UMLS:C1260386 - FACTA Search

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Query: UMLS:C1260386 (GSH)
38,102 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The activities of enzymes participating in the regeneration of reduced glutathione (GSH), and their subcellular distribution were studied in cultured rat adrenal cells. 2. It has previously been shown that the adrenocorticolytic agent 7-hydroxymethyl-12-methylbenz[a]anthracene (7-hydroxymethyl-12-MBA) causes a drastic and selective oxidation of mitochondrial GSH in rat adrenal cells. Treatment of the adrenal cells with 7-hydroxymethyl-12-MBA, resulted in a minor decrease in the content of cytochrome c oxidase, nicotinamide nucleotide transhydrogenase, isocitrate dehydrogenase and cytosolic GSH reductase, whereas the activity of lactate dehydrogenase and citrate synthase was unaffected. None of these effects were considered to be responsible for the massive oxidation of mitochondrial GSH induced by 7-hydroxymethyl-12-MBA. 3. 1,3-Bis-(2-chloroethyl)-1-nitrosourea (BCNU) was used to obtain rat adrenal cells cultures with inactivated cytosolic and mitochondrial GSH reductase. The oxidation of mitochondrial GSH, induced by 7-hydroxymethyl-12-MBA, was not dramatically enhanced by the inactivation of GSH reductase, indicating that this enzyme was not rate-limiting in the regeneration of GSH. 4. Fractionation of rat adrenal cells with increasing concentrations of digitonin resulted in an earlier release of citrate synthase in cells treated with 7-hydroxymethyl-12-MBA compared with controls. These results may indicate damage to mitochondrial membranes as a result of 7-hydroxymethyl-12-MBA treatment.
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PMID:Effect of 7-hydroxymethyl-12-methylbenz[a]anthracene and 1,3-bis-(2-chloroethyl)-1-nitrosourea on enzyme activities and oxidation of glutathione in cultured rat adrenal cells. 254 26

Although both direct and glutathione S-transferase (GST)-catalyzed interactions between many electrophiles and GSH generally result in inactivation of the former, there are several reports of compounds whose electrophilic, alkylating, and cytotoxic activities are potentiated by GSH. This study investigates the effects of direct in vitro interaction between GSH and BCNU at physiological pH (7.2) and temperature (37 degrees C) and how this affects the cytotoxic and DNA cross-linking activity of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in target human malignant brain tumor cells. The kinetics and dose-response relationship of this interaction were determined by measuring residual GSH and residual BCNU-cytotoxicity in aGSH/BCNU mixture over a 45-min period and at varying BCNU concentrations. The results demonstrate that reaction of BCNU with four times its molar concentration of GSH for 45 min significantly inactivates BCNU, as expressed by a 32% decrease in induction of cellular DNA cross-linking, a 21% increase in DNA synthesis, and a 15% increase in clonogenic survival of human brain tumor cells compared to incubates of BCNU alone. Equine liver (EL)-GST increased the inactivation of BCNU only slightly (insignificant at p = 0.05). These results suggest that, in contrast to agents such as the alkyl-N-nitro-N'-nitrosoguanidines which become more potent alkylators after reacting with GSH, the 2-chloroethylnitrosoureas (CENUs) undergo inactivation by GSH. We propose that such interactions between GSH and the CENUs may constitute an important aspect of CENU metabolism and provide a potential means by which brain tumor cells can circumvent CENU toxicity and exhibit resistance to this class of agents.
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PMID:Decreased DNA interstrand cross-linking and cytotoxicity induced in human brain tumor cells by 1,3-bis(2-chloroethyl)-1-nitrosourea after in vitro reaction with glutathione. 255 96

