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)

Oxidation of glutathione (GSH) by the myeloperoxidase (MPO) system was studied. The combination of MPO, H2O2, and a halide ion oxidized GSH. This occurred at a H2O2 concentration too low to oxidize GSH by itself. The MPO-mediated oxidation of GSH required the simultaneous presence of MPO, H2O2, and a halide ion. The system had an acid pH optimum of pH 5.5-6.0. Iodide was more effective than bromide which in turn was more effective than chloride. The oxidative product was shown to be GSSG, since it could be reduced back to GSH by glutathione reductase and NADPH. The MPO-mediated oxidation of GSH may be one mechanism by which this system damages microorganisms.
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PMID:Oxidation of glutathione by the myeloperoxidase system. 628 69

The metabolism, hepatotoxicity, and hepatic DNA damage of 1,2-dibromoethane (EDB) and tetradeutero-1,2-dibromoethane (d4EDB) were compared in male Swiss-Webster mice. In vitro studies that measured bromide ion released from the substrate to monitor the rate of metabolism showed that the hepatic microsomal metabolism of EDB was significantly reduced by deuterium substitution, while metabolism by the hepatic glutathione S-transferases was unaffected. Three hours after ip administration of EDB or d4EDB (50 mg/kg), there was 42% less bromide in the plasmaa of d4EDB-treated mice than in the plasm of EDB-treated mice. This difference demonstrates a significant deuterium isotope effect on the metabolism of EDB in vivo. Although the metabolism of d4EDB was less than that of EDB 3 hr after exposure, the DNA damage caused by both analogs was not significantly different at this time point. At later time points (8, 24, and 72 hr), d4EDB caused significantly greater DNA damage than EDB. Since the decreased metabolism of d4EDB was apparently due to a reduced rate of microsomal oxidation, these data support the hypothesis that conjugation with GSH is responsible for the genotoxic effects of EDB.
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PMID:Deuterium isotope effect on the metabolism and toxicity of 1,2-dibromoethane. 634 86

The metabolism and genotoxicity of 1,2-dibromoethane (EDB) and its deuterium substituted analog ( d4EDB ) were studied in isolated rat hepatocytes. There was a marked isotope effect on the metabolism of EDB by hepatocytes. This was due to decreased microsomal oxidation of d4EDB . Cytosolic metabolism of EDB, as measured by bromide ion release, was unaffected by deuterium substitution. The genotoxicity of the two analogs was assessed by assaying for the presence of EDB induced single-strand breaks in DNA. As measured by the alkaline elution technique, both compounds caused DNA single-strand breaks when incubated at a concentration of 0.1 mM with hepatocytes. No difference in the degree of DNA damage could be demonstrated between hepatocytes incubated with EDB or d4EDB . These data suggest that the GSH transferase mediated metabolism of EDB is responsible for the genotoxic effects of EDB observed in hepatocytes.
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PMID:The bioactivation of 1,2-dibromoethane in rat hepatocytes: deuterium isotope effect. 637 30

Tris(2,3-dibromopropyl)phosphate (Tris-BP) was found to be metabolized by liver microsomes obtained from untreated and phenobarbital-pretreated rats. Metabolites of Tris-BP, whose formation was dependent on NADPH and oxygen, included bromide ion and bis(2,3-dibromopropyl)phosphate (Bis-BP). The rates of formation of these metabolites were markedly increased in liver microsomes isolated from phenobarbital-pretreated rats compared to microsomes from untreated rats. In the presence of either SKF 525-A or metyrapone, the formation rates of bromide ion and Bis-BP were decreased, whereas alpha-naphthoflavone had no effect. The effects of the various treatments on bromide release and Bis-BP formation paralleled those that have been previously observed with respect to the activation of Tris-BP to mutagenic and covalently protein bound metabolites. Furthermore, rates of oxidative debromination of several Tris-BP analogs directly correlated with their respective mutagenicities. Addition of glutathione (GSH) to microsomal incubations of Tris-BP increased bromide release substantially over control, values but had no effect on Bis-BP formation. On the other hand, the addition of GSH to microsomes decreased covalent binding and mutagenicity of Tris-BP with increased formation of water soluble metabolites. GC/MS analysis of ethyl acetate extracts from incubations of rat liver microsomes with Tris-BP identified 2-bromoacrolein (2-BA) as a metabolite. Introducing deuterium at the carbon atom number 1 of the propyl moiety of Tris-BP had no effect on either bromide release or mutagenicity, whereas the analog labelled at carbon atom 3 showed significant isotope effects on both activities. In contrast, deuterium substitution at carbon atom 2 gave a significant isotope effect on bromide release, but not on mutagenicity. The data indicate that Tris-BP can be metabolized by rat liver microsomes to Bis-BP and 2-bromoacrolein catalyzed by cytochrome P-450 in a process liberating bromide ions. Further, the results are consistent with oxidation at the terminal carbon atom of Tris-BP thereby forming 2-bromoacrolein, which is postulated to be the metabolite mainly responsible for Tris-BP mutagenicity.
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PMID:Metabolism in vitro of tris(2,3-dibromopropyl)-phosphate: oxidative debromination and bis(2,3-dibromopropyl)phosphate formation as correlates of mutagenicity and covalent protein binding. 650 49

