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)

The effect of 1-bromlalkanes on intracellular glutathione (GSH) was studied in freshly isolated rat hepatocytes. Treatment of cells with bromoalkanes depleted cellular GSH levels without causing cytotoxicity. The extent of GSH depletion was directly proportional to the concentration and increasing chain length of 1-bromoalkanes (C2-C7). Bromoheptane (100 microM) depleted GSH by 87% in 30 mins which remained depleted for the 4 hr study period without causing cytotoxicity. A 30 fold higher concentration of bromoheptane was required before cytotoxicity ensued. Bromoheptane would therefore be particularly useful for studying the role of GSH in modulating xenobiotic cytotoxicity.
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PMID:1-bromoalkanes as new potent nontoxic glutathione depletors in isolated rat hepatocytes. 188 70

The in vivo effect of argemone oil on hepatic xenobiotic metabolizing enzymes was investigated in albino rats following either a single (10 ml kg-1 body wt.) or multiple intraparenteral doses (5 ml kg-1 body wt.) for three days. Animals sacrificed 72 h after a single intraparenteral dose of argemone oil exhibited a significant loss of hepatic cytochrome P-450 (35%) and cytochrome b5 (34%) contents and inhibition of aminopyrine-N-demethylase (APD), aryl hydrocarbon hydroxylase (AHH) and ethoxycoumarin-O-deethylase (ECD) activities (21-39%). Three successive 24-hourly intraparenteral injections of argemone oil followed by sacrificing the animals after 24 h of the last injection, showed a greater degree of inhibition of the content of cytochrome P-450 (58%) and its dependent mixed-function oxidases (35-63%). Also, multiple treatment of argemone oil caused a depletion of endogenous hepatic glutathione (GSH) content (72%) with a concomitant increase in lipid peroxidation (177%) and decrease in glutathione-S-transferase (GST) activity (30%). A significant decrease in relative liver weight (39%) was observed in animals treated with multiple treatment of argemone oil. These results suggest that argemone oil can alter both membrane and cytosolic defences and destabilizes the hepatic cytochrome P-450 dependent mixed-function oxidase system, so that it tips in the direction of autooxidative peroxidation of lipids.
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PMID:Biochemical toxicology of argemone oil. I. Effect on hepatic cytochrome P-450 and xenobiotic metabolizing enzymes. 191 95

Our studies provide evidence that thiols, such as N-acetyl-L-cysteine, inhibit both spontaneous mutations and induced mutations in bacteria, prevent the in vivo formation of carcinogen-DNA adducts, and suppress or delay the development of tumors or preneoplastic lesions in rodents. N-Acetylcysteine and other thiols exert antioxidant activity toward superoxide anion, hydrogen peroxide, and singlet oxygen, assessed in bacterial genotoxicity models. In addition, several other mechanisms were shown to contribute to their antimutagenic and anticarcinogenic activities, in the extracellular environment and in nontarget or target cells. These mechanisms include blocking of electrophilic metabolites and of direct-acting compounds, either of endogenous or exogenous source, modulation of several xenobiotic-metabolizing pathways, and protection of DNA-dependent nuclear enzymes. Chemoprevention of mutation and cancer by thiols is particularly useful under conditions of reduced glutathione (GSH) depletion due to toxic agents or to cancer-associated viral diseases, such as acquired immunodeficiency syndrome (AIDS) or viral hepatitis B.
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PMID:Antioxidant activity and other mechanisms of thiols involved in chemoprevention of mutation and cancer. 192 3

Glutathione (GSH) is important in detoxification and regulating cyclooxygenase activity. Since the liver has high levels of GSH, xenobiotic-induced changes in hepatic GSH could affect hepatic tissue blood perfusion (HP) via alterations in prostaglandin synthesis. In anesthetized male New Zealand rabbits, elevating GSH with GSH monoethyl ester had no affect on HP. Treatment of rabbits with diethyl maleate to deplete GSH also had no affect on HP in animals previously given GSH monoethyl ester. However, HP increased within 20 min in rabbits treated with diethyl maleate prior to GSH monoethyl ester. In another experiment, a similar rise in HP following GSH depletion was accompanied by arterial plasma 6-ketoPGF1 alpha (the stable metabolite of prostacyclin) levels that were 4-times higher than in the controls. Plasma TxB2 (the stable metabolite of thromboxane) also increased following diethyl maleate, but only to levels that were 25-times lower than for 6-ketoPGF1 alpha. Since indomethacin blocked the rise in HP, as well as the increases in 6-ketoPGF1 alpha and TxB2, these results indicate changes in HP may occur following GSH depletion as a result of increased synthesis of one or more arachidonic acid metabolites and implicate prostacyclin as a possible mediator of this phenomenon.
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PMID:Indomethacin attenuation of hepatic perfusion and plasma 6-ketoPGF1 alpha elevations following glutathione depletion in rabbits. 199 Nov 31