The maximal biliary excretion of sulfobromophthalein (BSP) during constant i.v. infusion (2.5 mg/min/kg) was inhibited 45% in pentobarbital-anesthetized Sprague-Dawley rats, 48 hr after treatment with 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU; 20 mg/kg i.p.). Thirty-six to 48 hr after treatment, BCNU also inhibited the biliary excretion of an i.v. bolus of indocyanine green (24 mg/kg) by 75 to 85%. This suggested that inhibition of glutathione-S-transferase activity was not the main site of action of BCNU in its interference with cholephilic dye excretion. Indeed, it was found that conjugation of BSP with reduced glutathione (GSH) mediated by liver cytosol isolated from BCNU-pretreated rats was unaltered. In addition, BCNU did not deplete hepatic GSH. On the contrary, the hepatic concentration of GSH was increased by 60% 48 hr after treatment with BCNU. Thus, the ability of BCNU to block BSP excretion is probably not due to decreased conjugation of BSP with GSH. Inhibition of excretion under the saturating conditions of constant infusion strongly suggests an effect on canalicular excretion.
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PMID:Effect of 1,3-bis-(2-chloroethyl)-1-nitrosourea on cholephilic dye metabolism and excretion in anesthetized rats. 272 33

Vitamin E and glutathione protect against oxidative damage in vivo. In this study the relationship between these two defenses has been examined in the isolated perfused rat liver. The activities of glutathione reductase and glutathione S-transferase were unaffected by vitamin E deficiency, while glutathione peroxidase activity was decreased slightly. The glutathione redox status of vitamin E-deficient and control livers was assessed. GSSG was slightly higher in vitamin E-deficient livers (70 +/- 5 nmol GSH equivalents/g liver) than in controls (56 +/- 3 nmol GSH equivalents/g liver) under basal conditions. However, biliary GSSG release was 41% lower in vitamin E-deficient livers (0.46 +/- 0.08 nmol GSH equivalents/g liver.min) than in controls (0.78 +/- 0.23 nmol GSH equivalents/g liver.min). Inhibition of GSSG reduction by BCNU raised liver and biliary GSSG by a similar amount in vitamin E-deficient and control livers. Thus biliary GSSG efflux, a frequently used index of oxidant stress, is not increased in vitamin E-deficient perfused livers compared with control. Therefore, in the perfused rat liver model, no evidence was obtained that vitamin E deficiency activates the hepatic glutathione system.
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PMID:Tissue and biliary glutathione disulfide in the perfused vitamin E-deficient rat liver. 272 89

A mechanistic study was performed to elucidate the biochemical events connected with the cocarcinogenic effect of sulfur dioxide (SO2). Glutathione S-sulfonate (GSSO3H), a competitive inhibitor of the glutathione S-transferases, forms in lung cells exposed in culture to sulfite, the hydrated form of SO2. Changes in glutathione status (total GSH) were also observed during a 1-h exposure. Some cells were pretreated with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) to inhibit glutathione reductase. In human lung cells GSSO3H formed in a concentration-dependent manner, while glutathione (GSH) increased and glutathione disulfide (GSSG) decreased as the extracellular sulfite concentration was increased from 0 to 20 mM. The ratio of GSH/GSSG increased greater than 5-fold and the GSH/GSSO3H ratio decreased to 10 with increasing sulfite concentration. GSSO3H formed in rat lung cells exposed to sulfite, with no detectable effect on GSH and GSSG. GSSO3H also formed from cellular GSH mixed disulfides. GSSO3H formed rapidly, reaching its maximum value in 15 min. The viability of both cell types was unaffected except at 20 mM sulfite. GSSO3H incubated with human lung cells did not affect cellular viability. BCNU inhibited cellular GSSO3H reductase to the same extent as GSSG reductase. These results indicate that GSSO3H is formed in cells exposed to sulfite, and could be the active metabolite of sulfite responsible for the cocarcinogenic effect of SO2 by inhibiting conjugation of electrophiles by GSH.
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PMID:Effects of sulfite on glutathione S-sulfonate and the glutathione status of lung cells. 273 75

