Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.5.1.18 (glutathione S-transferase)
 22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The monohalomethane methyl iodide (MeI) is toxic to a number of organ systems including the central nervous system. Clinical symptoms of neurotoxicity suggest that the cerebellum is the target within the brain, and we have now modelled the toxicity of MeI in cultured rat cerebellar granule cells. Cytotoxicity is maximal 24 h after a 5 min exposure to MeI, and the EC50 for MeI under these conditions was calculated to be 1.6 mM. The glutathione S-transferase (GST) dependent metabolism of MeI was investigated in these cultures. There was a marked decrease in intracellular glutathione (GSH) 15 min after exposure to MeI, and GSH concentrations then increased, reaching 130% of control levels 7 h after exposure. To investigate the role of conjugation with GSH in the toxicity of MeI, GSH levels were modulated prior to exposure. Depletion of GSH exacerbated the cytotoxicity of MeI while provision of a bioavailable source of GSH was protective. Inclusion of antioxidants [vitamin E, butylated hydroxytoluene (BHT) or desferrioxamine mesylate (DF)] also protected against the cytotoxicity of MeI. Our in vitro data suggest that MeI is conjugated with GSH in the cerebellum, and the resulting extensive depletion of GSH may be the first step en route to toxicity, rendering the tissue susceptible to methylation and/or oxidative stress.
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PMID:Methyl iodide toxicity in rat cerebellar granule cells in vitro: the role of glutathione. 1061 86

Cytotoxic effects of ionizing radiation on gastrointestinal epithelium may be related to oxidative stress. In this study, we wanted to investigate the effects of selenium, vitamin E and selenium plus vitamin E pretreatments prior to whole abdominal irradiation on intestinal injury. Irradiation caused increased lipid peroxide and decreased GSH levels in the intestine. Intestinal superoxide dismutase and glutathione peroxidase activities were increased, but glutathione transferase activity decreased following irradiation. Selenium and/or vitamin E pretreatments ameliorated these disturbances in prooxidant-antioxidant balance. This amelioriation has been verified with histopathological findings. These results indicate that antioxidant pretreatments prior to irradiation may have some beneficial effects against irradiation-induced intestinal injury.
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PMID:The effect of selenium and/or vitamin E treatments on radiation-induced intestinal injury in rats. 1082 Nov 15

This study was aimed to evaluate the oxidative damage, production of reactive oxygen species and the status of antioxidative defenses following cerebral GSH depletion induced by two classical depletors, diethylmaleate (DEM, 3 mmol/kg, i.p.) and phorone (PHO, 4 mmol/kg, i.p.). The treatment decreased (40-43%) brain glutathione levels at 2 h, followed by a partial recovery at 24 h. Cerebral glutathione depletion by these agents increased the levels of superoxide anion and hydroxyl radical at both the time intervals; however, hydrogen peroxide was high at 24 h only. It also produced a dramatic increase in the protein carbonyls at 2 h but not at 24h, without any significant effect on lipid peroxidation and conjugated diene levels. These rats showed a significantly lowered superoxide dismutase activity both at 2 h and 24 h of exposure, as compared to controls. Glutathione depletion enhanced catalase activity markedly at 2 h, followed by some recovery at 24 h. While Se-independent glutathione peroxidase (GPx) and glutathione S-transferase activities were increased at both 2 and 24 h time intervals, Se-dependent GPx and glucose-6-phosphate dehydrogenase were induced at 2 h only. Glutathione depletion decreased ceruloplasmin and vitamin E levels significantly at 2 h. However, ascorbic acid remained unaffected. It may be concluded that an acute cerebral glutathione depletion generates higher levels of reactive oxygen species, which may be responsible for oxidative modification of proteins. Some of these changes appear to recover soon after an activation of a variety of cellular antioxidant defense mechanisms and glutathione restoration. It appears that central nervous system is highly vulnerable to oxidative damage following a moderate glutathione depletion that may result from certain diseases or xenobiotic exposures.
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PMID:Cerebral antioxidant status and free radical generation following glutathione depletion and subsequent recovery. 1094 1