Mouse glutathione S-transferase GST YfYf (an orthologue of GST P or 7-7 in the rat and of GST pi in the human) was found to have a subunit Mr of 24,500 and cross-reacted with anti-(rat GST YfYf). N-Terminal analysis showed a close similarity to the rat, human and bovine orthologues. On isoelectric focusing the native enzyme had a pI of 8.3 and a pI of 7.3 in the presence of urea. Initial-rate studies with 1-chloro-2,4-dinitrobenzene (CDNB) and GSH as substrates and inhibition studies with the product of the enzyme-catalysed conjugation of CDNB and GSH, S-(2,4-dinitrophenyl)glutathione, indicated a rapid-equilibrium random mechanism for the enzyme. The diuretic drug ethacrynic acid was found to be simultaneously a competitive inhibitor and an uncompetitive activator of the enzyme (with CDNB as the substrate whose concentration was varied). By using a computer simulation program (EKPLOT) a model was developed that would explain the experimental data. It is proposed that ethacrynic acid can compete with CDNB at the active site but simultaneously bind to an allosteric site on the enzyme, causing an elevation in the Vmax. for the conjugation of CDNB and GSH. The implications of such an activation mechanism for an enzyme potentially conjugating a range of xenobiotic compounds are discussed.
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PMID:The initial-rate kinetics of mouse glutathione S-transferase YfYf. Evidence for an allosteric site for ethacrynic acid. 203 47

The effect of rifamycin SV on metabolic performance and cell viability was studied using isolated hepatocytes from fed, starved and glutathione (GSH) depleted rats. The relationships between GSH depletion, nutritional status of the cells, glucose metabolism, lactate dehydrogenase (LDH) leakage and malondialdehyde (MDA) production in the presence of rifamycin SV and transition metal ions was investigated. Glucose metabolism was impaired in isolated hepatocytes from both fed and starved animals, the effect is dependent on the rifamycin SV concentration and is enhanced by copper (II). Oxygen consumption by isolated hepatocytes from starved rats was also increased by copper (II) and a partial inhibition due to catalase was observed. Cellular GSH levels which decrease with increasing the rifamycin SV concentration were almost depleted in the presence of copper (II). A correlation between GSH depletion and LDH leakage was observed in fed and starved cells. Catalase induced a slight inhibition of the impairment of gluconeogenesis, GSH depletion and LDH leakage in starved hepatocytes incubated with rifamycin SV, iron (II) and copper (II) salts. Lipid peroxidation measured as MDA production by isolated hepatocytes was also augmented by rifamycin SV and copper (II), especially in hepatic cells isolated from starved and GSH depleted rats. Higher cytotoxicity was observed in isolated hepatocytes from fasted animals when compared with fed or GSH depleted animals. It seems likely that in addition to GSH level, there are other factors which may have an influence on the susceptibility of hepatic cells towards xenobiotic induced cytotoxicity.
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PMID:Effect of metal ion catalyzed oxidation of rifamycin SV on cell viability and metabolic performance of isolated rat hepatocytes. 204 2

This study was designed to investigate aspects of renal xenobiotic metabolism and the renal cellular response to drug-induced injury, in mediating cyclosporine nephrotoxicity. The relation between CsA and renal enzyme activity has not previously been investigated. In this study, CsA induced alterations in rat renal cortical microsomal NADPH cytochrome P-450 reductase activity, microsomal and mitochondrial lipid peroxidation, and renal cortical glutathione levels were investigated. CsA, in vivo (50 mg/kg/day for 4 days), increased in vitro lipid peroxidation in microsomes and mitochondria. CsA produced a significant uncompetitive inhibition of renal NADPH cytochrome P-450 reductase activity. The low activity and maximal enzyme velocity (Vmax) suggest that the amount of renal enzyme available for metabolism may be a rate-limiting step and could contribute to the development of toxicity. CsA in vivo reduced the renal cortical glutathione ratio (GSH/GSSG), which may also reduce the renal cellular response to CsA injury. This study has demonstrated that CsA nephrotoxicity may, in part, be mediated by CsA-induced alterations in renal xenobiotic metabolism.
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PMID:Evidence that alterations in renal metabolism and lipid peroxidation may contribute to cyclosporine nephrotoxicity. 211 35