The teratogenicity of phenytoin may be mediated through a reactive electrophilic and/or free radical intermediate which, if not detoxified, may interact with fetal cellular macromolecules and initiate teratologic effects. Glutathione (GSH) maintains cellular physiological processes and detoxifies xenobiotic reactive intermediates. The role of GSH in protection against phenytoin embryopathy was studied by altering GSH homeostasis using 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), an inhibitor of glutathione reductase. BCNU was administered to pregnant CD-1 mice on gestational day 12, in doses ranging from 10 to 50 mg/kg i.p., with or without phenytoin, 55 or 65 mg/kg i.p., given 4 and 24 hr after BCNU. BCNU alone in doses of 10, 25 or 50 mg/kg resulted in a dose-related increase in the incidence of resorptions, cleft palates and postpartum death (P less than .05), and in lowered fetal weight (P less than .05). Fetuses exposed to 50 mg/kg of BCNU had an array of gross abnormalities, and this dose was not used in subsequent studies. BCNU, 25 mg/kg, inhibited GSH reductase activity by 23% in the placenta (P less than .05) and by 30% in the embryo (P less than .05) at 4 hr after treatment. Embryonic, but not placental GSH reductase activity remained significantly inhibited at 24 hr after BCNU. A BCNU dose-related increase in the incidence of resorptions (P less than .0001) and postpartum death (P less than .05) was seen in groups treated with both BCNU and 65 mg/kg of phenytoin, compared to controls treated with either chemical alone.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation of embryonic glutathione reductase and phenytoin teratogenicity by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). 274 6

The role of the glutathione peroxidase/reductase (GSH-Px/GSSG-Rd) enzyme system in protection from paracetamol toxicity was investigated in isolated mouse hepatocytes in primary culture. The effect of inhibitors of these enzymes on the toxicity of paracetamol and on t-butylhydroperoxide (t-BOOH), used as a positive control, was determined. 1,3-Bis(chloroethyl)-1-nitrosourea (BCNU) was used to inhibit GSSG-Rd, and goldthioglucose (GTG) used to inhibit GSH-Px. Both these inhibitors increased cell membrane damage in response to oxidative stress initiated by t-BOOH. However, they also increased the susceptibility of hepatocytes to paracetamol toxicity, indicating that a component of paracetamol's toxic effect involves formation of species that are detoxified by the GSH-Px/GSSG-Rd enzymes. To further examine the role of these enzymes, age-related differences in their activity were exploited. Hepatocytes from two-week-old mice were less susceptible to both t-BOOH and paracetamol toxicity than were those from adult mice. This corresponds to higher activity of cytosolic GSH-Px/GSSG-Rd in this age group. However, after inhibition of GSSG-Rd with BCNU, hepatocytes from these postnatal mice were more susceptible to paracetamol toxicity. This suggests that the higher activity of GSH-Px/GSSG-Rd in hepatocytes from two-week-old mice is responsible for their reduced susceptibility to paracetamol toxicity. The data indicate that the GSH-Px/GSSG-Rd enzymes contribute to protection from paracetamol toxicity and suggest that formation of peroxides contributes to this drug's hepatotoxic effects.
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PMID:A role for the glutathione peroxidase/reductase enzyme system in the protection from paracetamol toxicity in isolated mouse hepatocytes. 281 29

Normal Swiss Webster mice were treated with monocrotaline or high doses of three antitumor alkylating agents (BCNU, cyclophosphamide, or mitomycin C), all of which have been connected with hepatic veno-occlusive disease at our clinic. Prior administration of WR-2721 did not improve the survival of monocrotaline-treated animals. Glutathione (GSH) improved the survival of these animals to a small degree. Glutathione monoethyl ester (GSHet) almost completely protected animals from the toxicity of monocrotaline. Pretreatment with WR-2721 produced moderate increases in survival at the highest doses of BCNU, and at the lower BCNU doses none of the animals pretreated with WR-2721 died before they were killed on day 150. Pretreatment with GSHet gave good protection from BCNU toxicity at the highest dose of the drug, and there were no deaths in the groups of animals treated with GSHet 1 hour before BCNU. On a multiple dose schedule, GSH provided some protection from cyclophosphamide toxicity; GSHet gave a very good level of protection from cyclophosphamide. In none of these treatment groups were lesions suggestive of hepatic or pulmonary venoocclusive disease identified. In all three experimental protocols (monocrotaline, BCNU, and cyclophosphamide), there was a consistent decrease in hepatic toxicity after GSHet pretreatment; this was not observed in GSH- or WR-2721-pretreated animals. There was no evidence of protection of the FSaIIC fibrosarcoma growing in C3H mice as assayed by tumor growth delay or tumor cell survival in groups treated with two different doses of GSHet 1 hour before each drug injection compared to those treated with the BCNU or cyclophosphamide alone, or BCNU with cyclophosphamide. Pretreatment with GSHet did not alter the toxicity of these drugs to bone marrow. GSHet appears to be an effective protector of critical normal tissue and does not appear to protect tumor.
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PMID:Glutathione monoethyl ester can selectively protect liver from high dose BCNU or cyclophosphamide. 284 75

