increased the level of liver enzymes involved with breaking down fat (acyl-CoA oxidase and medium-chain acyl-CoA dehydrogenase) [68]. In contrast, hepatic triacylglycerol and the liver enzyme fatty acid synthase were reduced [69]. Mechanistically, inhibition of the enzyme catechol-O-methyltransferase, an enzyme which degrades catecholamines, is thought to contribute to these effects [70]. Interestingly, EGCG has also been found to to block adipocyte proliferation and differentiation in vitro [71]. However, this effect is unlikely to be relevant in humans because the required plasma concentration is unfeasible [72].
Caffeine participates by increasing energy expenditure. It accomplishes this particularly by enhancing thermogenesis. This has been shown in humans, with 100 mg of caffeine increasing resting energy expenditure by around 10% over 12 hours [73]. Caffeine also promotes the lipolysis of fat, mediated by catecholamine signalling [74]. Though both catechins and caffeine contribute to green tea's anti-obesity activity, their combination provides synergistic effects greater than either alone [75,76].
Another likely mechanism is through decreasing nutrient absorption, leading to lower energy excess. Green tea's catechins are responsible for this. Firstly, they block the intestinal absorption of lipids as described earlier, by disrupting emulsification, lipase activity, and solubilisation of dietary fat and cholesterol. Furthermore, catechins also reduce carbohydrate absorption. Complex carbohydrates must be broken down into monosaccharides for intestinal absorption. Tea catechins inhibit various digestive glycosidase enzymes involved in this process [77,78,79]. In addition, the intestinal absorption of these products, principally glucose, is also disrupted. Glucose is imported into intestinal epithelial cells through specific transporters including the sodium-dependent glucose transporter (SGLT1) and others (GLUT2 and GLUT5). Green tea catechins inhibit glucose uptake by these proteins [80,81]. Consistent with these mechanisms, tea catechins decreased and slowed the glycemic response of mice fed starch [82].
Green tea and type 2 diabetes
Type 2 diabetes is a chronic metabolic condition characterized by chronically high blood sugar. In healthy individuals, insulin regulates blood glucose concentration by promoting its cellular uptake. Type 2 diabetes is caused by insulin resistance, where tissues fail to respond appropriately to this hormone. It can also be contributed to by beta cell dysfunction, which lowers insulin production. The above discussion of obesity is highly relevant to green tea's effect on type 2 diabetes. These ailments are are inexorably linked, leading to common use of the term "diabesity". Obesity is a major risk factor for the development of type 2 diabetes, with every extra kilogram of body weight increasing the risk of diabetes by 4.5% [83]. The causal link between obesity and type 2 diabetes is complex and not fully understood. Obesity causes increased secretions of leptin, adiponectin, cytokines, and non-esterified fatty acid from adipocytes [84]. The metabolic dysfunction which results from this promotes diabetes. Increased plasma levels of non-esterified fatty acid is thought to be particularily important, contributing directly to both insulin resistance and beta cell dysfunction.
It is reasonable to expect that green tea would benefit diabetes through its anti-obesity effects. Furthermore, the inhibition of carbohydrate digestion/intestinal glucose uptake could conceivably reduce glycemic load. However, the results of human studies have been inconsistent. Retrospective cohort studies in Japan and Taiwan found a large risk reduction for type 2 diabetes from green tea consumption [85,86]. Despite this, several human trials have failed to show improvement in type 2 diabetic patients [87,88,89]. An intriguing explanation for this lack of benefit relates to the activity of tea catechin EGCG on glucose transporter proteins. The inhibition of the intestinal glucose transporters benefits diabetic patients, but it turns out that EGCG lacks specificity. After tea consumption some EGCG enters the blood and can inhibit cellular glucose transporters, such as insulin-dependent GLUT4 [90]. This activity may exasperate insulin resistance, offsetting the otherwise beneficial effects in diabetic patients. Furthermore, there is significant variability between people in EGCG absorption, which complicates optimization of dosage and timing to mitigate this issue. Nonetheless, the anti-obesity effects of green tea may still be useful for diabetes prevention, if not its treatment. The encouraging results of the retrospective cohort studies are consistent with this, but it remains to be clarified.
