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)

The objectives of this study were to determine the LC50 of methyl bromide (MeBr) and the dose-response curve and to study the detoxication effect of reduced glutathione (GSH) on MeBr poisoning in mice. 1) The LC50 of 4-h exposure to MeBr was 405 ppm in male mice with 95% confidence limits of 386-425 ppm. 2) The mortality rates of mice exposed to 500 ppm MeBr for 105, 120, 130, 140, 150 and 180 min were 0, 0, 10.7, 15.0, 85.0 and 90.0%, respectively. 3) In contrast, the mortality rate of mice pretreated with GSH (i.p 500 mg/kg; GSH-group) was only 5.3% after exposure to 500 ppm MeBr for 150 min. 4) Metabolic substances (Br-, GSH, formaldehyde, formic acid and beta-glucuronidase) were analyzed after exposure to 500 ppm MeBr and compared with the GSH-group and the distilled water treated group (DW-group). Except for GSH, concentrations of all other substances were significantly lower in the GSH-group than in the DW-group. Erythrocyte osmotic fragility test showed a significant increase in fragility in the DW-group. These results suggested that the onset of symptoms or death due to MeBr poisoning suddenly occurs at some point of concentration and time exposure. It was also shown that pretreatment with GSH effectively reduced mortality due to MeBr exposure.
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PMID:[Experimental study on methyl bromide poisoning in mice. Acute inhalation study and the effect of glutathione as an antidote]. 202 Jan 25

The contents of S-(1,2-dicarboxyethyl)glutathione (DCE-GS) in several tissues of rat were determined by HPLC. The peptide was present at concentrations (nmol/g tissue) of 119 in lens, 71.6 in liver, and 27.4 in heart. It was, however, not detected in spleen, kidney, cerebrum, or cerebellum. In rat liver, DCE-GS was located primarily in the cytosolic fraction. The substrates for the enzymic synthesis of DCE-GS were GSH and L-malate. In rats, the DCE-GS-synthesizing activity was found to be highest in the liver and in the cytosol of rat liver subcellular fractions. The DCE-GS-synthesizing enzyme was partially purified from rat liver cytosolic fraction by ammonium sulfate fractionation, Phenyl Superose chromatography, hydroxyapatite chromatography, and gel filtration. The molecular mass of the enzyme was estimated to be 53 kDa by gel filtration and SDS-PAGE, showing it to be a monomeric protein. The Km values for GSH and L-malate were 2.3 and 4.0 mM at 37 degrees C, respectively. The enzyme did not utilize 1-chloro-2,4-dinitrobenzene, 1,2-dichloro-4-nitrobenzene, p-nitrophenyl bromide, trans-4-phenyl-3-buten-2-one, or p-nitrobenzyl chloride, which were substrates for previously characterized glutathione S-transferases. The isolated enzyme preparation showed no fumarase activity, which supported the conclusion that the formation of DCE-GS was not the result of a nonenzymic reaction following the synthesis of fumarate from L-malate by the isolated enzyme. The N-terminal amino acid of this polypeptide was presumably blocked since no sequence was obtained by automatic sequencing after electro-blotting onto a siliconized-glass fiber (SGF) sheet.
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PMID:S-(1,2-dicarboxyethyl)glutathione and activity for its synthesis in rat tissues. 235 27