Reduced glutathione (GSH) and activities of several glutathione-related enzymes were measured in two 9L rat brain tumor cell lines with differing sensitivities to both 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and nitrogen mustard. GSH, measured by a specific high-performance liquid chromatographic method, was found to be approximately twice as high in 9L cells sensitive to BCNU but resistant to nitrogen mustard. The nitrogen mustard resistant cell line was also found to have 2.5-fold more bulk glutathione transferase activity and approximately 3-fold more gamma-glutamyl transpeptidase activity. Glutathione reductase activity, protein thiol, and total protein content were similar in the two cell lines. Pretreatment of 9L cells with 50 microM buthionine sulfoximine for 24 h to deplete GSH only slightly potentiated BCNU cytotoxicity in a clonogenic assay whereas that of nitrogen mustard was markedly potentiated in both cell lines. Similarly, buthionine sulfoximine pretreatment had little effect on the induction of sister chromatid exchanges by BCNU, but significantly increased the number of sister chromatid exchanges induced by nitrogen mustard in both cell lines. Depleting GSH also had no significant effect on the cytotoxicity of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea and 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea to 9L cells. Pretreatment of 9L cells with 1 mM GSH significantly protected against nitrogen mustard cytotoxicity. Moreover, nitrogen mustard incubated with GSH and glutathione transferase was 4-fold less cytotoxic than nitrogen mustard incubated with GSH alone. Incubation of BCNU with GSH alone or with glutathione transferase had no effect on BCNU cytotoxicity. These results indicate that elevated GSH and glutathione transferase activity is one mechanism of cellular resistance to nitrogen mustard in the 9L cell line, but it does not correlate with resistance to BCNU or other clinically important nitrosoureas.
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PMID:Glutathione and related enzymes in rat brain tumor cell resistance to 1,3-bis(2-chloroethyl)-1-nitrosourea and nitrogen mustard. 288 34

1-(2-Chloroethyl)-1-nitrosoureas (CNUs) are alkylating agents that also possess carbamoylating activity, depending on the chemical nature of the substituent at N-3. Although effects on a variety of enzymes, including inhibition of glutathione reductase (GS-R) have been attributed to carbamoylation, the biological significance is still not well understood. This deficiency is due at least in part to the analytical method that has been used to measure carbamoylation:in-vitro reaction with the omega-amino group of lysine. Reaction of CNUs with glutathione (GSH) offers a better estimation of carbamoylating potential in vitro. The decrease in free thiol groups during incubation of GSH with various CNUs can be followed using the thiol reagent 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB). With this test, carbamoylating potential relative to that of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) as 100% was 94% for 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (MeCCNU), 86% for 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), 16% for 1-(2-chloroethyl)-3-(2-hydroxyethyl)-1-nitrosourea (HECNU) and 6% for chlorozotocin (CLZ). Various carbamoylated and alkylated GSH derivatives, such as S-(2-chloroethylcarbamoyl)-, S-(2-hydroxyethylcarbamoyl)-, S-(cyclohexylcarbamoyl)-, S-(4-methylcyclohexylcarbamoyl)- and S-(2-hydroxyethyl)glutathione, are formed on incubation of GSH with CNUs. High-performance liquid chromatography (HPLC) revealed that, in comparison to carbamoylated compounds, alkylated GSH derivatives are formed in only low yields (less than 3%). Formation of carbamoylated products during incubation correlated with the decrease in free thiol groups. Concentrations achieving 50% GS-R inhibition in vitro were 0.16 mM for BCNU and 1.9 mM for HECNU.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A method to determine the carbamoylating potential of 1-(2-chloroethyl)-1-nitrosoureas. 296 Jun 14

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