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)

Concentrations of rhein and nitrofurantoin in the micromolar range induce Ca2+ release and the development of increased inner membrane permeability in liver mitochondria. Both compounds inhibit the mitochondrial glutathione reductase causing a depletion of GSH and an accumulation of GSSG in energized mitochondria. Under these conditions, the compounds also alter the oxidation state of pyridine nucleotides, NADH becoming oxidized while NADPH remains reduced. Using rhein or nitrofurantoin, together with t-butyl-hydroperoxide and beta-hydroxybutyrate, it is possible to selectively alter the NAD/NADH, the NADP/NADPH, and the GSSG/GSH ratios and to determine the effect of these different states on the ability of Ca2+ to produce a permeable inner membrane. No correlation between pyridine nucleotide ratios and sensitivity to Ca2+ was observed. Mitochondria are stable to Ca2+ when the GSH content is high, but become permeable when Ca2+ is present and GSH is converted to GSSG. It is proposed that the GSSG/GSH ratio, by controlling the reduction state of critical sulfhydryl groups, regulates lysophospholipid acyltransferase activity and, therefore, the ability of mitochondria to remain impermeable upon activation of the intramitochondrial Ca2+ requiring phospholipase A2.
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PMID:The role of glutathione in the retention of Ca2+ by liver mitochondria. 669 85

Native divicine , a pyrimidine aglycone strongly implicated in the pathogenesis of favism, undergoes rapid auto-oxidation according to a 1:1 stoichiometry with respect to the oxygen disappeared. In the presence of oxygen divicine re-oxidizes both NADPH and NADH, whereby a red-ox cycling is perpetuated between hydroquinonic and quinonic species of divicine itself. The oxygen-dependent interaction of divicine with GSH involves a 90% oxidation to GSSG and the parallel formation of two distinct adducts. Both adducts have been isolated by means of HPLC and characterized in their spectral properties. The one having maximum absorption at 305 nm is susceptible of reduction by glutathione reductase, while the adduct with maximum absorption at 320 nm is stable and is likely to represent a dead-end complex of divicine .
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PMID:The interaction of divicine with glutathione and pyridine nucleotides. 673 86

Acetaminophen (APAP) was given orally to 6 mature cats (3 male and 3 female) in single progressive doses of 20 (low), 60 (medium), or 120 (high) mg APAP/kg body weight, each 3 weeks apart. Methemoglobin (MHB), reduced blood glutathione (GSH) and APAP blood concentrations, and blood NADH methemoglobin reductase and NADPH glutathione reductase activities were measured periodically for 8 days after dosing. A statistically significant increase in MHB formation (21.7% and 45.5%, respectively) occurred following the medium and high doses. NADH methemoglobin reductase activity at the high dose decreased significantly. Red blood cell GSH concentrations decreased significantly during the first 24 h after the high APAP dose and returned to normal by 192 h. NADPH glutathione reductase activity decreased significantly following the high dose, but not after the lower APAP doses.
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PMID:The effect of acetaminophen on methemoglobin and blood glutathione parameters in the cat. 674 Jul 6

The metabolism and toxicity of formaldehyde (CH2O) in isolated rat hepatocytes was found to be dependent upon the intracellular concentration of glutathione (GSH). Using hepatocytes depleted of GSH by treatment with diethyl maleate (DEM), the rate of CH2O (5.0 mM) disappearance was significantly decreased. Formaldehyde decreased the concentration of GSH in hepatocytes, probably by the extrusion of the CH2O-GSH adduct, S-hydroxymethylglutathione. Formaldehyde toxicity was potentiated in cells pretreated with 1.0 mM DEM as measured by the loss of membrane integrity (NADH stimulation of lactate dehydrogenase (LDH) activity) and an increase in lipid peroxidation (formation of thiobarbituric acid-reactive compounds). This potentiation of toxicity was both CH2O concentration-dependent and time-dependent. There was an excellent correlation between the increase in lipid peroxidation and the decrease in cell viability. L-Methionine (1.0 mM) both protected the cells from toxicity caused by the combination of 8.0 mM CH2O and 1.0 mM DEM and increased the cellular GSH concentration. The antioxidants, ascorbate, butylated hydroxytoluene (BHT) and alpha-tocopherol (10, 25 and 125 microM), all exhibited dose-dependent protection against toxicity produced by 8.0 mM CH2O and 1.0 mM DEM. At toxic concentrations of CH2O (10.0-13.0 mM), administered by itself, lipid peroxidation did not increase concomitantly with the decrease in cell viability and the addition of antioxidants (125 microM) did not influence CH2O toxicity. These results suggest that CH2O toxicity in GSH-depleted hepatocytes may be mediated by free radicals as a result of the effect of CH2O on a critical cellular pool of GSH. However, cells with normal concentrations of GSH are damaged by CH2O by a different mechanism.
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PMID:Relationships between formaldehyde metabolism and toxicity and glutathione concentrations in isolated rat hepatocytes. 674 74