Human lung acidic glutathione S-transferase is irreversibly inhibited by 1-chloro-2,4-dinitrobenzene (CDNB) in the absence of the co-substrate glutathione (GSH). The time-dependent inactivation is pseudo-first-order and demonstrates saturation kinetics, suggesting that inactivation occurs from an EI complex. The Ki was 0.14 mM; and kobs was 0.32 min-1 at 0.6 mM CDNB. The enzyme was protected against CDNB inactivation by GSH. The other two classes of glutathione S-transferase, the basic and near-neutral, are not significantly inactivated by CDNB. Incubation with [14C]CDNB indicated covalent binding to all three classes of transferase. One peptide fraction was found to be radiolabelled in both the basic and acidic transferases when these were incubated with [14C]CDNB and GSH, cleaved with cyanogen bromide, and chromatographed by HPLC. Incubation in the absence of GSH yielded one and two additional labelled peptide fractions for the basic and acidic transferases, respectively. Our results suggest that while CDNB arylates all three classes of human transferases, only the acidic transferase possesses a specific GSH-sensitive CDNB binding site, binding to which leads to time-dependent inactivation.
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PMID:Site-directed inactivation of human lung acidic glutathione S-transferase by 1-chloro-2,4-dinitrobenzene in the absence of glutathione. 273 Sep 17

The human testicular toxicant 1,2-dibromo-3-chloropropane (DBCP) was studied for the same end-point in 4 different species of laboratory animals. Marked necrosis and atrophy of the seminiferous epithelium were observed in rats and guinea pigs 10 days after a single i.p. administration of DBCP (170-340 mumol/kg), whereas significantly less damage was observed in hamsters and mice. The testicular concentrations of DBCP measured at various time-points after the i.p. injection of DBCP indicated that factors in addition to tissue concentration were of importance for the observed species differences in sensitivity towards DBCP-induced testicular damage. Also, there did not seem to be any direct correlation between DBCP-induced in vivo testicular toxicity and in vitro GSH-dependent dehalogenation, inasmuch as the rate of bromide release from DBCP with hamster testicular cytosol was as fast as that with rat cytosol. Testicular DNA damage, as determined by alkaline elution 60 min after in vivo administration of 170 mumol/kg DBCP, was observed only in rats and guinea pigs. Thus, induction of DNA damage correlates with the relative susceptibilities of the species towards DBCP-induced testicular necrosis. To further study species differences in testicular activation of DBCP to DNA-damaging intermediate(s), cells isolated from the testes of the 4 species were incubated with DBCP. Testicular cells from rats and guinea pigs were the only preparations developing substantial DNA damage after 60 min incubation with low concentrations of DBCP (5-50 microM). The findings indicate that rats are sensitive towards DBCP-induced testicular necrosis because rat testicular cells easily activate DBCP to a DNA-damaging intermediate(s). The relative high testicular DBCP concentration as well as the ability to activate DBCP may explain the sensitivity of guinea pigs towards DBCP-induced testicular toxicity.
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PMID:Species differences in testicular necrosis and DNA damage, distribution and metabolism of 1,2-dibromo-3-chloropropane (DBCP). 279 22

In vitro bromide release and in vivo glutathione (GSH) depletion in rat liver, kidney and testis by 1,2-dibromo-3-chloropropane (DBCP) and selectively methylated and deuterated DBCP analogs were studied. With liver microsomes from phenobarbital-pretreated rats the bromide release from the C1-C3-D4- and the perdeuterated DBCP analogs were 54% and 26% of that of DBCP, respectively. Inhibitors of P-450 reduced the bromide release to 10-20% of that without additions. This correlated with the effects of deuterium substitution and additions of P-450 inhibitors on DBCP-induced bacterial mutagenicity as reported elsewhere by this laboratory. To study the importance of GSH-dependent metabolism in DBCP toxicity, bromide release was assayed in cytosolic preparations using methylated analogs of DBCP. With the C1-methyl-derivative, bromide release was markedly reduced compared to that with DBCP in cytosols from liver, kidney and testis. A similar reduction in in vivo nephrotoxicity and testicular damage has recently been reported. The obtained correlation between in vitro GSH-dependent metabolism of methylated DBCP analogs and their in vivo organ damaging potential, points to an involvement of GSH-dependent metabolism in DBCP-induced in vivo toxicity. Both DBCP and the methylated analogs (360 mumol/kg i.p.) depleted the GSH levels in liver after 1 and 3 h and in kidney after 1 h, whereas in the testis no significant depletion of GSH was obtained. As kidney and testis are reported to be the primary target organs for DBCP, there was an apparent lack of correlation between tissue depletion of GSH and organ toxicity.
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PMID:Metabolism of selectively methylated and deuterated analogs of 1,2-dibromo-3-chloropropane: role in organ toxicity and mutagenicity. 291 29