The effects of fish oil and corn oil diets on diethylnitrosamine initiation/phenobarbital promotion of hepatic enzyme-altered foci in female Sprague-Dawley rats were investigated. Groups of 12 rats were initiated with diethylnitrosamine (15 mg/kg) at 24 h of age. After weaning, they received diets containing either 13.5% fish oil plus 1. 5% corn oil or 15% corn oil for 24 weeks. Rats fed fish oil had significantly greater liver weight, relative liver weight, spleen weight, and relative spleen weight than rats fed corn oil (p < 0.05). Hepatic phospholipid fatty-acid profile was significantly affected by the type of dietary lipid. The rats fed fish oil had significantly greater hepatic phospholipid 20:5 and 22:6 than rats fed corn oil; in contrast, the rats fed corn oil had significantly greater hepatic phospholipid 18:2 and 20:4 than rats fed fish oil (p < 0.05). Rats fed fish oil had significantly lower hepatic vitamin E and PGE(2) content but significantly greater hepatic lipid peroxidation than rats fed corn oil (p < 0.05). The hepatic levels of antioxidant enzymes (GSH reductase and GST) were significantly greater in rats fed fish oil than in rats fed corn oil (p < 0.05). Except for PGST-positive foci (foci area/tissue area), all the other foci parameters (GGT-positive foci area/tissue area, GGT-positive foci no./cm(2), GGT-positive foci no./cm(3), PGST-positive foci no. /cm(2), and PGST-positive foci no./cm(3)) measured in the fish oil group were 10-30% of those in the corn oil group (p < 0.05). Analyses of Pearson correlation coefficient revealed a positive correlation between hepatic GGT- or PGST-positive foci number (no. /cm(2)) and PGE(2) content (r = 0.66, P = 0.01; r = 0.56, P = 0.02, respectively) but a negative correlation between GGT- and PGST-positive foci (no./cm(2)) and lipid peroxidation (r = -0.8, P = 0.0006; r = -0.58, P = 0.01, respectively), GSH/(GSH + GSSG) ratio (r = -0.61, P = 0.05; r = -0.4, P = 0.14, respectively), GSH reductase (r = -0.75, P = 0.002; r = -0.53, P = 0.02, respectively), and GST activities (r = -0.65, P = 0.01; r = -0.44, P = 0.07, respectively). Similar correlation between foci number (no./cm(3)) and PGE(2), lipid peroxidation, GSH/(GSH + GSSG) ratio, GSH reductase, and GST activities were obtained. The results of this study show that dietary fish oil significantly inhibited hepatic enzyme-altered foci formation compared with corn oil in rats. These results suggest that the possible mechanisms involved in this process are the stimulation of hepatic detoxification system, changes in membrane composition, inhibition of PGE(2) synthesis, the enhancement of GSH-related antioxidant capacity, and the enhancement of lipid peroxidation by fish oil.
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PMID:Comparison of the effect of fish oil and corn oil on chemical-induced hepatic enzyme-altered foci in rats. 1099 28

alpha-Tocopherol is the most important fat-soluble, chain-breaking antioxidant. It is known that interplay between different protective mechanisms occurs. GSTs can catalyze glutathione conjugation with various electrophiles, many of which are toxic. We studied the influence of alpha-tocopherol on the activity of the cytosolic pi isoform of GST. alpha-Tocopherol inhibits glutathione S-transferase pi in a concentration-dependent manner, with an IC(50)-value of 0.5 microM. At alpha-tocopherol additions above 3 microM there was no GST pi activity left. alpha-Tocopherol lowered the V(max) values, but did not affect the K(m) for either CDNB or GSH. This indicates that the GST pi enzyme is noncompetitively inhibited by alpha-tocopherol. An inhibition of GST pi by alpha-tocopherol may have far-reaching implications for the application of vitamin E.
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PMID:alpha-Tocopherol inhibits human glutathione S-transferase pi. 1116 67