The role of various enzymes and biological molecules on the activation and deactivation of the metabolites of phenol was investigated in vitro. Phenol, the major metabolite of benzene, is metabolized to hydroquinone and catechol. Activation of these metabolites and deactivation of their oxidized forms was assessed by the amount of covalent binding to microsomal protein. [14C]Phenol and NADPH were incubated with hepatic microsomes isolated from phenobarbital-pretreated guinea pigs, and 2.33 nmoles of hydroquinone and 0.12 nmole of catechol were formed per minute per milligram of microsomal protein. Covalent binding of the metabolites to microsomal protein incubated with microsomes isolated from guinea pigs pretreated with phenobarbital was 252 pmoles bound/min/mg; with microsomes from untreated guinea pigs, covalent binding was 146 pmoles bound/min/mg. Covalent binding was inhibited greater than 90% with the addition of N-octylamine, ascorbate, or GSH. The addition of superoxide dismutase inhibited covalent binding with microsomes isolated from phenobarbital-pretreated guinea pigs 35% but did not inhibit it with microsomes isolated from untreated animals. Partially purified guinea pig hepatic DT-diaphorase [NAD(P)H (quinone acceptor) oxidoreductase, EC 1.6.99.2] inhibited covalent binding 70%. This effect was reversed in the presence of dicumarol, a specific inhibitor of DT-diaphorase. DT-diaphorase present in the 10(5) X g supernatant fraction was also active in inhibiting covalent binding but only after the removal of endogenous reduced glutathione. This effect could also be reversed by dicumarol. The addition of diaphorase (NADH:lipoamide oxidoreductase, EC 1.6.4.3) partially purified from Clostridium kluyveri inhibited covalent binding 86%. The addition of hydrogen peroxide and horseradish peroxidase (peroxidase, EC 1.11.17) or myeloperoxidase(s) increased covalent binding 30-fold and 6-fold, respectively. Ascorbate decreased this binding greater than 95%. These results indicate that hydroquinone, catechol, and phenol as well as their oxidized forms can be activated or deactivated by several of the above model systems. These systems may play a role in the myelotoxicity of benzene by modulating covalent binding.
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PMID:DT-diaphorase and peroxidase influence the covalent binding of the metabolites of phenol, the major metabolite of benzene. 674 27

A major biliary metabolite of the hepatocarcinogen, N,N-dimethyl-4-aminoazobenzene (DAB), in the rat was identified as N-(glutathion-S-methylene)-4-aminoazobenzene (GS-CH2-AB). This conjugate was prepared synthetically by a Mannich condensation of 4-aminoazobenzene (AB), formaldehyde (CH2O) and glutathione (GSH) and has been characterized by chemical analysis and by ultraviolet, visible and 13C-NMR spectroscopy. The same conjugate was also formed in vitro by incubating N-methyl-4-aminoazobenzene (MAB), NADPH, NADH and GSH with rat hepatic microsomes. Evidence is presented that GSH reacted with an intermediate resulting from a cytochrome P-450-dependent oxidation of the N-methyl substituent. This reactive intermediate is presumed to be either an N-methylol or a methimine derivative of AB. The significance of this detoxification mechanism is discussed. The presence of an additional major aminoazo-dye GSH conjugate is also noted.
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PMID:Formation of N-(glutathion-S-methylene)-4-aminoazobenzene following metabolic oxidation of the N-methyl group of the carcinogen, N-methyl-4-aminoazobenzene. 680 Jun 67

Malondialdehyde (MDA) formation in mouse liver homogenates was measured in the presence of various glutathione depletors (5 mmol/l). After a lag phase of 90 min, the MDA formation increased from 1.25 nmol/mg protein to 14.5 nmol/mg in the presence of diethyl maleate (DEM), to 10.5 with diethyl fumarate (DEF) and to 4 with cyclohexenon by 150 min. It remained at 1.25 nmol/mg with phorone and in the control. On the other hand, glutathione (GSH) dropped from 55 nmol/mg to 50 nmol/mg in the control to, less than 1 with DEM, to 46 with DEF, to 3 with cyclohexenon and to 7 with phorone. The data show that the potency to deplete GSH is not related to MDA production in this system. DEM stimulated in vitro ethane evolution in a concentration-dependent manner and was strongly inhibited by SKF 525A. From type I binding spectra to microsomal pigments the following spectroscopic binding constants were determined: 2.5 mmol/l for phorone, 1.2 mmol/l for cyclohexenon, 0.5 mmol/l for DEM and 0.3 mmol/l for DEF. In isolated mouse liver microsomes NADPH-cytochrome P-450 reductase and NADH-cytochrome b5 reductase activity were unaffected by the presence of DEM, whereas ethoxycoumarin dealkylation was inhibited. Following in vivo pretreatment, hepatic microsomal electron flow as determined in vitro was augmented in the presence of depleting as well as non-depleting agents, accompanied by a shift from O2- to H2O2 production. It is concluded that it is not the absence of GSH which causes lipid peroxidation after chemically-induced GSH depletion but rather the interaction of the chemicals with the microsomal monoxygenase system.
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PMID:Chemically-induced glutathione depletion and lipid peroxidation. 680 68

