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PubMed1995

Age-related changes in antioxidant enzymes, superoxide dismutase, catalase, glutathione peroxidase and glutathione in different regions of mouse brain.

It has been proposed that neurodegenerative processes of aging are associated with the generation of reactive oxygen species (ROS) during cellular metabolism. These reactive oxygen species are scavenged by antioxidant enzymes in biological systems. The present study was designed to determine the selective distribution of the antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase activity and reduced glutathione (GSH) levels in different regions of the C57BL/6N mouse brain and to determine if any alterations occurred with age. Catalase activity did not show any significant change except in cerebellum. Activity of superoxide dismutase was increased with age in all regions of the brain except in hippocampus of 2-yr-old mice. The glutathione peroxidase activity in the caudate nucleus increased in all regions of the brain, however, the activity did not change at one, six and 12 months. A significant increasing pattern of glutathione content was found in the cerebellum and brain stem with age. These data demonstrate that although the level of antioxidant enzymes varied in different regions of the brain, overall the enzyme activities tend to increase with age.

Aging↗

PubMedDate not supplied

Effect of ethanol on the microsomal glutathione S-transferase activity in glutathione-depleted rat liver.

Depletion of hepatic glutathione in male rats by starvation caused a significant increase in microsomal glutathione S-transferase activity, which was not affected by acute ethanol pretreatment. An additional depletion in fasted rats by diethylmaleate (0.5 g/kg) caused a further increase in the enzyme activity, but this increase was delayed in ethanol intoxicated rats. Although ethanol caused a small increase in hepatic microsomal lipid peroxidation in control animals, this effect of ethanol was not observed in diethylmaleate treated rats and thus was apparently not responsible for the delay in enzyme activation. It is suggested that the activation of microsomal glutathione S-transferase activity towards 1-chloro-2,4-dinitrobenzene in glutathione-depleted rat liver may be produced by changes in thiol/disulfid ratio and/or some reactive oxygen species.

Animals↗

PubMed1993

Evidence that the large loss of glutathione observed in ischemia/reperfusion of the small intestine is not due to oxidation to glutathione disulfide.

Reperfusion injury following ischemia is thought to be the consequence of reactive oxygen species possibly generated either by xanthine oxidase activity or by processes associated with neutrophil activation in the affected organ or tissue. The conversion of xanthine dehydrogenase to the oxidase as well as the interactions between endothelium and neutrophils in the margination and activation of the latter are all considered to be results of conditions resulting from the ischemic episode. Determination of the redox status of glutathione in an ischemic/reperfused organ is frequently employed as an indicator of oxidative stress created by the production of oxygen free radicals during the reperfusion period. In this procedure, the ratio of oxidized glutathione (GSSG) to total glutathione (GSH + GSSG) is utilized to demonstrate the proportion of glutathione oxidized during reperfusion. We determined this ratio in the rat small intestine during ischemia and reperfusion and found that while the ratio of GSSG/(GSH + GSSG) does increase, this increase was the result of GSH disappearance rather than an increase in GSSG, and that essentially all of this loss occurred during the ischemic episode. We demonstrated that no oxidation of GSH occurred that was attributable to reperfusion per se; nor was there an increase of GSSG during this reoxygenation period.

Animals↗

PubMed1996

Glutathione consumption and glutathione peroxidase inactivation in fibroblast cell lines by 4-hydroxy-2-nonenal.