2-Bromo-(diglutathion-S-yl)hydroquinone [2-Br-(diGSyl)HQ] causes severe necrosis of the proximal renal tubules in the rat, elevations in blood urea nitrogen (BUN) and increased urinary excretion of protein, glucose, and lactate dehydrogenase. In contrast, 2-Br-3-(GSyl)HQ, 2-Br-5-(GSyl)HQ, and 2-Br-6-(GSyl)HQ caused differentially less toxicity than the diglutathionyl conjugate. None of these conjugates had any apparent effect on liver pathology and serum glutamate-pyruvate transaminase remained within the normal range. Pretreatment of rats with probenecid, an organic anion transport inhibitor, offered only slight protection against 2-Br-(diGSyl)HQ-mediated elevations in BUN, proteinuria, or glucosuria. In contrast, quinine, an organic cation transport inhibitor, potentiated the nephrotoxicity of 2-Br-(di-GSyl)HQ. Thus, in contrast to other nephrotoxic sulfur conjugates, probenecid-sensitive organic ion transport systems do not contribute to the kidney-specific toxicity of 2-Br-(diGSyl)HQ. However, inhibition of renal gamma-glutamyl transpeptidase by AT-125 completely protected rats from the nephrotoxic effects of 2-Br-(diGSyl)HQ. Aminooxyacetic acid, an inhibitor of cysteine conjugate beta-lyase, caused a 20-25% decrease in 2-Br-(diGSyl)HQ-mediated elevations in BUN and urinary excretion parameters. The isomeric 35S conjugates covalently bound to rat kidney 10,000 x g homogenate in the order 2-Br-6-(GSyl)HQ greater than 2-Br-5-(GSyl)HQ greater than 2-Br-3-(GSyl)HQ greater than 2-Br-(diGSyl)HQ. AT-125 (0.4 mM) decreased covalent binding by 25%, 17%, 33%, and 28%, respectively. Aminooxyacetic acid (0.1 mM) inhibited covalent binding by 26%, 10%, 17%, and 17% respectively. Ascorbic acid (1.0 mM) inhibited covalent binding by 63%, 87%, 62%, and 28%, respectively, and this inhibition correlated, inversely, with the redox potential of the conjugates. Thus, the covalent binding is mediated preferentially by oxidation of the quinol moiety, although the formation of reactive thiols cannot be excluded. In addition, the initial conjugation of 2-BrHQ with GSH does not result in the formation of a less redox-active species. However, the subsequent addition of a second molecule of GSH results in the formation of a more redox-stable compound, which, paradoxically, enhances toxicity. The metabolism of 2-Br-(diGSyl)HQ by renal proximal tubular gamma-glutamyl transpeptidase and trans-membrane transport of the cysteine conjugate(s) followed by oxidation of the quinol moiety is probably responsible for the target organ toxicity of this compound.
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PMID:2-Bromo-(diglutathion-S-yl)hydroquinone nephrotoxicity: physiological, biochemical, and electrochemical determinants. 317 33