The nephrotoxin S-(1,2-dichlorovinyl)-L-cysteine (DCVC) is cleaved in the renal tubules to produce a reactive electrophilic intermediate. If this intermediate is responsible for the toxicity, addition of the nucleophilic scavenger glutathione (GSH) should decrease toxicity, and depletion of tubular GSH should enhance toxicity. GSH was added to isolated rabbit renal tubules simultaneously with, 15 min before, and 15 min after the addition of DCVC. The active accumulation of the organic anion para-aminohippuric acid (PAH) and organic cation tetraethylammonium bromide (TEA) was used as an index of renal toxicity. Incubation of renal tubules with 0.01-1 mM DCVC for 15 min decreased active transport, with complete inhibition at 1 mM. This was accompanied by a 50% decrease in non-protein sulfhydryl concentration. The addition of GSH (6 mM) simultaneously with DCVC completely prevented any decrease in active transport. The addition of GSH (6 mM) to tubules in which active transport was inhibited by DCVC reversed the inhibition to 80% of control. Similar enhancement of active transport occurred when tubules isolated 1 h after in vivo exposure to DCVC at 20-100 mg kg-1 were incubated with GSH (6 mM). Preincubation of renal tubules with GSH (5-15 mM) made them more refractory to the DCVC-induced decreased PAH and TEA transport. The inhibition of active transport by DCVC is enhanced if the tubular non-protein sulfhydryl is first lowered by diethyl maleate or glycidol. Thus, the tubular GSH concentration appears to be an integral component in regulating the alterations in active transport caused by DCVC.
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PMID:Regulation of a S(trans-1,2-dichlorovinyl)-L-cysteine-induced renal tubular toxicity by glutathione. 667 55

Lipid peroxidation in vitro in rat liver microsomes (microsomal fractions) initiated by ADP-Fe3+ and NADPH was inhibited by the rat liver soluble supernatant fraction. When this fraction was subjected to frontal-elution chromatography, most, if not all, of its inhibitory activity could be accounted for by the combined effects of two fractions, one containing Se-dependent glutathione (GSH) peroxidase activity and the other the GSH transferases. In the latter fraction, GSH transferases B and AA, but not GSH transferases A and C, possessed inhibitory activity. GSH transferase B replaced the soluble supernatant fraction as an effective inhibitor of lipid peroxidation in vitro. If the microsomes were pretreated with the phospholipase A2 inhibitor p-bromophenacyl bromide, neither the soluble supernatant fraction nor GSH transferase B inhibited lipid peroxidation in vitro. Similarly, if all microsomal enzymes were heat-inactivated and lipid peroxidation was initiated with FeCl3/sodium ascorbate neither the soluble supernatant fraction nor GSH transferase B caused inhibition, but in both cases inhibition could be restored by the addition of porcine pancreatic phospholipase A2 to the incubation. It is concluded that the inhibition of microsomal lipid peroxidation in vitro requires the consecutive action of phospholipase A2, which releases fatty acyl hydroperoxides from peroxidized phospholipids, and GSH peroxidases, which reduce them. The GSH peroxidases involved are the Se-dependent GSH peroxidase and the Se-independent GSH peroxidases GSH transferases B and AA.
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PMID:Inhibition of microsomal lipid peroxidation by glutathione and glutathione transferases B and AA. Role of endogenous phospholipase A2. 674 63

Glutathion (GSH) was covalently attached to dextrans with various molecular weights of 2, 5, 10, 40, and 70 kDa by the cyanogen bromide activation method. The conjugates obtained synthetically were white or pale yellowish powders containing 6-10% (w/w) of GSH. The average molecular weights of the conjugates were estimated to be larger and the molecular weight distribution was a little broader than that of each original dextran. The conjugates significantly stabilized GSH and liberated it gradually under physiological conditions (t1/2 = 0.99-1.6h). Mice depleted of GSH by treatment with buthionine sulfoximine, a potent inhibitor of gamma-glutamylcysteine synthetase, exhibited a significant increase in hepatic GSH level after intravenous injection of the conjugates. In mice given a hepatotoxic dose of acetaminophen, the survival rate increased progressively with coadministration of the conjugates, whereas a small improvement was found when free GSH was given. The conjugate of GSH attached to dextran with the molecular weight of 40 kDa exhibited the highest prophylactic effect on acetaminophen-induced hepatotoxicity in mice. The prolonged retention of the conjugates of larger molecular weight in the circulation would cause a higher hepatic accumulation. These results suggested that molecular size would be the most critical factor in the delivery of GSH, as a dextran conjugate, into the liver.
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PMID:A protective effect of glutathione-dextran macromolecular conjugates on acetaminophen-induced hepatotoxicity dependent on molecular size. 753 21

