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PubMed1985

Effect of glutathione depletion on the hepatotoxicity and covalent binding rat liver macromolecules of N-hydroxy-2-acetylaminofluorene.

Glutathione plays an important role in the protection of the liver against several hepatotoxins. The hepatocarcinogen N-hydroxy-2-acetylaminofluorene is converted in the rat in vivo to reactive metabolites that bind covalently to cellular macromolecules. These metabolites may also react with glutathione, resulting in the formation of glutathione conjugates and in the detoxification of reactive metabolites. The role of glutathione in detoxification was investigated by depletion of glutathione in the rat in vivo with diethyl maleate. When rats were pretreated with diethyl maleate, 45 min before the administration of N-hydroxy-2-acetylaminofluorene, excretion of 2-acetylaminofluorene:glutathione conjugates in bile was decreased by 60% as compared to controls. However, total covalent binding to rat liver protein was not increased, and total binding to DNA was even decreased (p less than 0.1), apparently at the expense of the acetylated carcinogen-DNA adducts. Formation of deacetylated, 2-aminofluorene adducts to DNA was not affected by diethyl maleate. Pretreatment with diethyl maleate had no major effect on the acute hepatotoxic effects of N-hydroxy-2-acetylaminofluorene. The results indicate that glutathione does not play a vital role in the detoxification of reactive metabolites generated from the carcinogen N-hydroxy-2-acetylaminofluorene, since glutathione is not very effective in competing with macromolecules for trapping of reactive metabolites of N-hydroxy-2-acetylaminofluorene. Thus, 1 mM glutathione did not decrease the covalent binding of 2-acetylaminofluorene-N-sulfate (one of the main reactive metabolites that is formed in vivo) to DNA in vitro, while 10 mM glutathione decreased the covalent binding to RNA by only 20% and to DNA by only 40%.

2-Acetylaminofluorene↗

PubMed1986

Covalent binding of 1,2-dihaloalkanes to DNA and stability of the major DNA adduct, S-[2-(N7-guanyl)ethyl]glutathione.

The major DNA adduct formed from the carcinogen ethylene dibromide (1,2-dibromoethane, EDB) is S-[2-(N7-guanyl)ethyl]glutathione, resulting from the reaction of guanyl residues with the half-mustard S-(2-bromoethyl)glutathione, which is generated by glutathione S-transferase-catalyzed conjugation of EDB with glutathione. The half-life of the alkylating species [putative S-(2-bromoethyl)glutathione or the derived episulfonium ion] was estimated to be less than 10 s. However, the stability was enough for approximately half of the alkylating metabolites to leave isolated rat hepatocytes before reacting with nucleic acids. Treatment of isolated rat hepatocytes with diethylmaleate decreased covalent binding of EDB to DNA, but treatment with 1-phenylimidazole did not, consistent with the view that conjugative metabolism is of greater importance than oxidation with regard to DNA binding. When EDB was administered to rats in vivo, only one major adduct, S-[2-(N7-guanyl)ethyl]glutathione, was formed in liver or kidney. S-[2-(N7-Guanyl)ethyl]glutathione was found in liver and kidney DNA of rats treated with 1,2-dichloroethane, but other adducts were also present. The gamma-glutamyl transpeptidase inhibitor AT-125 [L-(alpha-(5S)-alpha-amino-S-chloro-4,5-dihydro-5-isoxazoleacetic acid] did not affect the level of EDB bound to DNA by glutathione-fortified rat kidney homogenates or bound to liver or kidney DNA in vivo. The in vitro half-life of S-[2-(N7-guanyl)ethyl]glutathione in calf thymus DNA was 150 h; the half-life of the adduct in rat liver, kidney, stomach, and lung was between 70 and 100 h. Isolated S-[2-(N7-guanyl)ethyl]glutathione did not react with DNA to form new adducts. These results provide a further basis for understanding the carcinogenic action of 1,2-dihaloethanes.

Animals↗

PubMedDate not supplied

Toxicity of paracetamol in human hepatocytes. Comparison of the protective effects of sulfhydryl compounds acting as glutathione precursors.

