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Inhibition of glutamate transporter by theanine enhances the therapeutic efficacy of doxorubicin.
Theanine, a major amino acid existing in green tea, enhanced the antitumor activity of doxorubicin (DOX) due to inhibition of DOX efflux from tumor cells. In order to clarify the mechanism, we have investigated the contribution of glutamate transporters to the action of theanine, because theanine is a glutamate analogue. In M5076 ovarian sarcoma cells, glutamate transport inhibitors reduced the efflux of DOX, as well as theanine. Incidentally, theanine significantly inhibited the glutamate uptake by M5076 cells in a concentration-dependent manner similar to specific inhibitors. These results suggested that the inhibition of DOX efflux was induced by the inhibition of glutamate transport by theanine. In addition, RT-PCR and Western blot analysis revealed the expression of GLAST and GLT-1, astrocytic high-affinity glutamate transporters, in M5076 cells. Thus, theanine was shown to competitively inhibit the glutamate uptake by acting on these glutamate transporters. This action suggested the contribution of glutamate transporters to the inhibition of DOX efflux by theanine. We revealed the novel mechanism of enhancement of the antitumor efficacy of DOX via the inhibition of glutamate transporters by theanine.
Toxicol Lett 2001 Apr 30;121(2):89-96
Improvement of idarubicin induced antitumor activity and bone marrow suppression by theanine, a component of tea.
We have examined the effect of theanine, a specific amino acid in green tea, on idarubicin (IDA)-induced antitumor activity and toxicity. In combination with theanine, IDA (0.25 mg/kg per day x4 days, a dose that does not show antitumor activity) had significant antitumor activity in P388-bearing mice. The IDA concentration in the tumors in the theanine plus IDA group increased to twice the level in the IDA alone group. Furthermore, the decrease in tumor weight caused by IDA at 1.0 mg/kg per day x4 days (at this dose IDA exhibits antitumor activity) was significantly amplified by theanine. The numbers of leukocyte and bone marrow cells decreased significantly on IDA injection. Theanine significantly reversed these changes. These results suggest that theanine selectively moderates the IDA-induced toxicities. Until recently, the antitumor activity and related toxicities of this chemotherapeutic agent in leukemia could not be distinguished. Theanine increases the IDA-induced antitumor activity and ameliorates the toxicities.
Cancer Lett 2000 Oct 1;158(2):119-24
Inhibiting effects of theanine on caffeine stimulation evaluated by EEG in the rat.
In this study, the inhibiting action of theanine on the excitation by caffeine at the concentration regularly associated with drinking tea was investigated using electroencephalography (EEG) in rats. First, the stimulatory action by caffeine i.v. administration at a level higher than 5 micromol/kg (0.970 mg/kg) b.w. was shown by means of brain wave analysis, and this level was suggested as the minimum dose of caffeine as a stimulant. Next, the stimulatory effects of caffeine were inhibited by an i.v. administration of theanine at a level higher than 5 micromol/kg (0.781 mg/kg) b.w., and the results suggested that theanine has an antagonistic effect on caffeine’s stimulatory action at an almost equivalent molar concentration. On the other hand, the excitatory effects were shown in the rat i.v. administered 1 and 2 micromol/kg (0.174 and 0.348 mg/kg) b.w. of theanine alone. These results suggested two effects of theanine, depending on its concentration.
Biosci Biotechnol Biochem 2000 Feb;64(2):287-93
Mortality among female practitioners of Chanoyu-Japanese tea-ceremony.
A cohort study aimed to evaluate the effect of drinking green tea on longevity was performed. Three thousand three hundred and eighty female practitioners of chanoyu (Japanese tea-ceremony), living in Tokyo, were followed from 1980 to 1988, and 280 were dead during this period. Standardized mortality ratios were estimated 0.55 when all Japanese women was used as standard population and 0.57 when women living in Tokyo was used, indicating the possibility that green tea is a protective factor for several fatal diseases.
Tohoku J Exp Med 1992 Apr;166(4):475-7
Protective effect of gamma-glutamylethylamide (theanine) on ischemic delayed neuronal death in gerbils.
We examined the protective effect of gamma-glutamylethylamide (theanine) on ischemic delayed neuronal death in field CA1 of the gerbil hippocampus. One microliter of theanine from each three concentrations (50, 125 and 500 microM) was administered through the lateral ventricle 30 min before ischemia. Transient forebrain ischemia was induced by bilateral occlusion of the common carotid arteries for 3 min under careful control of brain temperature at approximately 37 degrees C. Seven days after ischemia, the number of intact CA1 neurons in the hippocampus was assessed. Ischemia-induced neuronal death in hippocampal CA1 region was significantly prevented in a dose-dependent manner in the theanine-pretreated groups. These findings indicate that theanine might be useful clinically for preventing ischemic neuronal damage.
