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)

Benzyl bromide is a selective alkylator of sulfur nucleophiles including methionine and cysteine. Only the mercaptide ion is a more efficient nucleophile than is the sulfur ether of methionine. Alkylation rates relative to methionine are 200: less than or equal to 0.03: less than or equal to 0.03: less than or equal to 0.02 for GS-, histidine, tryptophan, and GSH, respectively. Alkylation of methionine by benzyl bromide is more than 50 times faster than alkylation by iodoacetate. Fumarase is readily inactivated by exposure to benzyl bromide at pH 6.6 to 6.8 accompanied by alkylation of close to 1 methionine residue/subunit. Fumarase fully inactivated by exposure to benzyl bromide shows no detected alkylation of amino acid residues other than methionine. The rate of inactivation of fumarase by benzyl bromide is decreased about 4-fold by the presence of excess substrates. Denaturation of fumarase in 6 M urea at pH 6.5 exposes additional methionine as well as cysteine residues to alkylation.
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PMID:Facile alkylation of methionine by benzyl bromide and demonstration of fumarase inactivation accompanied by alkylation of a methionine residue. 0 97

Homogenates of Crithidia fasciculata (a species of Trypanosomidae) were shown to contain a phosphatase (EC 3.1.3.36) and a phosphodiesterase (EC 3.1.4.11) which hydrolyse triphosphoinositides. Approximately 30% of the diesterase and most of the phosphatase are present in the soluble fraction. The triphosphoinositide phosphatase is specifically dependent upon Mg(2+) and is stable to storage with or without freezing. The triphosphoinositide phosphodiesterase requires Ca(2+) and is inactivated during storage. Both activities are maximal in the presence of cetyltrimethylammonium bromide and require protection or reactivation by GSH or dithiothreitol. Unlike similar mammalian enzymes the protozoal triphosphoinositide phosphatase does not hydrolyse diphosphoinositides. The two enzymes may be separated by (NH4)2SO4 fractionation and gel filtration on Sephadex G-200.
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PMID:Hydrolysis of triphosphoinositides by a soluble fraction of Crithidia fasciculata. 18 23

Previous studies from our laboratory have shown that ethylene, vinyl fluoride monomer (VFM), vinyl chloride monomer (VCM), and vinyl bromide monomer (VBM) are all acutely hepatotoxic in rats pretreated with polychlorinated biphenyl (PCB). The time course of hepatic injury development after exposure and several parameters, environmental and chemical, affecting this toxicity were evaluated in the work reported here. Liver injury, as measured by serum alanine-alpha-ketoglutarate transaminase (SAKT) or sorbitol dehydrogenase (SDH), develops progressively over a 24-hr period following a 4-hr inhalation exposure of PCB-pretreated rats to ethylene or VCM. Environmental temperature during exposure to VCM does not affect hepatotoxicity or mortality below 30.3 degrees C. At 33.8 degrees C, however, mortality and SAKT are dramatically increased. Overnight fasting, which depletes hepatic glutathione (GSH) of PCB-pretreated rats before exposure to ethylene or VCM, significantly increases the hepatotoxicity of these compounds as measured by SDH. The combined effects of fasting and of trichloropropane epoxide (TCPE), an inhibitor of epoxide hydrase (EH), were also examined. TCPE treatment of fasted PCB-pretreated rats immediately before exposure was synergistic in increasing the acute toxicity of ethylene and VCM. TCPE increased mortality in fed or fasted rats exposed to VFM, but there was no effect of fasting alone. Both fasting and TCPE increased the sensitivity of PCB-pretreated rats to VBM, but there was not a clearly synergistic effect of fasting plus TCPE. These data suggest that the acute toxicity of these compounds is mediated through epoxide intermediates.
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PMID:Acute hepatotoxicity of ethylene and halogenated ethylenes after PCB pretreatment. 41 16