The hepatotoxicity of N-acetyl-p-aminophenol (acetaminophen, paracetamol) was investigated in hepatocyte cultures obtained from eight different human liver biopsies. Incubation of hepatocytes with paracetamol resulted in a dose- and time-dependent glutathione depletion. Glutathione decreased linearly for 8 h, reaching a minimum after 12 h of exposure. Cytotoxicity, assessed as loss of cellular protein from plates, was observed only when glutathione decreased below 20% for more than 12 h. However, in one donor, cytotoxicity was observed with even a moderate glutathione decrease. Prestimulation of hepatocytes with 1 mM phenobarbital or 2 microM methylcholanthrene for 48 h did not lead to a significant increase of paracetamol toxicity, although the glutathione levels in 3-methylcholanthrene-treated cells were somewhat lower. Several metabolic precursors were examined in vitro for their ability to increase intracellular glutathione and the results showed the following sequence: N-acetylcysteine greater than thioproline greater than cysteine greater than 2-oxo-4-thiazolidine carboxylic acid greater than methionine. However, only N-acetylcysteine, thioproline, and cysteine substantially increased glutathione levels when 1 mM paracetamol was present in the incubation medium and thus prevented its toxicity. N-acetylcysteine elevated glutathione even after 24 h of preexposure to paracetamol. The fact that cell damage did not correlate with glutathione levels in all human cultures suggests that glutathione depletion may not be the only determinant of paracetamol toxicity in human hepatocytes.

Acetaminophen↗

PubMed1986

Modification of human hemoglobin by glutathione. III. Perturbations of hemoglobin conformation analyzed by computer modeling.

The perturbations of the conformation of human deoxyhemoglobin induced by the covalent attachment of glutathione at cysteine beta 93 have been investigated by computer simulation in conjunction with molecular graphics. In the first phase of the analysis, a systematic search was carried out of the conformational space of glutathione attached to deoxyhemoglobin. In this search, the conformation of the hemoglobin molecule was held constant, while the relative energies of a series of 186,624 glutathione conformations involving systematic variation of six dihedral angels were calculated. From this search, the most favorable conformation was selected as the starting conformation for energy minimization of the glutathionyl hemoglobin molecule as a function of all Cartesian coordinates. In order to provide a reference state, an independent minimization by the same procedures was carried out for deoxyhemoglobin in the absence of glutathione. Comparison of the minimized structures with and without glutathione attached revealed a number of significant differences. The most conspicuous difference in the protein moiety concerned the salt bridge between aspartate beta 94 and histidine beta 146 which is destabilized upon minimization of the glutathionyl-hemoglobin complex due to interactions of the aspartate residue with the glycyl NH group of glutathione. Other observed differences in the minimized structures are located at the alpha 1-beta 2 interface and include displacement of the carboxyl group of aspartate beta 99. In the minimized complex, the glutathione portion assumes a quasi-cyclic conformation stabilized through interactions between the free (gamma-glutamyl) amino and (glycyl) carboxyl ends of the tripeptide and between this carboxyl end and the epsilon amino group of lysine alpha 40. In a parallel conformational study of glutathione alone, a similar structure was found as the lowest energy form. These quasi-cyclic conformations contrast with the extended structures reported by Wright (Wright, W.B. (1955) Acta Crystallogr. 11, 632-642) for crystals of glutathione where interactions between molecules play a major role. The conclusions of our analysis are in agreement with the experimental investigations reported in the two preceding papers and permit, moreover, a coherent interpretation of the observed functional and structural changes in deoxyhemoglobin induced by glutathione.

Binding Sites↗

PubMed1986

Horseradish peroxidase-catalyzed oxidation of acetaminophen to intermediates that form polymers or conjugate with glutathione.