Treatment of cultured fibroblasts, designated HA1 cells, with 4-hydroxy-2-nonenal (4HNE) in doses up to 50 nmol/10(6) cells for 3 h results in dose-dependent cytotoxicity measured by clonogenic cell survival with 50% cytotoxicity achieved at 32 nmol 4HNE/10(6) cells. 4HNE treatment also resulted in dose-dependent reduction of cellular glutathione (GSH) content and loss of glutathione peroxidase (GPx) activity at 4HNE doses greater than 15 nmol/10(6) cells. By comparison, a 95% oxygen-resistant variant of HA1 cells, designated O2R95 cells, and a hydrogen peroxide-resistant variant of HA1 cells, designated OC14 cells, were found resistant to 4HNE cytotoxicity requiring 54 nmol 4HNE/10(6) cells and 75 nmol 4HNE/10(6) cells, respectively, for 50% cytotoxicity. In O2R95 cells, dose-dependent decreases were seen in GSH levels and GPx activity. In OC14 cells, however, any reduction in cellular GSH levels required doses of 4HNE greater than 30 nmol/10(6) cells, and GPx activity remained unchanged. No changes were seen in glutathione-S-transferase activity in any of the cell lines at any dose tested. These data indicate a correlation between glutathione modification, in a manner that prevents its recycling, the ability to inactivate enzymes with active site selenocysteine residues and the cytotoxicity of alpha, beta-unsaturated aldehydes such as 4HNE.

Aldehydes↗

PubMed2006

Acetaldehyde does not inhibit glutathione peroxidase and glutathione reductase from mouse liver in vitro.

Acetaldehyde, the primary ethanol metabolite, has been implicated in the pathogenesis of alcoholic liver disease, but the mechanism involved is still under investigation. This study aims at the search for direct in vitro effects of different concentrations of acetaldehyde (30, 100 and 300microM) on the activities of glutathione reductase (GR), glutathione peroxidase (GPx) from liver supernatants, and the thiol-peroxidase activity of ebselen. They did not change after pre-incubation with acetaldehyde, which suggests that acetaldehyde does not have any direct effect. Nor were direct effects of acetaldehyde toward thiols, such as dithioerythritol and glutathione (GSH), observed either, even though GSH - measured as non-protein thiols from liver supernatants - were oxidized in the presence of acetaldehyde. In addition, acetaldehyde (up to 300microM) significantly oxidized GSH when incubated in the presence of commercially available gamma-glutamyltranspeptidase (GGT), but not in the presence of glutathione-S-transferase. The interaction between ebselen and GSH was also evaluated in an attempt to better understand the possible link between acetaldehyde and nucleophilic selenol groups. The formation and stability of ebselen intermediaries, produced in the chemical interaction between GSH and ebselen, were not affected by acetaldehyde either. Overall, the acetaldehyde oxidation of hepatic low-molecular thiols depends on mouse liver constituents and GGT is proposed as an important enzyme involved in this phenomenon. Thiol depletion, a phenomenon usually observed in the livers of alcoholic patients, can be related to GSH metabolism, and the involvement of GGT may reflect a molecular mechanism involved in thiol oxidation.

Acetaldehyde↗

PubMed2005

Effect of reduced glutathione treatment on selenosis, blood selenium concentration and glutathione peroxidase activity after repeated short-term selenium exposure in buffalo calves.

Effects of repeated feeding of selenium, when given alone or along with reduced glutathione, on whole blood selenium levels, selenosis and glutathione peroxidase activity, was studied in buffalo calves. After feeding 2.5 mg/kg of BW sodium selenite, good correlation was found between the onset of selenosis and whole blood selenium concentrations. Adverse effects appeared when the whole blood selenium concentrations increased above 2 microg/ml and mortality occurred when they exceeded 3.4 microg/ml. Reduced glutathione, given i.v. at 5 mg/kg of BW arrested the progress of selenosis and prevented mortality which was 100% in the sodium selenite supplemented group; also a reduced whole blood selenium concentration was noted. Whole blood selenium concentrations were a better and more sensitive indicator of selenium status than glutathione peroxidase activity alone.

Animals↗

PubMed1988

Identification of glutathione S-transferase as a substrate and glutathione as an inhibitor of in vitro calmodulin-stimulated protein methylation in rat liver cytosol.

