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)

L-buthionine-S,R-sulfoximine (BSO), a specific inhibitor of GSH biosynthesis, was administered four times daily to mouse pups on post-natal days 7 and 8, inducing initiation of opacification on day 9. The initial progression of the cataract (less than 24 hr) was divided into four stages: (1) developing floriform; (2) mature floriform; (3) degenerate floriform; and (4) amorphous translucent cataract. Following this, dense corticonuclear opacities developed within several days. Two-dimensional gel electrophoresis of water-soluble whole lens extracts indicated that the most rapid early cataractous changes, occurring mainly during stage 2, were loss of the two major components of the heavy beta-crystallin fraction, a 31-kDa basic polypeptide and an acidic component at 27 kDa, concomitant with the appearance of new species at 30 and 25 kDa. This was followed by more extensive modification of both alpha and beta-crystallins during stages 3 and 4 and the appearance of abnormal species at 26, 19 and 18 kDa, which were slightly more acidic than the major normal alpha A-crystallin polypeptide. The gamma-crystallin components, relatively unaffected at stage 4, were then lost rapidly as dense opacities ensued. By contrast with the water-soluble fraction, the normal day 9 urea-soluble fraction was deficient in gamma-crystallin polypeptides and enriched in anodic components whose relative electrophoretic mobilities were similar to those reported previously for phosphorylated bovine alpha A-crystallin and several cytoskeletal polypeptides. At stage 4 of the cataract, the modifications of normal alpha and beta-crystallin components in the urea-soluble fraction paralleled those in the water-soluble fraction, but the products seen were more numerous. In addition, the cytoskeletal proteins were no longer detectable. Substantial increases in lens Ca2+ that precede all of the above changes in lens polypeptide composition suggest that Ca(2+)-activated proteolysis may play a major role in development of BSO cataracts.
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PMID:Progressive modifications of mouse lens crystallins in cataracts induced by buthionine sulfoximine. 162 46

The objective of this study was to define the relationship between peroxyl radical-mediated cytotoxicity and lipid, protein and sulfhydryl oxidation using human erythrocytes as the target mammalian cell. We found that incubation of human erythrocytes with the peroxyl radical generator 2,2' azobis (2-amidinopropane) hydrochloride (AAPH) resulted in a time and dose-dependent increase in hemolysis such that at 50 mM AAPH maximum hemolysis was achieved at 120 min. Hemolysis was inhibited by hypoxia and by the addition of certain water soluble free radical scavengers such as 5-aminosalicylic acid (5-ASA), 4-ASA, N-acetyl-5-ASA and dimethyl thiourea. Peroxyl radical-mediated hemolysis did not appear to involve significant peroxidation of erythrocyte lipids nor did they enhance protein oxidation at times preceding hemolysis. Peroxyl radicals did however, significantly reduce by approximately 80% the intracellular levels of GSH and inhibit by approximately 90% erythrocyte Ca(2+)-Mg2+ ATPase activity at times preceding the hemolytic event. Our data as well as others suggest that extracellular oxidants promote the oxidation of intracellular compounds by interacting with certain redox active membrane components. Depletion of intracellular GSH stores using diamide did not result in hemolysis suggesting that oxidation of GSH alone does not promote hemolysis. Taken together, our data suggest that neither GSH oxidation, lipid peroxidation nor protein oxidation alone can account for peroxyl radical-mediated hemolysis. It remains to be determined whether free radical-mediated inactivation of Ca(2+)-Mg2+ ATPase is an important mechanism in this process.
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PMID:Peroxyl radical-mediated hemolysis: role of lipid, protein and sulfhydryl oxidation. 162 57

Chronic exposure of humans to toxic levels of fluoride in drinking water resulted in significant increase in blood GSH content with significant increase in the activities of erythrocyte glutathione metabolising enzymes viz., gamma-glutamylcysteine synthetase (E.C. 6.3.2.2), gamma-glutamyltranspeptidase (E.C. 2.3.2.2), GST (E.C. 2.5.1.18), GSH-Px (E.C. 1.11.1.9) and GR (E.C. 1.6.4.2). The data suggested a form of adaptation on the part of the erythrocytes to counteract the oxidative stress in red blood cells of fluorotic patients.
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PMID:Erythrocyte glutathione metabolism in human chronic fluoride toxicity. 167 68