An ATP-dependent transport process for S-(2,4-dinitrophenyl) glutathione (Dnp-SG) mediated by a novel ATPase designated as Dnp-SG ATPase has been demonstrated in human erythrocytes (LaBelle et al., FEBS Lett. 228, 53-51, 1988). In order to investigate whether the Dnp-SG ATPase system represents a generalized mechanism for the transport of xenobiotic conjugates of glutathione (GSH), stimulation of this ATPase by different GSH conjugates was studied in membrane vesicles prepared from human erythrocytes. Kinetic parameters for several GSH conjugates including S-(methyl)glutathione, S-(n-propyl)glutathione, S-(n-pentyl)glutathione, S-(n-decyl)glutathione, S-(p-chlorophenacyl)glutathione, S-(p-nitrobenzyl)glutathione, and the GSH conjugate of 9,10-epoxystearic acid were determined in order to evaluate their affinity for Dnp-SG ATPase. These studies reveal that all these conjugates stimulated Dnp-SG ATPase of human erythrocyte membrane. The apparent Km values of Dnp-SG ATPase for different conjugates were found to be in the range of 0.26-0.66 mM with Vmax values ranging from 0.55 to 4.44 nmol/min/mg protein. The results of these studies indicate that erythrocyte membrane Dnp-SG ATPase represents a generalized mechanism for the transport of GSH conjugates formed with xenobiotics as well as with the endogenously generated electrophilic compounds such as epoxystearic acid. It is suggested that Dnp-SG ATPase in conjunction with GSH and GSH S-transferase may play an important role in the protection of erythrocytes from exogenous as well as endogenous electrophilic toxicants.
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PMID:Stimulation of a human erythrocyte membrane ATPase by glutathione conjugates. 214 5

The hepatic glutathione (GSH) system and the influences of xenobiotics have been reviewed. Key steps in the regulation of hepatic GSH are GSH biosynthesis, the GSH-peroxidase/reductase cycle, the cystathionine pathway, and the carrier-mediated export processes. Influences of xenobiotics on these different pathways are discussed. Xenobiotics may lead to liver injury after biotransformation to highly reactive electrophilic metabolites (mainly cytochrome P-450 mediated), which easily conjugate with GSH, thus producing GSH depletion. This GSH depletion and probably an additional loss of protein sulfhydryl groups cause a disturbance of the intracellular calcium homeostasis which leads to an irreversible cell injury. The different acinar distribution of cytochromes P-450 and of GSH and GSH-related detoxication pathways points to a greater susceptibility of perivenous hepatocytes to xenobiotic-induced damage. Also, the intracellular compartmentation of GSH is important for the understanding of hepatocellular injury induced by several xenobiotics.
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PMID:The hepatic glutathione system--influences of xenobiotics. 219 11

The effects of cold-restraint as a physiological stressor on the glutathione (GSH) content of the liver and other tissues were examined in male mice. Mice of the ICR, NIH, ND/4, and B6C3F1 strains subjected to cold-restraint for 2 or 3 h experienced a loss of hepatic GSH concentrations ranging from approximately 15 to 50%. Though 3 of these strains (ICR, NIH, and B6C3F1) experienced hypothermia as result of the cold-restraint treatment, with average decreases in core body temperature ranging from 3.3 to 9.8 degrees C, hepatic GSH levels were depressed in the ND/4 mouse in the absence of changes in core body temperature. The ability of cold-restraint as a stressor to diminish hepatic GSH therefore could not be attributed simply to hypothermia. The decrease in hepatic GSH from cold-restraint in ND/4 mice was paralleled by a decrease in non-protein sulfhydryl (NPSH) content of the liver. In addition to its effects on liver GSH and NPSH concentrations, 1.5 h of cold-restraint stress significantly depressed plasma, heart, kidney, and lung NPSH concentrations. The extent of NPSH depression was equivalent to the GSH depression in the liver, heart, and kidney, despite the observation that the normal contribution of GSH to total NPSH content in these tissues ranged from a high of 89% (liver) to a low of 49% (heart). These results with cold-restraint in the ND/4 mouse suggest that other stressors may significantly depress cellular concentrations of GSH and other thiols, and may thereby render the affected tissues more susceptible to the toxicity of free radicals, electrophilic xenobiotic metabolites, or reactive oxygen species.
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PMID:Depression of glutathione by cold-restraint in mice. 231 51


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