This report describes the isolation of the major calmodulin-stimulated methyl acceptor protein of adult rat liver cytosol. This Mr 29,000 methyl acceptor protein (MeAP29) has been purified to apparent homogeneity using ammonium sulfate precipitation and chromatography on DEAE-cellulose, phosphocellulose, hydroxylapatite and Sephadex G-75. Affinity chromatography on glutathione-Sepharose and assays of enzyme activity indicate that MeAP29 is a member of the glutathione S-transferase family. We further show that glutathione can act as an inhibitor of calmodulin-stimulated in vitro methylation of MeAP29 and that MeAP29 methylation is enhanced in non-dialyzed liver cytosol from rats with lowered glutathione levels.

Animals↗

PubMed1998

Production of glutathione-coated microtitre plates for capturing recombinant glutathione S-transferase fusion proteins as antigens in immunoassays.

Glutathione S-transferase (GST) is commonly used as a fusion partner in producing recombinant proteins and this technology is increasingly being used to produce antigens for use in immunoassays to measure antibodies. To circumvent the requirement to purify such antigens before use, we developed a method for coupling glutathione to microtitre plates so that GST-containing recombinant proteins could be purified and immobilised in one step in a suitable state for immunoassays. This procedure involves covalent linkage (using the heterobifunctional cross-linker sulphosuccinimidyl 4-(p-maleimidophenyl)butyrate) of reduced glutathione through its sulphydryl group to lysine residues of haemoglobin previously immobilised on microtitre plates. Haemoglobin was superior over other proteins tested in giving the lowest non-specific binding; in this regard it was also important to limit the amount of cross-linker used to 0.1 mM. Using glutamic acid decarboxylase as a model antigen, the new affinity capture assay was at least as good as the two-step procedure involving direct adsorption to plates of previously purified antigen; it may have the additional advantage of preserving the antigen in a more native conformation than direct adsorption. The new assay also performed as well as an assay using anti-GST antibodies adsorbed onto plates; glutathione plates, unlike anti-GST plates, will only capture recombinant proteins containing functional GST--a significant point for some recombinant expression systems in which a large proportion of the protein product is insoluble because of incorrect folding.

Autoantibodies↗

PubMed1998

Cadmium-induced alterations of hepatic lipid peroxidation, glutathione S-transferase activity and reduced glutathione level and their possible correlation with chromosomal aberration in mice: a time course study.

Cadmium, a heavy metal, has been found to possess a potent toxic effect on liver and bone marrow. In the present study, attempts were made to understand whether or not any correlation existed between hepatic lipid peroxidation, glutathione S-transferase activity, reduced glutathione level and chromosome aberrations, micronucleus and mitotic index in bone marrow cells of Balb/C male mice. Cadmium chloride (2.5 mg/kg b.wt.), when administered subcutaneously for 7 alternate days, exerted duration-dependent toxic effects on hepatic biochemical and cytogenetic parameters of bone marrow. A shorter time interval (5 days) elicited no significant alteration in the case of biochemical parameters, but with the advancement of time (i.e. after 10 and 15 days) lipid peroxidation showed 102% (p < 0.001) elevation and after 15 days, glutathione S-transferase activity and reduced glutathione level decreased by 35%, (p < 0.001) and 32% (p < 0.001), respectively, from the control values with concomitant elevation of chromosomal aberrations (30%) and micronucleus (2.32%) but the mitotic index was inhibited by 1.26%. The results of our study, provided evidence of cadmium-induced duration-dependent depression of GSH-mediated GST-catalysed detoxication capacity of the host and that this was presumably related to the induction of chromosomal aberrations. The clastogenic efficacy of this heavy metal was thus evident from the study.

Animals↗

PubMed2000

Effects of chronic cold exposure on the activities of cytochrome c oxidase, glutathione peroxidase and glutathione reductase in rat tissues (Rattus norvegicus).