It is reasonable to expect that green tea would benefit diabetes through its anti-obesity effects. Furthermore, the inhibition of carbohydrate digestion/intestinal glucose uptake could conceivably reduce glycemic load. However, the results of human studies have been inconsistent. Retrospective cohort studies in Japan and Taiwan found a large risk reduction for type 2 diabetes from green tea consumption [85,86]. Despite this, several human trials have failed to show improvement in type 2 diabetic patients [87,88,89]. An intriguing explanation for this lack of benefit relates to the activity of tea catechin EGCG on glucose transporter proteins. The inhibition of the intestinal glucose transporters benefits diabetic patients, but it turns out that EGCG lacks specificity. After tea consumption some EGCG enters the blood and can inhibit cellular glucose transporters, such as insulin-dependent GLUT4 [90]. This activity may exasperate insulin resistance, offsetting the otherwise beneficial effects in diabetic patients. Furthermore, there is significant variability between people in EGCG absorption, which complicates optimization of dosage and timing to mitigate this issue. Nonetheless, the anti-obesity effects of green tea may still be useful for diabetes prevention, if not its treatment. The encouraging results of the retrospective cohort studies are consistent with this, but it remains to be clarified.
Green tea has broad anti-microbial activity
The biological function of many phytochemicals is to defend the plant against pathogens. Indeed, green tea phytochemicals have broad activity against a range of microorganisms. In fact, green tea has been shown to have anti-viral, anti-bacterial, and anti-fungal effects [91]. The anti-bacterial effects are thought to be mediated by disruption of bacterial membranes by polyphenols [92]. The potential relevance of these activities against human pathogens is an exciting possibility. For instance, green tea catechins have antibacterial activity against UTI-associated E. coli strains and synergize with various antibiotics [93]. Encouragingly, the catechin ECG is excreted in significant quantity in the urine. Furthermore, its concentration resulting from a single cup of tea is thought to be sufficient to achieve this activity in humans. Though the data to date are very promising, this antibacterial effect has not been evaluated in human studies yet.
Green tea may improve dental health
Evidence suggests that green tea promotes dental health through several mechanisms. Green tea extract was shown reduce cavity formation, both in vitro and in vivo using a hamster model [94]. Cavities and plaque are caused by acid-producing Streptococci sobrinus and mutans. These bacteria ferment simple sugars, producing acid as a by-product. Digestion of complex carbohydrates begins orally, the enzyme salivary amylase breaks down starch into simple sugars. This enzyme activity therefore contributes to the growth and acid production of these oral bacteria. Green tea inhibits oral salivary amylase activity in humans [95]. It also directly increases the resistance of human tooth enamel to acid. This is in part due to its fluoride content, but the observed effect is greater than expected due to the fluoride content alone. It has been shown that additional unidentified component(s) contribute synergistically [96]. As an additional mechanism, there is evidence that tea polyphenols inhibit bacterial attachment to tooth surfaces [97]. Lastly, green tea could retard bacterial growth directly through the anti-bacterial activity discussed above.
Green tea may prevent kidney stones (nephrolithiasis)
Most commonly, kidney stones are composed of calcium oxalate. High dietary intake of oxalates is a risk factor for the formation of kidney stones, as high concentration of oxalate in the urine promotes its crystallization. However, this alone is insufficient to cause kidney stones. Normally, such crystals are microscopic and get passed in the urine without consequence. For stones to form, it is necessary that the renal tubule becomes blocked. Adherence of crystals to damaged epithelial cell membranes or blockage of the tubules by dead or damaged cells may be important in this process [98]. There is now evidence that oxalates contribute to this step, having a more complex role than merely being the constituents of stones. High concentrations of oxalates have cytotoxic effects on renal tubular epithelial cells by inducing oxidative damage, though it is not currently clear how they mediate this. In support of this, treatment with N-acetylcysteine, which boosters antioxidant defense, was able to decrease nephrolithiasis in rats [99].
Given the now understood role of oxidative damage in nephrolithiasis, green tea has been hypothesized to prevent of kidney stones through its antioxidant effects. Consistent with this, the green tea catechin EGCG prevented oxalate-induced free radical generation and damage to cells in vitro [100]. Furthermore, in rats fed a high oxalate diet, co-administration of green tea or EGCG alone significantly decreased kidney stone formation [100].