Hydrocortisone-induced rat liver ornithine decarboxylase appears quite stable in the soluble fraction of the homogenate incubated at 37 degrees C. In contrast, the incubation of the whole homogenate causes a rapid loss of activity. The ornithine decarboxylase-inactivating capacity appears mainly bound to microsomes. Lysosomes seem to play a role only after the microsome-induced inactivation. Different reducing agents (dithiothreitol, NADPH, NADH, GSH) are effective both in preventing and in reversing ornithine decarboxylase inactivation. NADPH is peculiar in that it can reactivate the enzyme at very low concentrations. Oxidized glutathione potentiates the inactivating effect of microsomes. On the basis of present results it is suggested that ornithine decarboxylase may be reversibly inactivated through microsome-catalyzed formation of mixed or enzyme-enzyme disulfides and that NADPH plays a crucial role in ornithine decarboxylase reactivation, probably by cytosolic reductase(s).
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PMID:Studies on the mechanisms of ornithine decarboxylase in vitro inactivation. 682 89

A possible metabolic linkage between hepatic thyroxine (T4) 5'-deiodination and the NADPH-glutathione (GSH) cycle was studied in rat liver. Supplementation of 1 mM NADPH to stocked liver homogenates in vitro produced 4 fold increase in 3, 5, 3'-triiodothyronine (T3) formation from T4, whereas the effect of 1 mM FMN, FDN, NAD, NADH, or GSH was relatively small. An exponential dose-response relation was obtained between NADPH and T3 generated. The dose-dependent increase in T3 formation on GSH was eliminated in the presence of 1 mM MADPH, and the additive effect of GSH to NADPH was not apparent in comparison with NADPH alone. Inhibition of T3 generation by graded doses of methylene blue was not affected by the presence of 5 mM GSH. Furthermore, metabolic changes in the hexose-monophosphate shunt were produced in male Wistar rats aged 5 w by treating them with fasting-refeeding (FF group), with the administration of insulin and glucose (IG group), with propylthiouracil (PTU group) and with T4 (T4 group). All these treatments significantly reduced hepatic T4 5'-deiodinase activity (P less than 0.01-0.001 vs control), while glucose-6-phosphate dehydrogenase (G6PD) and glutathione reductase (GSSG-R) activities were increased. Between generated T3 and G6PD or GSSG-R activity, an inverse correlation was noted (r = -0.802 and -0.933, P less than 0.001). No consistent relation was found between T4 5'-deiodinase activity and GSH or non-protein SH contents. The addition of 1 mM NADPH and GSH to the homogenates of FF, T4 and the control group stocked for 4 w at -20 degrees C, restored T4 5'-deiodinase activity from a level of 10% to 60% of the initial value, whereas the activity remained depressed in PTU (19%) and the IG group (37%). These results indicate that both GSH and NADPH are important cofactors of the T3 generating system, but NADPH is more rate-limiting and its effect appears to be rather direct, not mediated by GSH formation. It is possible that T4 5'-deiodinase may be one of the NADPH-dependent enzymes.
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PMID:On the role of NADPH and glutathione in the catalytic mechanism of hepatic thyroxine 5'-deiodination. 705 28

Fava beans contain high amounts (up to 6.7 g/100 g dry weight) vicine and convicine. Their active aglycones divicine and isouramil have equivalent metabolic effects. They rapidly oxidize GSH to GSSG in normal and G6PD-deficient red cells. No regeneration of GSH occurs in deficient cells. The stoichiometry of the divicine oxidation of GSH is 1:1. Ascorbic acid is quickly oxidized by isouramil in both normal and deficient cells but regenerates only in normal cells. Isouramil oxidizes NADH at a much lesser extent than NADPH. Glycolysis is activated at the glyceraldehyde 3-phosphate dehydrogenase step. Divicine strongly stimulates hexone monophosphate shunt only in normal red cells. Divicine alone or associated with ascorbic acid has almost no effect in deficient red cells. Malonyl dialdehyde production is slight and virtually the same in normal and deficient cells treated with 5 mM isouramil. Large polypeptide aggregates are formed after 12 and 24 hours incubation with 1 mM divicine in deficient cells only. Divicine (0.25 mM) markedly decreases the filterability of deficient cells. The results are consistent with a causal role of divicine/isouramil in the genesis of the hemolytic crisis occurring in G6PD-deficient subjects after fava bean ingestion.
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PMID:Effect of divicine and isouramil on red cell metabolism in normal and G6PD-deficient (Mediterranean variant) subjects. Possible role in the genesis of favism. 729 Dec 3


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