The effects of cold acclimation on the activity levels of cytochrome c oxidase, glutathione peroxidase and glutathione reductase in various tissues of the rat (Rattus norvegicus) were investigated. One group was individually housed at 4 +/- 1 degrees C and the other at 24 +/- 1 degrees C for 6 months. Chronic cold acclimation resulted in significantly (P < 0.05) increased cytochrome c oxidase activity levels in liver, kidney, heart, interscapular brown adipose tissue and gastrocnemius muscle. The activity of glutathione peroxidase was significantly (P < 0.05) elevated in liver, interscapular brown adipose tissue, lung and muscle, whereas glutathione reductase was only significantly (P < 0.05) elevated in interscapular brown adipose tissue as a result of chronic cold exposure. The results obtained are possibly indicative of a positive compensatory response against the increased production of oxygen derived radicals as a result of chronic cold exposure.

Acclimatization↗

PubMed2000

The role of reduced glutathione and glutathione reductase in the cytotoxicity of chromium (VI) in osteoblasts.

It is accepted that to exert cytotoxicity and carcinogenicity chromium VI has to be reduced inside cells. The role of reduced glutathione (GSH) and glutathione reductase in the intracellular reduction of Cr VI was investigated using an immortalized rat osteoblast cell line, FFC. Alkaline phosphatase activity was the index of cytotoxicity measured. To investigate the role of GSH in Cr VI toxicity, GSH levels in the cells were elevated by pretreatment with L-cysteine, and depleted using buthionine sulfoximine (BSO), an inhibitor of GSH synthesis. Intracellular GSH levels were not depleted during the metabolism of Cr VI. Depletion of GSH by BSO caused the cells to be more resistant to the toxicity of Cr VI, indicating that GSH is involved in reduction of the Cr VI. Inhibition of glutathione reductase by carmustine (BCNU) partially protected against the cytotoxicity of Cr VI irrespective of the intracellular GSH. The cytotoxic response was similar if cells were pretreated with BCNU plus L-cysteine, or with BCNU plus BSO, although the GSH levels were markedly different. The results indicate that glutathione reductase plays an important role in the intracellular reduction of Cr VI in osteoblasts.

Alkaline Phosphatase↗

PubMed1998

Macrophage glutathione content and glutathione peroxidase activity are inversely related to cell-mediated oxidation of LDL: in vitro and in vivo studies.

Macrophage-mediated oxidation of low-density lipoprotein (LDL) is thought to play a key role during early atherogenesis, and cellular oxygenases were shown to mediate this process. As macrophage antioxidants may also contribute to the extent of cell-mediated oxidation of LDL, we analyzed the role of cellular reduced glutathione (GSH) and glutathione peroxidase (GPx) in LDL oxidation. The present study examined the effect of the macrophage GSH-GPx status on the ability of the cells to oxidize LDL. Upon incubation of J-774 A.1 macrophages for 20 h at 37 degrees C with 50 microM of buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis, cellular GSH content and GPx activity were reduced by 89 and 50%, respectively, and this effect was associated with a twofold elevation in macrophage-mediated oxidation of LDL. The BSO-treated cells contained high levels of peroxides, and released 32% more superoxide anions than nontreated cells in response to their stimulation with LDL in the presence of copper ions. To increase macrophage GSH content and GPx activity we have used L-2-oxothiazolidine-4-carboxylic acid (OTC), which delivers cysteine residues to the cells for GSH synthesis, and also selenium, which activates GPx and increases cellular glutathione synthesis. GSH content and GPx activity in J-774 A.1 macrophages were increased by 80 and 50%, respectively, following cells incubation with 2 mM OTC for 20 h at 37 degrees C, and this was paralleled by a 47% inhibition in LDL oxidation by these cells. An inverse correlation was found between the extent of macrophage-mediated oxidation of LDL and cellular GSH content (r = .97), or GPx activity (r = .95). Upon incubation of J-774 A.1 macrophages with selenomethionine (10 ng/ml) for 1 week, cellular GSH content and GPx activity were increased by about twofold compared to control cells, and this effect was associated with a 30% reduction in cell-mediated oxidation of LDL. Dietary selenium supplementation (1 microg/d/mouse) to the atherosclerotic apolipoprotein E-deficient mice for a 6-month period, increased GSH content and GPx activity in the mice peritoneal macrophages by 36 and 30%, respectively, and this effect was associated with a 46% reduction in cell-mediated oxidation of LDL. Finally, the atherosclerotic lesion area in the aortas derived from these mice after selenium supplementation was found to be reduced by 30% compared to the lesion area found in nontreated mice. Our results demonstrate an inverse relationship between macrophage GSH content/GPx activity and cell-mediated oxidation of LDL. Intervention means to enhance the macrophage GSH-GPx status may thus contribute to attenuation of the atherosclerotic process.

