Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1260386 (GSH)
 38,102 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glutathione-deficient mutants of Escherichia coli K12/343/408 and Salmonella typhimurium TA1535 and TA100 were characterized biochemically by measuring the rate of formation of (14C)gamma-glutamylcysteine and (14C)glutathione in cell-free extracts of the strains. gamma-Glutamylcysteine synthetase activity was found to be absent in the NGR-2 mutant of E. coli and in the Salmonella mutants TA1535/NG-19, TA100/NG-57 and TA100/NG-11, while only low activities were found in the NGR-9 and NG-54 mutant of E. coli and Salmonella respectively. These results correspond with the decreased levels of glutathione found in these strains. Extracts of the parent strains have normal glutathione levels and show high gamma-glutamylcysteine synthetase activities. It is concluded that the present GSH-deficient strains of E. coli and Salmonella are gshA mutants, analogous to those previously described in E. coli. In addition, the present results show that the fluorometric method used for the determination of glutathione, employing o-phthalaldehyde as a reagent, is not specific for glutathione (at pH 8.0), but also sensitively reacts with gamma-glutamylcysteine.
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PMID:Biochemical characterization of glutathione-deficient mutants of Escherichia coli K12 and Salmonella strains TA1535 and TA100. 289 22

The present findings provide experimental evidence for the hypothesis that compromised cellular defense mechanisms, i.e., glutathione (GSH), GSH-peroxidase and catalase in the brain may be involved in neuronal degeneration caused by manganese (Mn) neurotoxicity. Moreover, data are presented demonstrating that the striatum is particularly susceptible to the deleterious effects of Mn. Specifically, exposure to subchronic MnCl2 produced significant reductions in GSH-peroxidase activity in the cytosol and mitochondrial fractions of the whole brain and the striatum. The decrease in GSH-peroxidase was most pronounced in the mitochondrial fraction of the striatum where the activity was reduced to 35% of the control. Catalase activity was also decreased in the striatum of rats treated with Mn but not in the whole brain. GSH content was markedly depleted (20% of the control) in the striatum, although only modestly decreased in whole brain (80% of the control). The alterations in the above parameters were accompanied by depletion of dopamine and dopamine metabolites in the striatum. The treatment of rats with Mn also decreased the activity of oxidized glutathione-reductase; the same treatment increased the activity of gamma-glutamyltranspeptidase. The activity of gamma-glutamylcysteine synthetase was not altered by Mn. The possible relevancy of the findings of this study to understanding the mechanism of Mn neurotoxicity of dopamine systems is discussed.
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PMID:Selective vulnerability of glutathione metabolism and cellular defense mechanisms in rat striatum to manganese. 290 11

The zonal distribution of GSH metabolism was investigated by comparing hepatocytes obtained from the periportal (zone 1) or perivenous (zone 3) region by digitonin/collagenase perfusion. Freshly isolated periportal and perivenous cells had similar viability (dye exclusion, lactate dehydrogenase leakage and ATP content) and GSH content (2.4 and 2.7 mumol/g respectively). During incubation, periportal cells slowly accumulated GSH (0.35 mumol/h per g), whereas in perivenous cells a decrease occurred (-0.14 mumol/h per g). Also, in the presence of either L-methionine or L-cysteine (0.5 mM) periportal hepatocytes accumulated GSH much faster (3.5 mumol/h per g) than did perivenous cells (1.9 mumol/h per g). These periportal-perivenous differences were also found in cells from fasted rats. Efflux of GSH was faster from perivenous cells than from periportal cells, but this difference only explained 10-20% of the periportal-perivenous difference in accumulation. Furthermore, periportal cells accumulated GSH to a plateau 26-40% higher than in perivenous cells. There was no significant difference in gamma-glutamylcysteine synthetase or glutathione synthetase activity between the periportal and perivenous cell preparations. The periportal-perivenous difference in GSH accumulation was unaffected by inhibition of gamma-glutamyl transpeptidase or by 5 mM-glutamate or -glutamine, but was slightly diminished by 2 mM-L-methionine. This suggests differences between periportal and perivenous cells in their metabolism and/or transport of (sulphur) amino acids. Our results suggest that a lower GSH replenishment capacity of the hepatocytes from the perivenous region may contribute to the greater vulnerability of this region to xenobiotic damage.
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PMID:Glutathione replenishment capacity is lower in isolated perivenous than in periportal hepatocytes. 290 50