Buthionine sulfoximine inhibits gamma-glutamylcysteine synthetase, the enzyme catalyzing the first reaction of glutathione (GSH) biosynthesis. GSH synthesis is blocked in animals or cultured cells exposed to buthionine sulfoximine, and GSH is substantially depleted in cells or tissues with moderate to high rates of GSH utilization. Studies reported to date have used DL-buthionine (SR)-sulfoximine or L-buthionine (SR)-sulfoximine, mixtures of four and two isomers, respectively. The present report describes a chiral solvent HPLC procedure for the analytical separation of the diastereomers of L-buthionine (SR)-sulfoximine and the separation of those isomers from the unresolved diastereomers of D-buthionine (SR)-sulfoximine. L-buthionine (R)-sulfoximine was isolated preparatively by repeated crystallization of L-buthionine (SR)-sulfoximine from water; L-buthionine (S)-sulfoximine was obtained by crystallization as the trifluoroacetate salt in ethanol/hexane mixtures. The absolute configuration, bond lengths and angles of L-buthionine (R)-sulfoximine were determined by X-ray diffraction. In vitro studies demonstrate that L-buthionine (R)-sulfoximine is a relatively weak inhibitor of rat kidney gamma-glutamylcysteine synthetase; binding is competitive with L-glutamate. L-buthionine (S)-sulfoximine is a tight-binding, mechanism-based inhibitor of the enzyme. Since L-buthionine sulfoximine is initially bound as a transition-state analogue, identification of the inhibitory diastereomer elucidates the steric relationships among ATP, glutamate, and cysteine within the active site. When administered to mice, L-buthionine (S)-sulfoximine (0.2 mmol/kg) was as effective as L-buthionine (SR)-sulfoximine (0.4 mmol/kg) in causing GSH depletion in liver, kidney, and pancreas. L-Buthionine (R)-sulfoximine (0.2 mmol/kg) did not cause significant GSH depletion in liver or pancreas. The L-(R)-diastereomer caused a modest GSH depletion in kidney that is tentatively attributed to interference with gamma-glutamylcyst(e)ine transport.
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PMID:Analytical and preparative separation of the diastereomers of L-buthionine (SR)-sulfoximine, a potent inhibitor of glutathione biosynthesis. 167 99

The accumulation and retention mechanisms of 99mTc-d, 1-hexamethylpropyleneamine oxime (99mTc-d, 1-HMPAO) were investigated in cultures of the dissociated rat cerebellum. Our experiments indicate a linear dependency of the uptake on incubation time and on the concentration of the radioligand. Upon chloroform extraction and distribution between the lipophilic and the hydrophilic phases, we located 69.1% of the retained radioactivity in the hydrophilic phase, 24.1% in a bound state and 6.8% in the lipophilic phase. The water-soluble, unbound radioactive contents of the cultures were identified as 99mTcO4- by HPLC analysis. Treatment of cultures with diethyl maleate (DEM) inhibited the accumulation of radioactivity along with a reduction of the GSH contents of the cultures. However, even in the absence of GSH, significant amounts of radioactivity were accumulated. DEM reduced the radioactive contents of cultures predominantly by diminishing the aqueous phase of the chloroform-extracted material. By contrast, the metabolic state, manipulated by treating the cultures with oligomycin B or 2,4-dinitrophenol, had no significant effect on the accumulation of radioactivity. Our experiments suggest two major mechanisms for the retention of radioactivity following the exposure of neuronal tissue to 99mTc-d, 1-HMPAO: Conversion of the lipophilic complex to the hydrophilic product, 99mTcO4-, and binding to non-diffusible cell components.
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PMID:Uptake mechanism of technetium-99m-d, 1-HMPAO in cell cultures of the dissociated postnatal rat cerebellum. 173 Sep 73

The effect of trolox C, a water soluble vitamin E analogue, propyl gallate and ascorbate on vanadate hepatotoxicity was investigated in vitro. In isolated perfused livers from fasted rats, sodium orthovanadate (2 mmol/l) led to toxic responses including reduction of oxygen consumption, release of cytosolic (glutamate-pyruvate-transaminase (GPT) and lactate dehydrogenase (LDH)) and mitochondrial (glutamate-dehydrogenase (GLDH)) enzymes, intracellular accumulation of calcium, a marked depletion of glutathione (GSH) and an enhanced formation and release of thiobarbituric acid- (TBA) reactive material. Trolox C and propyl gallate inhibited the release of GPT and LDH partially and that of GLDH totally, but had no influence on vanadate-induced calcium accumulation or on the reduction of oxygen consumption. Both agents suppressed vanadate-induced lipid peroxidation (LPO) and partially prevented GSH depletion. Ascorbate failed to provide any protection probably due to the interference of its pro-oxidant potential with its antioxidant activity. The protection, mainly of mitochondria, afforded by those agents which also inhibited LPO substantiates our previous findings that the pro-oxidant activity of vanadate is mainly responsible for its direct hepatotoxic actions [2]. Besides, reduction of organ perfusion rate due to vasoconstriction also contributes to vanadate toxicity, but oxidative stress is not involved in this indirect toxic activity.
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PMID:Effect of antioxidants on vanadate-induced toxicity towards isolated perfused rat livers. 176 11