Animals↗

PubMed2003

Selenium modifies glutathione peroxidase activity and glutathione concentration in mice exposed to ozone-provoked oxidative stress.

The aim of this study was to show the direct effect of selenium on glutathione peroxidase (GSH-Px) activity and GSH/GSSG concentrations in 3- and 6-month-old mice. An ozone-oxygen mixture was used to provoke an oxygen stress. To measure the Se-effect mice were gavaged with sodium selenite. GSH-Px activity and total glutathione concentrations were determined in serum and in the postnuclear fraction of liver and lungs. Additionally glutathione concentrations were determined in whole blood. Both ozone and selenium, administered separately, reduced GSH-Px activity in lungs of 6-month-old animals, while in young mice an opposite effect of Se was observed. Ozone administered jointly with Se did not influence GSH-Px activity in 6-month-old mice, while in young, 3-month-old mice, a stimulatory effect in lungs was observed. There were no significant changes in GSH-Px activity in the liver of 6-month-old mice, but the stimulatory effect occurred in young mice treated with Se and Se & ozone jointly. In young mice, ozone (also ozone with Se) augmented glutathione concentrations. The response to ozone and selenium strictly depended on age and the antagonism between selenium and ozone was observed only in a few cases.

Animals↗

PubMed1999

Identification of S-(n-butylcarbamoyl)glutathione, a reactive carbamoylating metabolite of tolbutamide in the rat, and evaluation of its inhibitory effects on glutathione reductase in vitro.

Tolbutamide (TOLB), a widely used hypoglycemic agent in the therapy of non-insulin-dependent diabetes mellitus, has been reported to be teratogenic and/or embryotoxic in several animal species and humans. It has been proposed that the teratogenic effects of TOLB are linked to drug-mediated depletion of glutathione (GSH) through inhibition of the enzyme glutathione reductase (GR), although the mechanism by which this inhibition occurs remains unknown. In the study presented here, rats were injected with TOLB (200 mg/kg ip), and bile was collected for analysis by liquid chromatography/tandem mass spectrometry (LC/MS/MS). This led to the identification of S-(n-butylcarbamoyl)glutathione (SBuG), a reactive GSH conjugate derived from n-butyl isocyanate, as a minor metabolite of TOLB in bile. Upon incubation of SBuG (0.25-1.0 mM) with GR from either yeast or bovine intestinal mucosa in the presence of NADPH (0.20 mM), enzyme activity was lost in a time- and concentration-dependent manner. No inhibition was observed when NADPH was omitted from incubations, or when the natural substrate for the enzyme, glutathione disulfide (GSSG, 0.05 mM), was added. TOLB itself did not inhibit GR over the concentration range of 0.8-2.0 mM. It is concluded that metabolic activation of TOLB in vivo leads to the generation of reactive intermediates (n-butyl isocyanate and SBuG) which carbamoylate and thereby inhibit GR. At critical periods of organogenesis, the resulting perturbation of GSH homeostasis in exposed tissues may play a key role in the teratogenic and/or embryotoxic effects of TOLB.

Animals↗

PubMed2004

S-Acetylglutathione normalizes intracellular glutathione content in cultured fibroblasts from patients with glutathione synthetase deficiency.