The unprecedented ability of cyclosporin A, when given for six days at a dose of 25 mg/kg/d or 50 mg/kg/d, to cause a marked and sustained increase in renal glutathione (GSH) concentration in rat kidney is described. This response was particular to the kidney insofar as the GSH concentration in the liver was not increased in response to a lower dose of cyclosporin and was decreased in the liver of animals treated with the higher dose of the drug. The increase in kidney GSH concentration did not appear to be due to an increased rate of production or to an inhibition of the degradation of the tripeptide. This suggestion is based on the finding that the activities of the GSH synthesis pathways, GSSG-reductase and gamma-glutamylcysteine synthetase, were unchanged or decreased, respectively, and those of the catabolic enzymes, GSH-peroxidase and gamma-glutamyltranspeptidase, were unchanged or increased, respectively. It is suggested that the elevation of renal GSH content in the face of diminished synthetic capacity and an apparent increased utilization may result from an enhanced uptake of GSH as the result of alterations caused by cyclosporin in the renal transport system.
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PMID:Cyclosporin-mediated increase in kidney glutathione and effects on gamma-glutamyl-cycle enzymes. 290

The antirheumatic drug aurothioglucose is an inhibitor of the selenoenzyme GSH peroxidase. During chrysotherapy, the decreased levels of erythrocyte GSH and serum sulfhydryls of rheumatoid arthritis patients are normalized concomitant with clinical efficacy. This investigation examined the in vivo and in vitro effect of gold(I) as aurothioglucose on enzymes related to the GSH redox cycle or metabolism. The enzymes measured were GSH peroxidase, GSSG reductase, gamma-glutamyl transpeptidase, gamma-glutamylcysteine synthetase, GSH S-transferase, GSH thiotransferase, glucose-6-phosphate dehydrogenase, superoxide dismutase and catalase. Rats were injected with 30 mumol aurothioglucose/kg body wt. daily for 7 days by intramuscular injection. GSH levels in aurothioglucose-treated rats were 68% higher in erythrocytes (P less than 0.005) and 45% higher in kidney (P less than 0.001) than in control rats. Treatment with aurothioglucose did not elevate plasma or liver GSH. The enzyme activities that were changed by aurothioglucose treatment were GSH peroxidase in kidney (41% decreased, P = 0.005) and liver (13% decreased, P less than 0.05), gamma-glutamyl transpeptidase in kidney (15% decreased, P less than 0.05), and catalase in kidney (58% decreased, P less than 0.001). Kidney glucose-6-phosphate dehydrogenase activity was increased 50% (P less than 0.005) and GSH S-transferase was increased 72% (P less than 0.001). In vitro the only liver enzymes inhibited more than 50% by concentrations of less than 50 microM aurothioglucose were GSH peroxidase (50% inhibited by 25 microM aurothioglucose) and GSH thiotransferase (50% inhibited by 5 microM aurothioglucose). Studies of in vitro enzyme inhibition by aurothioglucose could not be used to predict decreased enzyme activities in vivo. Although decreased activities of two major enzymes that utilize GSH, GSH peroxidase and gamma-glutamyl transpeptidase, coincided with elevated GSH in kidneys of aurothioglucose-treated rats, a direct cause and effect relationship remains speculative.
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PMID:Effect of aurothioglucose on glutathione and glutathione-metabolizing and related enzymes in rat liver and kidney. 312 Nov 94