Cholestyramine treatment in children with heterozygous familial hypercholesterolemia (FHHe) can interfere with fat absorption from the intestinal tract, and has the potential to decrease the absorption of fat-soluble vitamins. The aim of this study was to examine the effect of cholestyramine treatment on the levels of the fat soluble vitamins (vitamin E, beta-carotene and lycopene) in LDL, on the glutathione system and on the susceptibility of LDL to oxidation in FHHe children. Patients were 16 children (seven girls, nine boys), age 14+/-4 years, non-smokers. Plasma LDL level before cholestyramine treatment but after dietary treatment was 239+/-50 mg% with no secondary cause for hypercholesterolemia. A control group was comprised of ten children (seven girls, three boys), age 14+/-4 years with plasma LDL level of 100+/-14 mg%. Blood was drawn from 16 FHHe children and five control children after fasting for 14 h. Thereafter cholestyramine treatment was begun in the patient group, at a dose of 8 g/day for 2 months. At the end of this period the dose was increased to 12-16 g/day for an additional 2 months. After 4 months from the beginning of the treatment, blood was drawn again. Plasma LDL cholesterol decreased after treatment by 14% (from 239+/-67 mg% before treatment to 205+/-55 mg% after treatment, P=0.07). Malondialdehyde (MDA) levels measured by thiobarbituric reactive substances (TBARS) assay in LDL at the end of oxidation were 30% higher in FHHe children in comparison to controls (P=0.02). After treatment TBARS levels in LDL (after in vitro oxidation) from FHHe children were decreased by 23% (P=0.02). Vitamin E levels in LDL from FHHe children after treatment were decreased by 65%, while beta-carotene and lycopene contents in LDL, paradoxically increased by 90 and 102%, respectively. In red blood cells (RBC), glutathione peroxidase (GPx) and glutathione transferase (GTf) activities were decreased by 29 and 24%, respectively, while glutathione reductase activity, total and oxidized glutathione contents from FHHe children did not change after cholestyramine treatment. LDL was more prone to oxidation in FHHe children than in controls, when measured by TBARS levels after LDL oxidation (with 10 &mgr;M CuSO(4)). Cholestyramine treatment for 4 months normalized LDL susceptibility to oxidation measured by TBARS levels, despite the decrease in vitamin E content in LDL from treated FHHe children. This is presumably due to the increased LDL content of beta-carotene and lycopene after treatment. GPx and GTf activities decreased after treatment, presumably due to the drop in oxidative stress within the RBCs, in parallel to the decreased LDL tendency to oxidation. Cholestyramine treatment in FHHe children has an overall antioxidant effect on LDL.
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PMID:Reduced susceptibility of low density lipoprotein to lipid peroxidation after cholestyramine treatment in heterozygous familial hypercholesterolemic children. 1147 69

We hypothesize that smokers with the null genotype for GSTM1 (GSTM1-0), who thus lack the detoxification enzyme glutathione S-transferase mu-1, develop atherosclerosis at an increased rate compared to smokers with the positive genotype (GSTM1-1). We used data from a 2-year randomized placebo-controlled trial on the effect of vitamin E on atherosclerosis among 189 male smokers. Progression of atherosclerosis was measured by 2-year change of the common carotid intima media thickness (CCA-IMT) as measured by B-mode ultrasonography. The frequency of GSTM1-0 genotype was 0.5 in both the placebo and the vitamin E group. Smokers with GSTM1-0 genotype had a tendency to higher baseline CCA-IMT values than those with GSTM1-1 (0.97 versus 0.92 mm, P=0.09). Within the placebo group, more CCA-IMT progression was found for smokers with the GSTM1-0 than for smokers with the GSTM1-1 genotype after adjustment for baseline IMT and major CVD risk factors (0.050 versus -0.002 mm, P=0.046). In the vitamin E group no effect of GSTM1 genotype on atherosclerosis progression was found. Overall, smokers with GSTM1-0 genotype had a higher mean 2-year progression compared to those with GSTM1-1 as shown by a difference in increase of 0.042 mm (95% CI 0.006; 0.078, P=0.02). In conclusion, our data suggest that smokers lacking the detoxifying enzyme GST mu-1 develop progression of atherosclerosis at an increased rate.
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PMID:Effect of glutathione S-transferase M1 genotype on progression of atherosclerosis in lifelong male smokers. 1150 Jan 95

Glutathione S-transferases and glutathione play an important role in the detoxification of most toxic agents. In the present study, the protective effects of some antioxidants (L-ascorbic acid (AA), vitamin E (VE) or garlic) on carbon tetrachloride-induced changes in the activity of alanine amino transferase (ALT), aspartate amino transferase (AST), glutathione S-transferase (GST), and the level of glutathione (GSH) and thiobarbituric acid reactive substances (TBARS) were studied. The activities of ALT, and AST were assayed in plasma, whereas the activity of GST and the levels of GSH and TBARS were determined in the livers of rats. The current study included two experiments. In the first experiment, animals received single oral dose of CCl4 (400 mg/kg body weight) after administration of AA (100 mg/kg b.w.), VE (100 mg/kg b.w.) or garlic (800 mg/kg b.w.) as single oral doses. In the second experiment, rats received repeated oral doses of antioxidants for 12 consecutive days followed by a single oral dose of CCl4 on the 13th day and killed after that by 24 h. Treatment of male rats with CCl4 significantly increased the activity of ALT and AST in plasma, and the levels of both GSH and TBARS in the liver. On the other hand, CCl4 inhibited the activity of GST after single dose treatment. Single-dose treatments of rats with AA, VE or garlic prior to the administration of CCl4 could not restore the alterations in the activity of ALT and AST caused by CCl4 to the normal control level. However, repeated dose treatments with these agents restored such alterations to the normal level. We observed that VE is more effective than AA and garlic in restoring the inhibition of GST activity caused by CCl4 to the normal level after single dose treatments. On the other hand, AA and VE are more effective than garlic in restoring the induced TBARS level caused by CCl4 to the normal control level after repeated dose treatments. It has been observed that the tested antioxidants were able to antagonize the toxic effects of CCl4, and such counteracting effects were more pronounced when they were administered as repeated doses prior to administration of CCl4.
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PMID:Carbon tetrachloride-induced changes in the activity of phase II drug-metabolizing enzyme in the liver of male rats: role of antioxidants. 1152 80