Glutathione synthetase deficiency is an autosomal recessive inherited metabolic defect in the gamma-glutamyl cycle. Decreased intracellular glutathione levels are one of the characteristic biochemical features. In this study we show that addition of S-acetylglutathione to the medium raised intracellular glutathione content in cultured fibroblasts from patients with glutathione synthetase deficiency. This has implications for the treatment of patients with this inborn error of metabolism.

Cells, Cultured↗

PubMed1983

The purification of the hepatic glutathione S-transferases of rainbow trout by glutathione affinity chromatography alters their isoelectric behaviour.

1. The basic glutathione S-transferases from rainbow-trout liver were more stable than the acidic ones. 2. The apparent pI values of these enzymes were lowered when they were eluted from a glutathione affinity column by reduced glutathione at pH 8.85. 3. The pI effect was not a function of the high pH alone, was diminished under conditions less favourable to glutathione oxidation, and did not occur when S-hexylglutathione affinity chromatography was used instead.

Animals↗

PubMed1983

Glutathione peroxidase (EC 1.11.1.9), glutathione-S-transferase (EC 2.5.1.13), superoxide dismutase (EC 1.15.1.1) and catalase (EC 1.11.1.6) activities in tissues of ducklings deprived of vitamin E and selenium.

Vitamin E and selenium deficiencies were produced in the Pekin duckling (Anser cinerens) and were characterized by the development of lesions after 14 d in gizzard, intestine, heart and skeletal muscle. The activities of glutathione peroxidase (EC 1.11.1.9), using hydrogen peroxide and cumene hydroperoxide as substrates, glutathione-S-transferase (EC 2.5.1.13), superoxide dismutase (EC 1.15.1.1) and catalase (EC 1.11.1.6) were measured in homogenate supernatant fractions of liver, heart, intestine, gizzard and skeletal muscle of deficient ducklings and of control birds given vitamin E or Se or both. Glutathione peroxidase activities were dramatically lower in tissues of Se-deficient ducklings, and this was unaffected by vitamin E. No adaptive changes were seen in the activity of the other enzymes, even after 21 d when the deficiency was severe. It appeared likely that the variability of the enzyme activities, other than glutathione peroxidase, in the different tissues studied might explain differences among the tissues in susceptibility to peroxidative damage.

Animals↗

PubMed1995

Effect of ovariectomy and sex hormone replacement on glutathione and glutathione-related enzymes in rat hepatocarcinogenesis.

The effects of ovariectomy and hormone replacement in control and carcinogen treated female rats were investigated by measuring whole blood and liver glutathione (WGSH, HGSH), glutathione S-transferase (GST), glutathione peroxidase (GPx), and glutathione reductase (GRx) and histological evaluation. Hepatocarcinogenesis was induced by diethylnitrosamine and 2-acetylaminofluorene. In control rats not receiving carcinogen, ovariectomy significantly increased the GST and GRx activities. Replacement with either estrogen or progesterone reduced the GST activities to below intact female values whereas replacement of both hormones together brought the GST activities to that of intact females. GRx activities were brought to intact female values by replacement with estrogen or progesterone, either singly or in combination. Neither ovariectomy nor sex hormone/s replacement influenced the levels of WGSH, HGSH and GPx activities. Carcinogen administration to intact rats increased all the parameters measured. Ovariectomized rats treated with carcinogen showed lower GPx and GRx activities at 2 mths. However, replacement with either progesterone or combined estrogen and progesterone increased GPx and GRx activities to original values. On the other hand GST and GPx activities in ovariectomized rats which had carcinogen treatment were lower than intact rats after 5 mths. Replacement with hormones either singly or both brought GST and GPx activities up to intact rat levels receiving carcinogen. The levels of WGSH, HGSH and GRx activities (5 mths) in carcinogen treated rats were not influenced by ovariectomy and/or hormone/s replacement. The results from this study suggested that ovariectomy reduced the severity of hepatocarcinogenesis which was restored by sex hormone/s replacement.

2-Acetylaminofluorene↗