Hepatocyte cytotoxicity caused by substituted benzoquinones was associated with increased cytosolic Ca2+ concentration. p-Benzoquinone-induced hepatotoxicity was enhanced when the hepatocytes were loaded with Ca2+ by preincubation with ATP. A similar order of potency of the substituted benzoquinones in releasing Ca2+ from isolated mitochondria and inducing hepatocyte cytotoxicity was found; in decreasing order, this was 2-Br-, unsubstituted-, 2-CH3-, 2,6-(CH3O)2-, 2,6-(CH3)2-, 2,5-(CH3)2-, 2,3,5-(CH3)3-, and 2,3,5,6-(CH3)4-benzoquinones (duroquinone). The cellular products of quinone metabolism, hydroquinones and glutathione conjugates, did not cause mitochondrial Ca2+ release. Benzoquinone-induced mitochondrial Ca2+ release was preceded by GSH conjugate formation and NAD(P)H oxidation but followed by mitochondrial swelling. With duroquinone, a slow GSH and NADPH oxidation preceded Ca2+ release, but GSH oxidation did not occur with Se-deficient mitochondria lacking glutathione peroxidase activity. Cyanide-insensitive respiration was also observed with duroquinone but not with benzoquinone, suggesting that duroquinone undergoes redox cycling. GSH was depleted by both arylation and oxidation with 2,6-(CH3O)2-, 2,6-(CH3)2-, 2,5(CH3)2-, and 2,3,5-(CH3)3-benzoquinones. Benzoquinone concentrations that totally depleted GSH did not cause Ca2+ release until intramitochondrial NAD(P)H was oxidized. Ca2+ release was also prevented when NAD(P)H generation was stimulated by the presence of isocitrate or 3-hydroxybutyrate. This suggests that mitochondrial Ca2+ release is associated with NAD(P)H oxidation catalyzed by NADH dehydrogenase with benzoquinone or by the glutathione peroxidase-glutathione reductase system with duroquinone.
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PMID:Quinone toxicity in hepatocytes: studies on mitochondrial Ca2+ release induced by benzoquinone derivatives. 342 29

The toxicity of quinones is believed to be mediated via redox cycling involving formation of semiquinone radicals which autoxidize to form active oxygen species. However, when the cytotoxicity of benzoquinones was compared using freshly isolated rat hepatocytes, benzoquinones which did not mediate oxidative stress were highly toxic. Thus, the benzoquinone analogs in decreasing order of cytotoxicity were 2-CH3-, 2-Br-, unsubstituted, 2,6-(CH3)2-, 2,5-(CH3)2-, and 2,3,5-(CH3)3-benzoquinone. Cellular thiols were rapidly depleted and glutathione (GSH) was converted to a quinone conjugate without oxidation to glutathione disulfide. No increase in cyanide-resistant respiration was observed and benzoquinone-induced cytotoxicity was not enhanced by inactivation of catalase or glutathione reductase. In contrast, duroquinone [2,3,5,6-(CH3)4-benzoquinone], which stimulated cyanide-resistant respiration and GSH oxidation, was only cytotoxic when catalase or glutathione reductase was inactivated. These results suggest that alkylation and/or oxidative stress may be important mechanisms in the cytotoxicity of benzoquinone derivatives.
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PMID:Quinone toxicity in hepatocytes without oxidative stress. 378 32