Horseradish peroxidase catalyzed the polymerization of acetaminophen. Addition of reduced glutathione (GSH) to reaction mixtures resulted in decreased polymerization and formation of minor amounts of GSH-acetaminophen conjugates. The conjugates were identified as 3-(glutathion-S-yl)acetaminophen and 3-(glutathion-S-yl)diacetaminophen. Horseradish peroxidase also catalyzed polymerization of synthetic 3-(glutathion-S-yl)acetaminophen to a dimer conjugate. In contrast to acetaminophen, 3-(glutathion-S-yl)acetaminophen oxidation was slowly catalyzed by horseradish peroxidase. However, in reaction mixtures containing equimolar concentrations of acetaminophen and synthetic 3-(glutathion-S-yl)acetaminophen, the formation of 3-(glutathion-S-yl)diacetaminophen and 3-(diglutathion-S-yl)diacetaminophen was rapid and accounted for approximately 95% of the products, whereas acetaminophen polymers accounted for only 5% of the products. These findings suggest that horseradish peroxidase catalyzed the one-electron oxidation of acetaminophen to N-acetyl-p-benzosemiquinone imine which preferentially polymerized rather than reacted with GSH. N-Acetyl-p-benzosemiquinone imine may also oxidize 3-(glutathion-S-yl)acetaminophen to form acetaminophen and 3-(glutathion-S-yl)-N-acetyl-p-benzosemiquinone imine. The data indicate that once this conjugate radical is formed it reacts with either N-acetyl-p-benzosemiquinone minine or 3-(glutathion-S-yl)-N-acetyl-p-benzosemiquinone imine via a radical termination mechanism.

Acetaminophen↗

PubMed1985

Piglet blood glutathione peroxidase levels and preweaning mortality.

The blood glutathione peroxidase levels of one day old piglets from 22 litters were examined. Body weight and piglet survival were monitored in order to assess the relationship between these two factors and blood glutathione peroxidase activity. The mean blood glutathione peroxidase level of one day old piglets (65 mu/gHb) was significantly lower (p0.001) than the mean level (85 mu/gHb) at weaning. The mean blood glutathione peroxidase activity of one day old piglets was not related to the size of the litter, but was related (p less than 0.1) to the mean litter blood glutathione peroxidase level at weaning time. Piglet blood glutathione peroxidase was not related to piglet body weight. The blood glutathione peroxidase level of the sows at one-day post-farrowing was not related to the mean blood glutathione peroxidase activity of their litters at one day of age but was correlated (p less than 0.1) with the mean blood glutathione peroxidase levels of their litters at weaning. Piglet viability was shown to be strongly correlated (p less than 0.001) with body weight at one day of age. The blood glutathione peroxidase level of one day old piglets was weakly associated (p less than 0.1) with piglet survival. Further work is required to clarify this latter observation, which suggests that selenium supplementation to newborn piglets may be beneficial regardless of the dams nutritional status.

Animals↗

PubMed1984

Extracellular metabolism of glutathione accounts for its disappearance from the basolateral circulation of the kidney.

Glutathione labeled in each of its amino acid residues, the corresponding free amino acids, and gamma-glutamyl-amino acids were used to evaluate their renal basolateral transport and metabolism at physiological levels of glutathione. Recovery of label in the venous outflow was compared to that of co-administered inulin after a single-pass in vivo infusion of rat kidney. Metabolites of glutathione and of its constituent amino acids were determined. No net basolateral transport of glutathione was detected; instead there was extensive breakdown of glutathione by the actions of basolateral gamma-glutamyl transpeptidase and dipeptidase. Glutamate and 5-oxoproline showed net basolateral uptake. Recoveries of 35S greater than those of inulin were found after perfusion of [35S]cysteine and [35S]glutathione suggesting rapid net tubular reabsorption of cyst(e)ine. Recovery of label from perfused [U-14C]glycine was equivalent to that of inulin consistent with little or no net flux. Co-administration of large amounts of unlabeled metabolites together with the labeled glutathiones led to label recoveries closer to those of inulin, consistent with competitive inhibition of labeled metabolite transport. Treatment of rats with an inhibitor of gamma-glutamyl transpeptidase decreased basolateral glutathione metabolism and thus indirectly decreased transport of labeled metabolites. No net basolateral transport of gamma-glutamyl-amino acids was detected. Significant amounts of label perfused as [Glu-U-14C]glutathione appeared in the gamma-glutamyl-amino acid fraction of the renal venous outflows, providing direct evidence that glutathione is used in vivo for the formation of gamma-glutamyl-amino acids.

Animals↗

PubMed1978

Glutathione in rabbit corneal endothelia: the effects of selected perfusion fluids.