Neurosci Lett 2000 Aug 11;289(3):189-92
Coffee and tea intake and the risk of myocardial infarction.
The authors investigated the association of caffeinated coffee, decaffeinated coffee, and tea with myocardial infarction in a study of 340 cases and age-, sex-, and community-matched controls. The odds ratio for drinking > or = 4 cups/day of caffeinated coffee versus drinking < or = 1 cup/week was 0.84 (95% confidence interval (CI) 0.49-1.42) after adjustment for coronary risk factors (1 cup = 237 ml). The odds ratio for drinking > 1 cup/day of decaffeinated coffee versus nondrinkers was 1.25 (95% CI 0.76-2.04). For tea, the odds ratio for drinking > or = 1 cup/day versus nondrinkers was 0.56 (95% CI 0.35-0.90). In these data, only tea was associated with a lower risk of myocardial infarction.
Am J Epidemiol 1999 Jan 15;149(2):162-7
Hypotensive effect of gamma-glutamylmethylamide in spontaneously hypertensive rats.
The effect of gamma-glutamylmethylamide(GMA), one of the components of green tea extract, on the blood pressure in spontaneously hypertensive rats (SHR) was investigated. The effect of glutamic acid and r-glutamylethylamide (theanine), which is structurally similar to GMA, was also examined. When SHR were injected with glutamic acid (2000mg/kg), the blood pressure was not altered. The same dose of theanine decreased it significantly. GMA administration to SHR reduced the blood pressure significantly, and its degree of hypotensive action was more effective than that by theanine administration.
Life Sci 1998;62(12):1065-8
Reduction effect of theanine on blood pressure and brain 5-hydroxyindoles in spontaneously hypertensive rats.
The effect of theanine, one of the components of green tea, on the blood pressure and brain 5-hydroxyindoles in spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY) was investigated by intraperitoneally administering theanine. The effect of glutamine, which is structurally similar to theanine, was also examined. When SHR were injected with various amounts of theanine (0, 500, 1000, 1500 and 2000 mg/kg), the change was dose-dependent, and a significant decrease in blood pressure was observed with the high doses (1500 and 2000 mg/kg). A dose of 2000 mg/kg of theanine did not alter the blood pressure of WKY, while the same dose to SHR decreased it significantly. On the other hand, glutamine administration to SHR did not change either the blood pressure or the heart rate. The brain 5-hydroxyindole level was significantly decreased by theanine administration to both WKY and SHR, the decrease being dose-dependent.
Biosci Biotechnol Biochem 1995 Apr;59(4):615-8
Coenzyme Q10 improves mitochondrial respiration in patients with mitochondrial cytopathies. An in vivo study on brain and skeletal muscle by phosphorous magnetic resonance spectroscopy.
With phosphorus magnetic resonance spectroscopy (31P-MRS) we studied in vivo the effect of six-month coenzyme Q10 treatment on the efficiency of brain and skeletal muscle mitochondrial respiration in six patients with different mitochondrial cytopathies. Before CoQ10 we found a low phosphocreatine content (average of 25% decrease from controls) in the occipital lobes of all patients. Calculated [ADP] and the relative rate of ATP synthesis were high (as an average, 57% and 16% above control group respectively), whereas the cytosolic phosphorylation potential was low (as an average, 60% of control value). 31P-MRS also revealed an average of 29% reduction of the mitochondrial function in the skeletal muscle of patients compared with controls. After a six-month treatment with 150 mg CoQ10/day all brain variables were remarkably improved in all patients, returning within the control range in all cases. Treatment with CoQ10 also improved the muscle mitochondrial functionality enough to reduce the average deficit to 56% of the control group. These in vivo findings show the beneficial effect of CoQ10 in patients with mitochondrial cytopathies, and are consistent with the view that increased CoQ10 concentration in the mitochondrial membrane increases the efficiency of oxidative phosphorylation independently of enzyme deficit.
Cell Mol Biol 1997 Jul;43(5):741-9
Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects.
Coenzyme Q10 is an essential cofactor of the electron transport chain as well as a potent free radical scavenger in lipid and mitochondrial membranes. Feeding with coenzyme Q10 increased cerebral cortex concentrations in 12- and 24-month-old rats. In 12-month-old rats administration of coenzyme Q10 resulted in significant increases in cerebral cortex mitochondrial concentrations of coenzyme Q10. Oral administration of coenzyme Q10 markedly attenuated striatal lesions produced by systemic administration of 3-nitropropionic acid and significantly increased life span in a transgenic mouse model of familial amyotrophic lateral sclerosis. These results show that oral administration of coenzyme Q10 increases both brain and brain mitochondrial concentrations. They provide further evidence that coenzyme Q10 can exert neuroprotective effects that might be useful in the treatment of neurodegenerative diseases.
Proc Natl Acad Sci U S A 1998 Jul 21;95(15):8892-7