Fisher 344 rats injected with a total of 20.8 +/- 1.5 mg of gold (Au) as aurothioglucose over an 8-wk period were used to study the effect of long-term Au treatment on selenium-dependent glutathione peroxidase (SeGSHPx), other enzymes related to GSH metabolism, GSH, nonprotein sulfhydryls, and total sulfhydryls (SH) in various tissues. The indirect coupled assay for SeGSHPx revealed decreased activity in platelets of Au-treated rats but not in other tissues. Inhibition of SeGSHPx by Au is reversible upon dilution. A direct assay of GSH consumption by concentrated tissue cytosols that was developed to minimize enzyme dilution provided evidence of in vivo inhibition of SeGSHPx in kidney and liver from Au-injected rats. Kidneys of these rats had decreased (P less than 0.05) activities of GSSG reductase (36%), gamma-glutamylcysteine synthetase (19%), and gamma-glutamyl transpeptidase (26%), and increased (P less than 0.05) activities of glucose 6-phosphate dehydrogenase (90%) and GSH S-transferase (130%). The reactivity of fresh plasma SH groups with 5,5'-dithiobis-(2-nitrobenzoic acid) increased as a function of injection time. Enhanced SH reactivity suggests that Au may react with protein GSH-disulfides to release GSH. New findings were (i) decreased platelet SeGSHPx and kidney GSSG reductase in aurothioglucose-injected rats, (ii) direct in vivo inhibition of kidney and liver SeGSHPx in aurothioglucose-injected rats, and (iii) no significant correlation between the activity of GSH-metabolizing enzymes and levels of tissue GSH.
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PMID:Aurothioglucose effect on sulfhydryls and glutathione-metabolizing enzymes: in vivo inhibition of selenium-dependent glutathione peroxidase. 312 51

Analysis with radiotracer and high performance liquid chromatography techniques showed that glutathione (GSH) is transported intact into cells primarily of proximal tubule origin. Characteristics of GSH uptake were the same as previously reported for basal-lateral membrane vesicles, namely, uptake was Na+-dependent, inhibited by gamma-glutamylglutamate and/or probenecid, and not inhibited by cysteinylglycine or the constituent amino acids. Studies with inhibitors of gamma-glutamyltransferase (acivicin) and gamma-glutamylcysteine synthetase (buthionine sulfoximine) showed that GSH uptake, degradation and resynthesis are independent processes. The GSH uptake rate with 1 mM GSH was approximately three-fold greater than the GSH synthetic rate with 1 mM amino acids. To examine whether uptake of GSH can supplement synthesis to protect against injury, we incubated cells with a toxic concentration of t-butylhydroperoxide with or without GSH or its constituent amino acids. Although amino acids provided significant protection, GSH provided greater protection (cells with t-butylhydroperoxide plus GSH were not significantly different from cells alone). This protection by GSH was eliminated by gamma-glutamylglutamate or probenecid, indicating that GSH uptake was required for the protection seen. Protection was also eliminated when the GSSG reductase/GSH peroxidase system was inhibited by bischloronitrosourea (BCNU), indicating that GSH transport affords protection by maintaining GSH levels in the cell. Thus, intact GSH is transported into isolated proximal tubule cells by a Na+-dependent system, and this transported GSH can be used to supplement endogenous synthesis and GSSG reduction to protect cells against oxidative injury.
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PMID:Glutathione uptake and protection against oxidative injury in isolated kidney cells. 317 38