Although the ameliorating effect of glutathione on corneal deturgescence is known, its chemical mechanism is not understood. An endeavor toward the latter was made by perfusing freshly excised rabbit corneas with selected perfusion fluids, measuring corneal thickness, and assaying the endothelial cells for reduced and oxidized glutathione after 2 and 5 hr of perfusion. Ringer's solution, containing either lactate or bicarbonate, caused significant decreases in both forms of glutathione after perfusion. The corneas increased in thickness considerably during these periods. When 5 mM glucose was added to bicarbonate-Ringer's solution, the corneas swelled about half as much as before. However, glutathione levels were as depressed as with simple Ringer's fluid. Adenosine (0.5 mM) in the presence of glucose (bicarbonate-Ringer's) caused a further swelling decrease so that the corneas were maintained at near normal thickness. The levels of glutathione were 84% of control values compared to 35% to 45% for Ringer's solutions (+/- glucose). The addition of glutathione to glucose (bicarbonate-Ringer's) caused intracellular glutathione levels to be higher than control values while allowing minimal tissue swelling. Glutathione in combination with adenosine, glucose, and bicarbonate produced the highest intracellular glutathione levels and a slight corneal deswelling. After oxidation of intracellular glutathione with t-butyl hydroperoxide in glucose (bicarbonate-Ringer's), endothelial cells were destroyed within 1 hr. The oxidant, however, may have had a direct effect upon the endothelial cell membranes.

Adenosine↗

PubMed1984

NMR and computer modeling studies of the conformations of glutathione derivatives at the active site of glyoxalase I.

The conformations of four derivatives of glutathione bound at the active site of the metalloenzyme glyoxalase I have been determined by NMR measurements and by computer model building using a distance geometry approach. Paramagnetic effects of Mn2+-glyoxalase I on the longitudinal relaxation rates of the carbon-bound protons of the substrate analog S-(acetonyl)-glutathione at three frequencies, the hydrophobic competitive inhibitor S-(propyl)glutathione at four frequencies, and the charged competitive inhibitor S-(carboxymethyl)glutathione at a single frequency were used to calculate Mn2+ to proton distances in each complex. These and previously determined distances from Mn2+ to the protons and 13C-enriched carbon atoms of the product S-(D-lactoyl)glutathione were used in a distance geometry program to compute the conformations of each enzyme-bound derivative which best fit the measured distances and other known constraints such as bond lengths, van der Waals radii, planar and trans-peptide bonds, and thioester linkages. The distance geometry program also provided a measure of the uniqueness of the conformations consistent with the experimental data. Extended Y-shaped conformations were detected for each of the bound glutathione derivatives, similar to the x-ray structure and the theoretically calculated conformation of glutathione itself, suggesting this to be a low energy form. Acceptable conformations of each enzyme-bound derivative fell into two classes with the metal either above or below the mean plane through the glutathione compound. The conformational uncertainty within each class was relatively small, ranging from deviations of 0.9-1.9 A in the average positions of each of the atoms. A small but significant difference in the conformation of the substrate analog as compared to the product was detected in the position of the reaction center carbon directly bonded to the glutathione sulfur atom. Unlike the second-sphere metal complexes formed by the bound substrate analog, the product, or the hydrophobic competitive inhibitor, the charged competitive inhibitor S-(carboxymethyl)glutathione binds farther from the metal, in the third coordination sphere.

Binding Sites↗

PubMed1994

The effect of L-buthionine-[S,R]-sulfoximine on the pancreas in mice. A model of weakening glutathione-based defense mechanisms.

L-Buthionine-[S,R]-Sulfoximine (BSO) decreases glutathione levels in various organs by inhibition of gamma-glutamylcysteine synthetase. We have examined the levels of total glutathione and oxidized glutathione in the pancreas of mice, as well as serum amylase and pancreatic histology, after BSO administration in two different ways. The injection of a single dose of BSO (5 mmol/kg body wt) decreased total glutathione to 10% of the control value. A similar depletion was observed after 24 h of oral administration of a 10 mM BSO solution, without changes in the levels of oxidized glutathione. BSO-induced pancreatic glutathione depletion--even if maintained for up to 14 d--did not cause morphological alterations of the pancreas or hyperamylasemia. Thus pancreatic glutathione depletion in itself does not lead to pancreatitis, although during development of experimental acute pancreatitis, glutathione depletion has been described. BSO might be used in animal models to weaken the glutathione-based acinar defense mechanisms against oxidant stress or to alter other physiologic processes in which glutathione is involved.