To study the putative role of de novo synthesis of glutathione (GSH) in the regulation of the cell cycle, we exposed NIH-3T3 cells to buthionine sulfoximine (BSO) and analysed cell cycle kinetics with continuous bromodeoxyuridine (BrdU) labeling and bivariate Hoechst 33258/ethidium bromide flow cytometry. Treating quiescent cells, which themselves had a low GSH content, with BSO did not affect subsequent entry into and progression through the cell cycle. Adding BSO during serum stimulation, however, provoked a dose-dependent inhibition of cell growth and a delayed increase in GSH level. The cell kinetic mechanism underlying BSO-induced growth inhibition is a diminished entry into the cell cycle and a permanent arrest in the S and G2 phase of the cell cycle. Our results are consistent with the hypothesis that GSH de novo synthesis is required for cell activation and proper S and G2 phase transit.
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PMID:De novo synthesis of glutathione is required for both entry into and progression through the cell cycle. 753 13

A number of investigations have suggested that the widely observed oxygen enhancement of radiation-induced cell killing or intracellular DNA damage requires the presence of glutathione (GSH) or other thiols. We have adapted an in vitro model system to investigate the effects of GSH on radiation-induced DNA double-strand breaks (DSBs), lesions felt to be critical to cell death. Superhelical SV40 DNA, 25 micrograms/ml, was irradiated in air or nitrogen in the presence of 0-20 mM GSH and single-strand breaks (SSBs) and DSBs were measured using neutral gel electrophoresis/ethidium bromide fluorescence. Control experiments demonstrated that a substantial concentration of free SH was still present after irradiation. Dose-response curves for SSBs and DSBs in air or nitrogen were predominantly linear at all GSH concentrations tested from 0-20 mM, except for 20 mM GSH in nitrogen, indicating that both SSB and DSB formation are predominantly by one-hit mechanisms under these conditions. Dose-response curves for both SSBs and DSBs in nitrogen at 20 mM GSH closely tracked the corresponding linear curves in air for doses up to about 200 Gy, then reached a plateau at higher doses. Induction efficiencies in 20 mM GSH, calculated from these initial slopes for both SSBs and DSBs in nitrogen, were unexpectedly higher than the corresponding efficiencies in 5 mM GSH, suggesting additional damage, rather than the expected additional protection. The possible mechanism for a damaging effect from GSH is discussed. Oxygen enhancement ratios (OERs) were calculated from the slopes of dose-response curves. The OERs for SSBs did not differ substantially from those for DSBs at the same [GSH], contrary to the observations of Prise et al. (Radiat. Res. 134, 102-106, 1993). The OERs for SSBs and DSBs peaked at 6.5 and 8, respectively, at 5 mM GSH. These similarities suggest that the much lower OERs (2.5-3.0) generally reported for radiation killing of cells, which also typically contain about 5 mM GSH, cannot be accounted for by differences in OER between lethal lesions, represented by DSBs, and nonlethal lesions, represented by SSBs. In view of the present results, another possible explanation, that intracellular compounds other than reduced thiols are important in the chemical modification of the response of DNA to radiation, seems to be much more likely.
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PMID:Modification of radiation-induced strand breaks by glutathione: comparison of single- and double-strand breaks in SV40 DNA. 756 62

Velnacrine maleate (Mentane) is an aminoacridine drug developed for the treatment of Alzheimer's disease. Although velnacrine maleate has not been observed to cause prominent cytotoxicity in in vitro hepatocyte cultures, this drug was associated with elevated serum levels of hepatic enzymes in clinical trials. The purpose of the present study was to manipulate cultures of rat hepatocytes in an attempt to elicit a cytotoxic response from this drug and to better understand the in vitro mechanisms of action. Cytotoxicity was evaluated by measuring lactate dehydrogenase (LDH) leakage, neutral red (NR) uptake, and 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide (MTT) reduction. Preliminary studies with fluorescent probes did not indicate a role for calcium influx or the formation of reactive oxygen species in the cytotoxicity of velnacrine maleate. However, depletion of cellular glutathione (GSH) by diamide (DA) pretreatment resulted in a cytotoxic response at concentrations of velnacrine maleate (1 and 10 micrograms/ml) which were approximately 25-fold lower than those in the absence of DA. Similarly, pretreatment with velnacrine maleate enhanced the cytotoxicity of DA. Pre-exposure of cells to a mixture of DA and t-butyl hydroperoxide (t-BHP) at non-toxic concentrations resulted in significant cytotoxicity of the hepatocyte cultures by velnacrine maleate. Results from these studies indicate that oxidative stress and GSH depletion may enhance Alzheimer patients' susceptibility to the hepatotoxic potential of aminoacridine drugs.
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PMID:Effect of glutathione depletion and oxidative stress on the in vitro cytotoxicity of velnacrine maleate. 776 13


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