This study was designed to investigate the role of lipid peroxidation in the pathogenesis of renal dysfunction in glutathione (GSH)-depleted rats. Renal function parameters and acid-base status were analyzed in diethylmaleate (DEM)-treated rats previously injected with vitamin E (Vit.E). Vit.E was effective in inhibiting the elevation in renal lipid peroxidation found in GSH-depleted rats. Vit.E also ameliorated the renal response to the metabolic acidosis without modification in lactate production induced by DEM administration. The increase in sodium and water urine excretion and the diminution of the urine to plasma osmolalities ratio were not reversed in these animals. These results lead us to conclude that lipid peroxidation is associated with distal acidification impairment observed with GSH-depletion, but it is not related to the sodium reabsorption alteration in the ascending loop of Henle.
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PMID:Role of lipid peroxidation on renal dysfunction associated with glutathione depletion. Effects of vitamin E. 176 13

S-(1,2-Dichlorovinyl)-L-cysteine (DCVC) sulfoxide, a putative metabolite of the toxic cysteine S-conjugate DCVC, was synthesized by the reaction of DCVC with H2O2 and characterized by fast atom bombardment mass spectrometry (FAB-MS) and proton nuclear magnetic resonance spectroscopy. DCVC sulfoxide was stable when kept at room temperature overnight in phosphate buffer (pH 6.8-7.8) or when heated in phosphate buffer (pH 7.2 or 7.6) or H2O (pH 3.5 or 10.5) for 20 min at 37 degrees C. However, in the presence of glutathione (GSH), DCVC sulfoxide was readily converted to S-[1-chloro-2-(S-glutathionyl)vinyl]-L-cysteine sulfoxide (I), a product formed by the Michael addition of GSH to DCVC sulfoxide followed by the loss of HCl. Evidence for the mechanism of this reaction was obtained by the finding that DCVC, which cannot act as a Michael acceptor, did not react with GSH under conditions similar to those used with DCVC sulfoxide. When the reaction of DCVC sulfoxide with GSH was carried out at room temperature and pH 7.4, formation of I was complete at 5 min, but when the reaction was carried out for 2 h at pH 6.0 or 4.4 at 37 degrees C, product formation was nearly 37 or 3% of that formed at pH 7.4, respectively; product formation did not increase when the reaction was carried out at pH 8.5. When DCVC sulfoxide (100 mg/kg) was administered to rats, hepatic and renal reduced nonprotein thiol concentrations were decreased at 1 h to 74 and 27% of that in control rats, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Reactivity of cysteine S-conjugate sulfoxides: formation of S-[1-chloro-2-(S-glutathionyl)vinyl]-L-cysteine sulfoxide by the reaction of S-(1,2-dichlorovinyl)-L-cysteine sulfoxide with glutathione. 180 49

A simple and sensitive spectrophotometric method suitable for the stability control of pharmaceutical dosage forms containing glutathione (gamma-glutamyl-cysteinyl-glycine), GSH, is described. Besides GSH, the method quantitatively determines its oxidation product, GSSG. The colour reactions of GSH and GSSG with ammonium tetrachloropalladate have been investigated and the optimum reaction conditions, spectral characteristics and composition of the yellow water-soluble complexes have been established. The assay results of pharmaceutical formulations showed good accuracy and precision over the concentration range of 5 x 10(-5)-6 x 10(-4) M GSH.
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PMID:Spectrophotometric determination of glutathione and of its oxidation product in pharmaceutical dosage forms. 182 70

The activities of tissue glutathione (reduced and oxidized) and glutathione-dependent enzymes such as glutathione S-transferase (GSH S-transferase), glutathione reductase (GSSG reductase) and glutathione peroxidase (GSH-Px) were determined for control and uremic rats. Acute renal failure (ARF) was produced by glycerol-water injection. Cytosolic and microsomal GSH S-transferase activity in the kidney was decreased by 38% and 15%, respectively. Hepatic microsomal GSH S-transferase was also decreased by 40% in uremic rats. GSH-Px activity was decreased by 51% in the cytosolic fraction and 33% in the microsomal fraction in the kidney, but was not affected in the liver and whole blood. GSSG reductase activity was also decreased by 48% in the cytosolic fraction in the kidney of uremic rats. In whole blood, however, GSSG reductase activity was increased by 12-fold (0.66 +/- 0.12 mumol NADPH oxidized/min/ml blood in the control; 8.03 +/- 3.29 mumol NADPH oxidized/min/ml blood in uremia). Although the total glutathione concentrations were not significantly affected, the GSSG/GSH ratio, which is an indication of oxidative stress, was significantly increased in the liver and whole blood of uremic rats. In addition to the decreases in hepatic and renal GSH S-transferase activities, which is important in drug disposition, ARF caused decreases in GSSG reductase and GSH-Px activity, which are essential for the protection against lipid peroxidation.
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PMID:Effects of glycerol-induced acute renal failure on tissue glutathione and glutathione-dependent enzymes in the rat. 187 Mar 54


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