Acute Disease↗

PubMed1995

Increased levels of oxidized glutathione in CD4+ lymphocytes associated with disturbed intracellular redox balance in human immunodeficiency virus type 1 infection.

We investigated the intracellular glutathione redox status in isolated lymphocyte subpopulations and monocytes in patients with human immunodeficiency virus type 1 (HIV-1) infection and in healthy controls. CD4+ lymphocytes from HIV-1-infected patients were primarily characterized by a substantial increase in oxidized glutathione levels and a considerable decrease in the ratio of reduced to total glutathione, in most cases below 0.5 in patients with symptomatic HIV-1 infection, rather than decreased levels of reduced glutathione. The increase in oxidized glutathione was strongly correlated with low numbers of CD4+ lymphocytes in peripheral blood and impaired stimulated interleukin-2 production and proliferation in peripheral blood mononuclear cells, which is compatible with an immunopathogenic role for these redox disturbances. The HIV-1-infected patients with the most advanced clinical and immunologic disease were also characterized by an increase in levels of reduced glutathione in monocytes, suggesting that the glutathione redox cycle may be differentially regulated in CD4+ lymphocytes and monocytes. We could not confirm previous reports suggesting cysteine deficiency as a major cause of disturbed glutathione homeostasis during HIV-1 infection. The demonstrated glutathione abnormalities were correlated with raised serum levels of tumor necrosis factor alpha. These findings suggest that a therapeutical approach, which can restore the glutathione redox dysbalance in CD4+ lymphocytes and decrease the inflammatory stress, may be worthwhile exploring in HIV-1 infection.

CD4-Positive T-Lymphocytes↗

PubMed1996

Glutathione regulates 3,3',4,4'-tetrachlorobiphenyl induced cytochrome P450 metabolism: evidence for a cross-talk between the two major detoxication pathways.

The cytochrome P450 and the glutathione systems are two major pathways of xenobiotic metabolism. We tested the effect of hepatic glutathione content on P450 CYP1A1/2 induction by 3,3',4,4'-tetrachlorobiphenyl in rainbow trout (Oncorhynchus mykiss). Hepatic glutathione status of tetrachlorobiphenyl injected fish could be successfully manipulated by injecting (i.p.) glutathione or L-buthionine-[S,R]-sulfoximine to arrest glutathione synthesis. Tetrachlorobiphenyl injection resulted in a 17-fold increase in CYP1A catalytic (ethoxyresorufin O-deethylase [EROD]) activity. This effect was further potentiated by 2.7-fold in fish in which hepatic glutathione content was elevated by 3.6-fold. The induction of EROD activity by tetrachlorobiphenyl was 7-fold lower in glutathione deficient (78%) liver. Hepatic glutathione deficiency also downregulated tetrachlorobiphenyl-induced CYP1A gene expression as indicated by lower CYP1A RNA levels. Elevated hepatic glutathione did not influence tetrachlorobiphenyl-induced CYP1A RNA level, but enhanced CYP1A protein expression. These enzyme activity, RNA and protein expression data present compelling evidence suggesting the involvement of tissue glutathione in the regulation of tetrachlorobiphenyl-induced cytochrome P450 dependent metabolism.

Animals↗

PubMed1998

Utilization of cysteine and cysteine precursors for the synthesis of glutathione in astroglial cultures: preference for cystine.