The lactoperoxidase-catalyzed oxidation of glutathione (GSH) and thiocyanate (SCN-) was studied. Oxidation of SCN- was recorded by ultraviolet spectroscopy and by electron spin resonance (ESR). Consumption of GSH was measured by amperometric titration. One or two moles of GSH was oxidized per mole of H2O2 added, depending on the reaction conditions. Omission of SCN- prevented the oxidation of GSH. The oxidation of GSH required only catalytic amounts of SCN-, which was therefore recycled. Iodide (I-) could replace SCN-, while chloride or bromide were ineffective. The apparent Michaelis constant for SCN- was 17 microM. Oxidation of SCN- gave rise to two reactive intermediates, one stable and one unstable. The stable intermediate (-OSC. = N-(?)) decayed by a second-order reaction with a rate constant of 1.1 M-1 s-1. The decay of the unstable radical was very fast. The data (a) explain the short- and long-term antibacterial effects of lactoperoxidase-halide-H2O2 system, (b) point to possible deleterious effects due to glutathione depletion, (c) are of relevance for free radical diseases involving sulphur-centered free radicals, and (d) support previous observations on lipid peroxidation/halogenation in biological membranes, liposomes, and unsaturated fatty acids.
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PMID:Free radical generation and coupled thiol oxidation by lactoperoxidase/SCN-/H2O2. 132 2

Water-soluble and alkaline-soluble crude polysaccharides which were separated from the roots or leaves of Panax ginseng C. A. Meyer, were compared for their anti-ulcer activity. Of these four polysaccharide fractions, the water-soluble crude polysaccharide fraction (GL-2) from the leaves and the alkaline-soluble crude polysaccharide fraction (GRA-2) from the roots prevented HCl/ethanol-induced ulcerogenesis in mice potently. The most potent fraction, GL-2, was further fractionated into four polysaccharide fractions by precipitation with cethyltrimethylammonium bromide, and the weakly acidic polysaccharide fraction, GL-4, showed the most potent inhibition of gastric lesion formation. The activity of GL-4 decreased after treatment with periodate or digestion with endo-polygalacturonase, indicating that the carbohydrate moiety may contribute to the expression of the activity. GL-4 was further purified by anion-exchange chromatography and gel filtration, and the most active purified polysaccharide, GL-4IIb1III was obtained. GL-4IIb1III (average relative molecular mass, 16,000 d) had the nature of a pectic polysaccharide, and was composed mainly of galactose and galacturonic acid with small proportions of rhamnose, arabinose, mannose, glucose, and glucuronic acid. GL-4IIIb1III prevented HCl/ethanol-induced ulcerogenesis in mice dose dependently.
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PMID:Purification of an anti-ulcer polysaccharide from the leaves of Panax ginseng. 147 Jun 69

Glutathione (GSH) has been shown to modulate the cytotoxicity of a variety of chemotherapeutic agents. The effect of mitomycin C (MMC) treatment duration and the effect of GSH depletion on in vitro cytotoxicity against the human colon cancer cell line HT-29 was studied under aerobic conditions. Continuous-exposure experiments revealed that the cytotoxicity of 0.1 microM MMC, as measured by clonogenic cell survival, exhibited a shoulder until exposure time was at least 12 h, after which time exponential cytotoxicity was observed. Lowering GSH levels to less than 3% of control using buthionine sulfoximine (BSO) did not enhance cytotoxicity of MMC given for 1 h or continuously for less than 12 h. However, GSH depletion did enhance cytotoxicity of MMC given continuously for at least 12 h, with a dose-modifying factor at 1% survival of 1.4 for a 24-h treatment. GSH depletion under these conditions enhanced cytotoxicity of even minimally cytotoxic MMC concentrations (0.02 microM). Absolute levels of GSH-related enzymes, including glutathione-S-transferase, and the MMC-metabolizing enzyme DT-diaphorase did not change appreciably. A tetrazolium [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay was used to verify the results further and to determine the optimal sequence of BSO administration with a 24-h MMC treatment. BSO added simultaneously with MMC did not increase cytotoxicity, compared to MMC alone. BSO added and then removed prior to MMC was effective (dose-modifying factor at 50% survival = 1.3), but the greatest cytotoxicity was noted when BSO was present before and during MMC treatment (dose-modifying factor = 1.5). GSH depletion in another cell line (SW480) showed similar enhancement of 24-h MMC cytotoxicity. These studies show that aerobic cytotoxicity of MMC is improved by administration of the drug in continuous fashion for at least 12 h, as opposed to continuous administration for shorter periods or 1-h bolus administration. Cytotoxicity of continuous (at least 12-h) MMC treatment can be modestly enhanced by GSH depletion, which must precede MMC exposure in order to be effective.
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PMID:Effect of treatment duration and glutathione depletion on mitomycin C cytotoxicity in vitro. 151 28