RRR-alpha-tocopherol succinate (vitamin E succinate, VES) is a potent, selective apoptotic agent for cancer cells but not normal cells. VES has been shown to inhibit the growth of a wide variety of tumor cells in cell culture and animal models. Studies addressing mechanisms of action of VES-induced apoptosis have identified transforming growth factor-beta, Fas/CD95-APO-1, and mitogen-activated protein kinase (MAPK) signaling pathway involvement. Here we show that MAPKs, the extracellular signal-regulated kinases (ERK), and the stress-activated protein kinases, c-Jun NH2-terminal kinases (JNK), but not p38, are critical mediators in VES-induced apoptosis of human breast cancer MDA-MB-435 cells. VES activates ERK1/2 and JNK both in level and duration of kinase activity. Expression of dominant negative mutants of ERK1, MAPK/ERK activator-1, or JNK1 but not p38 blocked phosphorylation of the substrate glutathione S-transferase-c-Jun and inhibited VES-induced apoptosis. Increased phosphorylation and transactivation activity of nuclear transcription factors c-Jun, ATF-2, and Elk-1 are observed after VES treatments; however, only c-Jun and ATF-2 appear to be involved in VES-induced apoptosis based on antisense blockage experiments. Collectively, these results imply a critical role for ERK1 and JNK1 but not p38 in VES-induced apoptosis of human MDA-MB-435 breast cancer cells.
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PMID:Activation of extracellular signal-regulated kinase and c-Jun-NH(2)-terminal kinase but not p38 mitogen-activated protein kinases is required for RRR-alpha-tocopheryl succinate-induced apoptosis of human breast cancer cells. 1152 56

Minks were fed different fish-based diets and exposed to 1 mg/d of the commercial polychlorinated biphenyl (PCB) mixture Aroclor 1242 for 4 wk (November-December 1995) or 21 wk (July-December 1998). In all the dietary groups, the PCBs increased hepatic phospholipid (PL) content. No significant increase was detected in hepatic triacylglycerols (TGs). In the minks fed the different fish diets, the PCBs caused qualitatively and quantitatively different changes in the microsomal fatty acids. In the minks that were fed a diet rich in fat and low in polyunsaturated fatty acids (PUFAs), the PCBs increased the percentage of oleic acid (18:1n-9, characteristic of the storage TGs) at the expense of n-3 PUFAs. This seemed to be due to inclusions of TGs in the membrane fragments and partly due to incorporation of TG-derived fatty acids into the membrane PLs. In addition, significant decrease of PUFAs was detected also in the hepatic TGs. The concomitant decrease in the concentrations of hepatic vitamin E suggested that lipid oxidation may also contribute to the decrease of the PUFAs. In the liver of the minks fed a low-fat but PUFA- and vitamin E-rich diet, the fatty acid changes due to the PCBs (the 21-wk exposure) remained small but the cytochrome P-450 system was significantly activated. In the minks fed Baltic herring (rich in organochlorines via the foodweb), the cytosolic glutathione S-transferase (GST) activity, levels of microsomal thiobarbituric acid-reactive substances (TBARS), and hepatic PLs were significantly elevated. In conclusion, in the mink the microsomal fatty acid changes were not directly connected with the ethoxyresorufin O-deethylase (EROD) activity or P-450 expression. Apparently, the PCBs produced definite fatty acid changes only in certain lipid matrices of tissue. In addition, a rich dietary supply of PUFAs and vitamin E may prevent these changes, even in a long-term subchronic exposure.
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PMID:Fatty acids, lipids, and cytochrome p-450 monooxygenase in hepatic microsomes of minks fed fish-based diets and exposed to Aroclor 1242. 1170 7


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