The ability of astroglia-rich primary cultures derived from the brains of neonatal rats to take up and metabolize various sulfur containing compounds to cysteine was investigated using the content of intracellular glutathione as an indicator. Astroglial cells were partially depleted of glutathione by starvation for 24 h. Subsequent feeding for 4 h with glucose, glycine, and glutamate resulted in a restoration of the glutathione level, if cysteine was present. Substitution of cysteine by cystine during resynthesis of glutathione led to a glutathione content which exceeded that of cysteine-refed cells by 41%. Half-maximal content of glutathione was found at a concentration of about 12 microM cysteine and a maximal content at a concentration of at least 50 microM cysteine. In contrast, no plateau in the glutathione level was reached with increasing concentrations of cystine. The cystine effect could not be due to a contamination, since it was abolished after reduction of cystine by dithiothreitol. Since the cystine effect was not affected by inhibiting gamma-glutamyl transpeptidase, a promotion of cystine uptake by formation of gamma-glutamylcystine can also be excluded. Of the potential cysteine precursors tested, N-acetylcysteine was able to replace cysteine half-maximally at a concentration of 1 mM and fully at 5 mM. Feeding 2-oxothiazolidine-4-carboxylic acid at a concentration of 5 mM resulted in 64% of the glutathione level found in the presence of cysteine. A half-maximal glutathione content was attained at 50 microM 2-oxothiazolidine-4-carboxylic acid. While cystathionine could partially replace cysteine, methionine and homocysteine were not at all able to substitute for cysteine. These results demonstrate that astroglial cells prefer cystine from cysteine for glutathione synthesis and express uptake systems for N-acetylcysteine, 2-oxothiazolidine-4-carboxylic acid, and cystathionine, as well as the enzymes N-deacetylase, 5-oxoprolinase, and cystathionine gamma-lyase.

Animals↗

PubMed1997

Free radicals and not acetaldehyde influence the circulating levels of glutathione after acute or chronic alcohol abuse: in vivo and in vitro studies.

BACKGROUND: The oxidation of ethanol and acetaldehyde enhances the production of various free radicals involved in membrane lipoperoxidation, and decreases glutathione levels. AIMS: We evaluated the effects of acute and chronic ethanol use in vivo, with or without the administration of S-adenosyl-methionine (SAME, 2 g I.v.), and the effects of ethanol and acetaldehyde in vitro, on the erythrocyte levels of malonyldialdehyde and glutathione, and of its principal synthesizing enzymes, gamma-glutamyl-cysteine-synthetase and glutathione-synthetase. METHODS: Twelve healthy volunteers (age range 26-44 years, median 32 years) and 20 chronic alcohol abusers without liver disease (age range 26-57 years, median 44 years) were studied. Malonyldialdehyde was evaluated by thiobarbituric acid; glutathione and its enzymes by high performance liquid chromatography using a fluorescent detector. RESULTS: In the healthy subjects, an acute load of ethanol induced a significant decrease in plasma levels of glutathione, which was inhibited by the infusion of S-adenosyl-methionine. In the erythrocytes of alcoholic patients, glutathione and glutathione-synthetase were decreased while malonyldialdehyde was increased. In vitro, acetaldehyde did not affect either the glutathione or the glutathione-related enzyme levels. CONCLUSIONS: Our data suggest that the alterations in glutathione metabolism in the erythrocytes of alcoholics may be due principally to the production of free radicals, as supported by the high levels of malonyldialdehyde observed.

Acetaldehyde↗

PubMed1998

Maturation-dependent vulnerability of oligodendrocytes to oxidative stress-induced death caused by glutathione depletion.

Death of oligodendrocyte (OL) precursors can be triggered in vitro by cystine deprivation, a form of oxidative stress that involves depletion of intracellular glutathione. We report here that OLs demonstrate maturation-dependent differences in survival when subjected to free radical-mediated injury induced by glutathione depletion. Using immunopanning to isolate rat preoligodendrocytes (preOLs), we generated highly enriched populations of preOLs and mature OLs under chemically defined conditions. Cystine deprivation caused a similar decrease in glutathione levels in OLs at both stages. However, preOLs were completely killed by cystine deprivation, whereas mature OLs remained viable. Although the glutathione-depleting agents buthionine sulfoximine and diethylmaleate were more potent in depleting glutathione in mature OLs, both agents were significantly more toxic to preOLs. Glutathione depletion markedly increased intracellular free radical generation in preOLs, but not in mature OLs, as indicated by oxidation of the redox-sensitive probe dihydrorhodamine 123. The antioxidants alpha-tocopherol, idebenone, and glutathione monoethylester prevented the oxidation of dihydrorhodamine in cystine-depleted preOLs and markedly protected against cell death. When the intracellular glutathione level was not manipulated, preOLs were also more vulnerable than mature OLs to exogenous free radical toxicity generated by a xanthine-xanthine oxidase system. Ultrastructural features of free radical-mediated injury in glutathione-depleted preOLs included nuclear condensation, margination of chromatin, and mitochondrial swelling. These observations indicate that preOLs are significantly more sensitive to the toxic effects of glutathione depletion and that oligodendroglial maturation is associated with decreased susceptibility to oxidative stress.