Both metabolic and neurotransmitter changes have been implicated in the pathogenesis of monohalomethane neurotoxicity in rodents. This study in male and female F344 rats examined the effects of methyl bromide (MeBr) on regional brain glutathione-S-transferase (GST) activities and concentrations of glutathione (GSH), monoamines, and amino acid. Inhalation exposure to 150 ppm MeBr (6 hr/day x 5 days) yielded no histologic evidence of brain lesions but resulted in a number of biochemical changes. GSH depletion and GST inhibition were detected in the frontal cortex, caudate nucleus, hippocampus (examined for GSH only), brain stem, and cerebellum from animals of both sexes. Differences between sexes were detected for GSH depletion. Simultaneous treatment of rats with the inhibitor of monohalomethane toxicity, BW 755C (3-amino-1-[m-(trifluoromethyl)phenyl]-2-pyrazoline; 10 mg/kg bw ip, 1 hr pre- and 1 hr postexposure) completely protected against GST inhibition in all brain regions of both sexes. Partial protection by BW 755C against GSH depletion was observed in the cerebral cortex and in the cerebellum only. In males, MeBr exposure had no effect on the regional concentrations of the monoamines dopamine and serotonin and the amino acids glutamate, glutamine, taurine, and gamma-aminobutyric acid. Regional increases of brain aspartate and glycine levels were observed after exposure of males to MeBr but BW 755C had no effect on these changes induced by MeBr. Thus, of all the parameters studied, only GST, and in some brain areas GSH, correlated with inhibition of toxicity. It is concluded that, in contrast to the monoamines and the amino acids, GST and GSH are sensitive and potentially relevant indicators of MeBr neurotoxicity which could explain sex and regional differences in response to the monohalomethanes.
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PMID:Effect of methyl bromide on regional brain glutathione, glutathione-S-transferases, monoamines, and amino acids in F344 rats. 173 43

Glutathione transferases (GSTs) of a novel class, which it is proposed to term Theta, were purified from rat and human liver. Two, named GST 5-5 and GST 12-12, were obtained from the rat, and one, named GST theta, was from the human. Unlike other mammalian GSTs they lack activity towards 1-chloro-2,4-dinitrobenzene and are not retained by GSH affinity matrices. Only GST 5-5 retains full activity during purification, and its activities towards the substrates 1,2-epoxy-3-(p-nitrophenoxy)propane, p-nitrobenzyl chloride, p-nitrophenethyl bromide, cumene hydroperoxide, dichloromethane and DNA hydroperoxide are 185, 86, 67, 42, 11 and 0.03 mumol/min per mg of protein respectively. Earlier preparations of GST 5-5 or GST E were probably a mixture of GST 5-5 and GST 12-12, which was largely inactive, and may also have been contaminated by less than 1% with another GSH peroxidase of far greater activity. Partial analysis of primary structure shows that subunits 5, 12 and theta are related to each other, particularly at the N-terminus, where 25 of 27 residues are identical, but have little relationship to the Alpha, Mu and Pi classes of mammalian GSTs. They do, however, show some relatedness to subunit I of Drosophila melanogaster [Toung, Hsieh & Tu (1990) Proc. Natl. Acad. Sci. U.S.A. 87, 31-35] and the dichloromethane dehalogenase of Methylobacterium DM4 [La Roche & Leisinger (1990) J. Bacteriol, 172, 164-171].
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PMID:Theta, a new class of glutathione transferases purified from rat and man. 184 57