Green tea may also prevent nephrolithiasis by modifying the crystal structure of calcium oxalate crystals. Green tea extract was found to significantly modify the crystal morphology [101]. Without green tea, calcium oxalate forms monohydrate crystals with regular, flat tetragonal bipyramid morphology. Increasing concentration of green tea extract favors a dihydrate crystal, it roughens the surface and gives way to an irregular, porous structure. It is proposed that hydrogen bonding between tea polyphenols and the face of the growing oxalate crystals is responsible for this. This modification is thought to limit the size of the crystals and reduce their stability, potentially contributing to green tea’s prevention of kidney stones.
While the in vitro and in vivo animal data are very promising, this does not guarantee these effects will be relevant in humans. Fortunately, several large human cohort studies have found an inverse association between tea consumption and kidney stone formation. This includes a study which followed 127k middle-aged and elderly Chinese, as well as one of 200k American healthcare professionals [102,103]. These results are encouraging, but causal demonstration of this in controlled human trials is still required. A small pilot trial was conducted recently, but failed to demonstrate statistically significant, beneficial effects [104]. However, the study used a rather small number of test subjects (n=8) and evaluated the effects after a mere 30 days. A much larger and longer trial is necessary to provide sufficient statistical power. Pending this, I am optimistic that green tea will prove useful for preventing nephrolithiasis in humans.
Given the now understood role of oxidative damage in nephrolithiasis, green tea has been hypothesized to prevent of kidney stones through its antioxidant effects. Consistent with this, the green tea catechin EGCG prevented oxalate-induced free radical generation and damage to cells in vitro [100]. Furthermore, in rats fed a high oxalate diet, co-administration of green tea or EGCG alone significantly decreased kidney stone formation [100].
Green tea may also prevent nephrolithiasis by modifying the crystal structure of calcium oxalate crystals. Green tea extract was found to significantly modify the crystal morphology [101]. Without green tea, calcium oxalate forms monohydrate crystals with regular, flat tetragonal bipyramid morphology. Increasing concentration of green tea extract favors a dihydrate crystal, it roughens the surface and gives way to an irregular, porous structure. It is proposed that hydrogen bonding between tea polyphenols and the face of the growing oxalate crystals is responsible for this. This modification is thought to limit the size of the crystals and reduce their stability, potentially contributing to green tea’s prevention of kidney stones.
While the in vitro and in vivo animal data are very promising, this does not guarantee these effects will be relevant in humans. Fortunately, several large human cohort studies have found an inverse association between tea consumption and kidney stone formation. This includes a study which followed 127k middle-aged and elderly Chinese, as well as one of 200k American healthcare professionals [102,103]. These results are encouraging, but causal demonstration of this in controlled human trials is still required. A small pilot trial was conducted recently, but failed to demonstrate statistically significant, beneficial effects [104]. However, the study used a rather small number of test subjects (n=8) and evaluated the effects after a mere 30 days. A much larger and longer trial is necessary to provide sufficient statistical power. Pending this, I am optimistic that green tea will prove useful for preventing nephrolithiasis in humans.
Harmful effects of green tea
Iron absorption
The catechins present in green tea coordinate free iron, decreasing its intestinal absorption [105]. However, animal sources of iron (meat, fish, or poultry) contain heme-iron, which is more readily absorbed and is not sequestered by tea catechins. Therefore, this adverse effect is mainly a concern in individuals with low dietary intake of non-heme iron (e.g. vegetarians) or individuals already at risk for iron deficiency. This harm can be mitigated by adjusting the timing of tea consumption so as to not overlap with meals, or by increasing iron intake.
Fluorosis
The amount of fluoride in green tea is safe, and in fact beneficial. Even given relatively high daily consumption, the dosage would normally be well below harmful levels. However, it does contain more fluoride than other beverages consumed in the developed world, and it is still possible to exceed a safe fluoride limit if it is consumed in grotesque excess. Notably, in 2013 a case of skeletal fluorosis was described in a 47 year old female caused by tea consumption [106]. However, this was only after daily consumption of concentrated tea pitchers made from 100-150 teabags for 17 years! That this isolated case study was remarkable enough to be published in the New England Journal of Medicine informs the rarity of this concern. The lack of other health problems arising from this chronic mega-dosing of tea provides added reassurance of just how safe it is.
RSS Feed