Animals↗

PubMed2004

Arsenic intoxication-induced reduction of glutathione level and of the activity of related enzymes in rat brain regions: reversal by DL-alpha-lipoic acid.

The purpose of this study was to examine the effects of DL: -alpha-lipoic acid (LA) on arsenic (As) induced alteration of glutathione (GSH) level and of the activity of glutathione-related enzymes-glutathione peroxidase (GSH-Px), glutathione reductase (GR), and glucose-6-phosphate dehydrogenase (G6PDH)-in rat brain regions (cortex, hypothalamus, striatum, cerebellum and hippocampus). Male Wistar rats of 150+/-10 g weight were divided into four groups: control and three experimental groups supplemented with arsenic (sodium arsenite) alone (100 ppm mixed in drinking water), lipoic acid alone (70 mg kg(-1) body weight), arsenic plus lipoic acid (100 ppm arsenic in drinking water plus 70 mg lipoic acid kg(-1) body weight). The arsenic content of brain regions was found to increase with the administration of sodium arsenite. Arsenic exposure elicited a significant decline in glutathione content and in the activity of related enzymes, with the greatest decreases seen in the cortex, striatum, and hippocampus, whereas there were no significant differences between control rats and the group treated with lipoic acid alone. Highly elevated content of the thiobarbituric acid-reactive substance malondialdehyde (MDA) in the brain regions of arsenic-exposed rats reflected extensive lipid peroxidation (LPO) processes. Simultaneous lipoic acid treatment was effective in reducing brain regional arsenic levels and lipid peroxidation and in increasing the glutathione content and the activity of its related enzymes. Lipoic acid, by acting as an alternative sulfhydryl nucleophile to glutathione, prevents its oxidation to glutathione disulfide in detoxifying reactions against reactive oxygen species and consequently increases the activity of glutathione-related enzymes.

Animals↗

PubMed1984

Isoproterenol-induced changes in glutathione metabolism in the rat parotid gland.

Rat parotid glands were removed at timed intervals after intraperitoneal injection of isoproterenol (IPR). Reduced/oxidized glutathione ratios, glutathione peroxidase, glutathione reductase and amylase activities were determined. Parotid gland amylase content fell to less than 5 per cent of control values within 1 h after IPR, then slowly returned to control levels by 24 h. The ratio of reduced/oxidized glutathione was decreased at 2 h after IPR injection, returned to near control values at 6 h, then increased above control levels at 9, 12 and 24 h. Glutathione peroxidase activity was increased only at 12 h after injection of IPR, whereas glutathione reductase activity initially decreased, then reached peak values at 12 h. These results indicate that alterations in metabolic activity during the secretory cycle are accompanied by changes in the reduced/oxidized glutathione ratio and the activity of glutathione-metabolizing enzymes. Cellular events contributing to these alterations in glutathione metabolism may include exocytosis, endocytosis and membrane recycling, increased amino-acid transport and resynthesis of secretory proteins.

Amylases↗

PubMed1980

Rat hepatic cytosolic glutathione-dependent enzyme protection against lipid peroxidation in the NADPH-microsomal lipid peroxidation system.

Dialyzed rat liver cytosol (105 000 X g supernatant), when added along with 2.5 mM glutathione, blocked malonaldehyde formation in the NADPH-microsomal lipid peroxidation system, thus protecting against lipid peroxidation. Preheating the cytosol for 10 min at 60 degrees C destroyed its protective ability. Ammonium sulfate fractionation and Sephadex G-100 gel filtration of cytosol indicated that more than one glutathione-dependent protective enzyme was present. Fractions from the G-100 column containing the selenoenzyme glutathione peroxidase failed to protect, but fractions containing the glutathione S-transferases, which have non selenium-dependent glutathione peroxidase activity, did protect. The glutathione S-transferases were purified further with ion exchange chromatography and shown to have protective activity. Thus the rat hepatic cytosolic glutathione-dependent enzyme protection against lipid peroxidation in the NADPH-microsomal lipid peroxidation system is in part due to some of the glutathione S-transferases. The selenium-dependent glutathione peroxidase appears to have no protective effect in this system.

Animals↗