We have previously shown that the renal necrosis observed after 2-bromohydroquinone (2-BrHQ) administration to rats is probably caused by the formation of 2-Br-(diglutathion-S-yl)HQ (2-Br-[diGSyl]HQ), since injection of this conjugate caused severe proximal tubular necrosis. In the present study we report the in vivo metabolism and covalent binding of 2-[14C]-BrHQ in male Sprague-Dawley rats. The major urinary and biliary metabolite was a glucuronide conjugate. In addition, 2-Br-(di-GSyl)HQ, 2-Br-3-(GSyl)HQ, 2-Br-5-(GSyl)HQ, and 2-Br-6-(GSyl)HQ were all detected as urinary and biliary metabolites of 2-BrHQ. The in vivo covalent binding of 2-[14C]BrHQ to kidney, pancreas, seminal vesicles, intestine, bone marrow, and liver was 21.8, 1.5, 1.2, 4.4, 1.8, and 2.6 nmol/mg protein, respectively. gamma-Glutamyl transpeptidase (gamma-GT) activity measured in these tissues was 947, 159, 55, 31 and 5.5 U/mg. Liver gamma-GT activity was negligible (0.07 U/mg). Thus, maximum covalent binding and gamma-GT activity occurred in the kidney. Renal covalent binding and gamma-GT activity were positively correlated with nephrotoxicity. Pretreatment of rats with L(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazole-acetic acid (AT-125) inhibited renal gamma-GT, after 24 hr, by 76%, renal covalent binding by 73%, and 2-BrHQ-mediated nephrotoxicity, as assessed by elevations in blood urea nitrogen (BUN), by 70%. These alterations were accompanied by an increase in the urinary excretion of each of the GSH conjugates, an increase in the fecal excretion of total radioactivity, and a decrease in plasma radioactivity at 24 hr. The present data provide evidence that 2-BrHQ is metabolized in vivo to nephrotoxic GSH conjugates. In addition, AT-125 probably inhibits nephrotoxicity by decreasing the gamma-GT-mediated renal proximal tubule accumulation of the toxic metabolites, thereby facilitating their excretion into urine. Although AT-125 inhibited extrarenal gamma-GT activity by 34-77%, it had variable effects on extrarenal covalent binding. Whereas covalent binding to renal tissue is probably mediated by reactive metabolites of the isomeric 2-Br-(GSyl)HQ conjugates, binding to extrarenal tissue may be mediated by both the conjugates and by 2-bromohydroquinone per se.
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PMID:The in vivo disposition of 2-bromo-[14C]hydroquinone and the effect of gamma-glutamyl transpeptidase inhibition. 196 81

Administration of 2-bromo-(diglutathion-S-yl)hydroquinone (2-Br-[diGSyl]HQ) (10-30 mumol/kg; i.v.) to rats causes severe renal proximal tubular necrosis. gamma-Glutamyl transpeptidase (gamma-GT) catalyses the first step in the metabolism of glutathione (GSH) and its S-conjugates and the toxicity of 2-Br-(diGSyl)HQ can be emeliorated by inhibition of renal gamma-GT. Species differences in the specific activity of renal gamma-GT have been reported and we now describe the relationship between renal gamma-GT and species differences in susceptibility to 2-Br-(diGSyl)HQ nephrotoxicity. Although rats exhibited the highest specific activity of renal gamma-GT, and were the most sensitive species toward 2-Br-(diGSyl)HQ-mediated nephrotoxicity, renal gamma-GT activity did not correlate with susceptibility in the other species examined. Indeed, the guinea pig, which expressed the lowest activity of renal gamma-GT between the species (8% of the rat) was the only other rodent found to be responsive toward 2-Br-(diGSyl)HQ at the highest dose tested (200 mumol/kg; intracardiac). Thus, factors other than gamma-GT activity probably play an important role in modulating species susceptibility to 2-Br-(diGSyl)HQ nephrotoxicity. Although the reason(s) for the interspecies variation in response to 2-Br-(diGSyl)HQ are unclear at present, it seems possible that differences in both renal biochemistry, such as differences in the relative activities of cysteine conjugate N-acetyl transferase and deacetylase, and renal physiology, contribute to the observed results.
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PMID:Species differences in renal gamma-glutamyl transpeptidase activity do not correlate with susceptibility to 2-bromo-(diglutathion-S-yl)-hydroquinone nephrotoxicity. 198 38


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