To evaluate the protective role of cell glutathione (GSH) against the toxicity of cadmium, the effect of GSH depletion on the metal toxicity was investigated and the role of glutathione was compared with that of zinc-induced metallothioneins (MTs). A 6-h incubation of cultured Chinese hamster V79 cells with 0.2 mM L-buthionine-SR-sulfoximine (BSO), a selective inhibitor of gamma-glutamylcysteine synthetase, resulted in approx. 95% depletion of GSH in the cells. The depletion of GSH did not influence the rate of cell growth, the amount of cell protein or the chromosome structure during culture for at least 24 h. Cells depleted or not depleted of GSH were challenged with (1-5).10(-5) M CdCl2 for 2 h and subsequent cell growth was evaluated. The cytotoxicity of cadmium was enhanced with increasing duration of BSO pretreatment and was correlated with the decrease of cell GSH, indicating that GSH constitutes a cellular defense against toxicity by cadmium. Inducibility of MTs by zinc was investigated in cultured V79 cells. Incubation of the cells with 1.10(-4) M zinc acetate did not result in accumulation of MTs over the control values for up to 2 h. Thereafter, however, the synthesis of MTs increased with increasing duration of zinc treatment and an approx. 9-fold increase in the amount of MTs was observed 10 h after addition of zinc. Depletion of cell GSH by BSO did not much influence the increased accumulation of MTs by zinc. In contrast, zinc at the same concentration did not influence the level of cell glutathione up to 12 h. The cytotoxicity of cadmium was markedly reduced in the cells pretreated with zinc and the protective effect of zinc was dependent upon duration of pretreatment, being parallel with the increased accumulation of MTs. Protection of cells from cadmium toxicity by zinc pretreatment was as or a little more effective in the cells depleted of GSH as in those not depleted. Thus, glutathione appears to be an intrinsic protector against cadmium toxicity, while MTs serve as an induced cellular defense that is mobilized against heavy metal stress, but takes more than 2 h to accumulate in significant amounts. Accordingly, it is suggested that GSH and MTs have cooperative protective roles against cadmium toxicity, as an initial defense for the former and a second-stage defense for the latter.
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PMID:Glutathione and metallothioneins as cellular defense against cadmium toxicity in cultured Chinese hamster cells. 334 70

The mechanisms responsible for the cross-resistance between radiation and certain antineoplastic agents have been examined in human ovarian cancer cell lines. Cell lines established from patients at a time when they were resistant to combination chemotherapy regimens, which included cisplatin and an alkylating agent as well as cell lines with resistance induced in vitro to melphalan and cisplatin, all have increased cellular levels of glutathione (GSH) compared with drug-sensitive cell lines from untreated patients. In addition, cell lines with acquired resistance to melphalan and cisplatin, but not to doxorubicin, were cross-resistant to radiation. L-Buthionine sulfoximine (BSO), an irreversible inhibitor of gamma-glutamylcysteine synthetase, lowered GSH levels in all the resistant cell lines studied. Lowering of GSH levels to less than 10% of control values potentiated the in vitro cytotoxicity of melphalan and cisplatin. Furthermore, BSO was also shown to potentiate the cytotoxicity of melphalan in a nude mouse model system of ovarian cancer in which mice die of disseminated intra-abdominal carcinomatosis. The BSO administered in the drinking water decreased GSH levels by 96%. A single melphalan treatment of 5 mg/kg following GSH depletion produced a 72% increase in median survival time compared with treatment with melphalan alone. In addition, depletion of GSH levels in cell lines with acquired resistance to melphalan led to a marked sensitization of these cells to irradiation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanisms of cross-resistance between radiation and antineoplastic drugs. 335 59

Treatment of cultured rat hepatocytes with 10 microM 1-chloro-2,4-dinitrobenzene (CDNB) resulted in an acute loss of cellular glutathione (GSH) within 30 min and a marked increase in spontaneous lactic dehydrogenase (LDH) leakage to the culture medium after 24 h, with obvious cellular degeneration as viewed by phase-contrast microscopy. Simultaneous treatment of the cells with alpha-tocopherol markedly protected the cells not only against LDH leakage but cellular degeneration in a dose-dependent manner. The EC50 of alpha-tocopherol was 0.1 microM, ca. 200 times less than normal plasma levels in the rat. In response to the inhibitory effects of alpha-tocopherol on the cytolysis as measured by LDH leakage, GSH biosynthesis was stimulated by CDNB, and cellular GSH levels returned to control levels. The recovery was inhibited by 0.2 mM buthionine-SR-sulfoximine (BSO), a specific inhibitor of gamma-glutamylcysteine synthetase. However, the stimulation of GSH biosynthesis apparently was not essential for the protection from cytolysis by GSH depletion during the experimental period, because treatment with 0.2 mM BSO and 20 microM tocopherol completely protected the cells against the lysis induced by BSO up to 32 h without cellular GSH recovery. The results suggest that alpha-tocopherol may be a primary natural inhibitor of the cytolysis induced by xenobiotics which consume the cellular GSH in vivo.
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PMID:Alpha-tocopherol and inhibition of cytolysis in glutathione-depleted hepatocytes in primary culture. 339 3


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