Bioactive phytochemicals of green tea
Green tea has beneficial psychological effects
There is also evidence that L-theanine has anti-fatigue effects. That has been demonstrated in a mouse model . Physiologically, it raised dopamine concentrations and increased hepatic glycogen, while it decreased serotonin and serum urea.
Synergy between caffeine and L-theanine
Green tea prevents cardiovascular disease
Consistent with this mechanism, these chemicals were found to scavenge reactive oxygen and reactive nitrogen species, preventing cholesterol and LDL oxidation in vitro . 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 .
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 . 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 .
Inhibition of vascular smooth muscle proliferation
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 . 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 . 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 . 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 . Surprisingly, in addition to the catechins, L-theanine has hypercholesterolemic activity through increasing bile acid excretion . The mechanism through which L-theanine alone can achieve this is currently unknown.
Lowering blood pressure
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 . The ability of green tea catechins to directly neutralize reactive oxygen species, which may otherwise destroy nitric oxide, may also contribute to this .
Green tea may prevent cardiovascular disease, in part, through anti-thrombotic effects . 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 . In addition, catechins dose-dependently inhibit aggregation of human platelet cells in vitro . 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) . 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) . 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
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 . 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 . 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.
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 . It is hypothesized that the ability of catechins to directly and indirectly quench ROS could modulate these cellular pathways favorably towards inhibiting carcinogenesis .
Enzyme inhibition and modulation of signalling pathways
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 .
It is currently unclear which, if any, of these mechanisms would be relevant in humans . 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
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 . 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
Green tea has anti-obesity effects
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) . In contrast, hepatic triacylglycerol and the liver enzyme fatty acid synthase were reduced . Mechanistically, inhibition of the enzyme catechol-O-methyltransferase, an enzyme which degrades catecholamines, is thought to contribute to these effects . Interestingly, EGCG has also been found to to block adipocyte proliferation and differentiation in vitro . However, this effect is unlikely to be relevant in humans because the required plasma concentration is unfeasible .
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 . Caffeine also promotes the lipolysis of fat, mediated by catecholamine signalling . 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 .
Green tea and type 2 diabetes
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 . 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
Green tea may improve dental health
Green tea may prevent kidney stones (nephrolithiasis)
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 . Furthermore, in rats fed a high oxalate diet, co-administration of green tea or EGCG alone significantly decreased kidney stone formation .
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 . 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 . 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.