A large proportion of the metabolites formed from benzo[a]pyrene (BP) in cell cultures from rodents, fish and humans result from conjugation of an oxidized metabolite of BP with sulfate, glucuronic acid or glutathione (GSH). To improve the analysis of these metabolites, a reversed-phase ion-pair h.p.l.c. system using a step gradient of methanol:tetrabutyl-ammonium bromide in ammonium formate buffer has been developed for the separation of these three classes of conjugates. This system separated 3-hydroxy-BP glucuronide and sulfate conjugates and resolved them from GSH conjugates of BP 4,5-oxide, 7,8-oxide and 7,8-diol-9,10-epoxide. Cultures of early passage Syrian hamster, Wistar rat and Sencar mouse embryo cells, a bluegill fry (BF-2) cell line and a human hepatoma cell line (HepG2) were exposed to [3H]BP for 24 h. Medium samples from each were extracted with chloroform: methanol:water, and the water-soluble metabolites were analyzed by ion-pair h.p.l.c. The largest peak of metabolites in the media from cell cultures from rodents and the bluegill fry cell line co-eluted with the glucuronic acid conjugate of 3-hydroxy-BP. These phenol-glucuronides represented 48-62% of the total water-soluble metabolites in the fish and rodent cell cultures. Treatment of this material with beta-glucuronidase released 3-hydroxy-BP and 9-hydroxy-BP in ratios from 3:4 to 13.3:1 in various cultures. Media from the bluegill fry cell line and the mouse embryo cell cultures also contained a peak of BP-diol glucuronides; treatment of these peaks with beta-glucuronidase released mainly BP-7,8-diol. In HepG2 cells, 40% of the water-soluble metabolites were identified as sulfate conjugates of 3-hydroxy-BP and 9-hydroxy-BP. No glucuronic acid conjugates of BP metabolites were detected in HepG2 cells. Only small amounts of the water-soluble metabolites from these cell cultures eluted in the same volumes as the synthetic GSH conjugate of BP-4,5-oxide, BP-7,8-oxide and BP-7,8-diol-9,10-oxide. These studies indicate that conjugation with glucuronic acid represents a major pathway of formation of water-soluble metabolites from BP in cells derived from a number of species and demonstrate the value of this ion-pair h.p.l.c. system for the analysis of conjugates formed from BP.
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PMID:Separation by ion-pair high-performance liquid chromatography of the glucuronide, sulfate and glutathione conjugates formed from benzo[a]pyrene in cell cultures from rodents, fish and humans. 380 96

Dihalomethanes are metabolized by two major pathways: an oxidative, cytochrome P-450-mediated pathway that has been previously thought to yield only CO, and a glutathione (GSH)-dependent one that yields CO2. Both give 2 mol of halide ion. We studied the kinetic properties of the two pathways in vivo by exposing male rats to various inhaled concentrations of CH2Cl2,CH2F2, CH2FCl, CH2BrCl, and CH2Br2 and determining end-exposure carboxyhemoglobin (HbCO) and plasma bromide (where appropriate). Closed atmosphere gas uptake studies were employed for CH2F2, CH2FCl, CH2Cl2, and CH2BrCl metabolism. A physiologically based kinetic model was used to determine kinetic constants based on gas uptake or plasma bromide data and these constants were used to predict HbCO concentrations. Oxidation was high affinity, low capacity. The maximum metabolic rates for this pathway with CH2Br2, CH2BrCl, and CH2Cl2 were, respectively, 72, 54, and 47 mumol metabolized/kg/hr. CH2FCl did not undergo significant oxidative metabolism and appears more like CH3C1 than a dihalomethane in its metabolic reactivity. The GSH pathway was low affinity, but high capacity and could be described as a single first-order process at all accessible exposure concentrations. The rate constant for this first-order GSH-dependent pathway was related as CH2BrCl greater than CH2Cl2 congruent to CH2FCl greater than CH2Br2 greater than CH2F2. Presumably bromide is a preferred leaving group but steric hindrance in the initial reaction with GSH is important with CH2Br2. We also studied the effects of pyrazole (which inhibits microsomal oxidation) and 2,3-epoxypropanol (which depletes GSH) on dihalomethane metabolism. Pyrazole abolished CO production from CH2Br2, CH2BrCl, and CH2Cl2. GSH depletion did not change the yield of halide ion from the high-affinity pathway; it did increase the steady-state HbCO concentrations with CH2Cl2 and CH2ClBr, but not with CH2Br2. The putative formyl chloride (FC) intermediate from CH2Cl2 or CH2BrCl appears to have a longer life than the formyl bromide from CH2Br2 and a significant portion of the FC (congruent to 20-30%) may react with other cellular nucleophiles instead of spontaneously decomposing to CO. This portion of the oxidative pathway probably yields CO2.
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PMID:Metabolism of inhaled dihalomethanes in vivo: differentiation of kinetic constants for two independent pathways. 394 49

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