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PubMed1996

Catalytic role of the alpha-carboxylate of the Glu residue of glutathione in glutathione S-transferases.

The recently proposed catalytic role of the alpha-carboxylate of the Glu residue of glutathione in glutathione S-transferases (Widersten et al, Biochemistry 35, 7731-7742 (1996)) was examined. Based on structural considerations, it is clear that conformational changes in both glutathione and glutathione S-transferase are required. Recent kinetic studies by Ricci and coworkers (Ricci et al, J. Biol. Chem. 271, 16187-16192 (1996) and Caccuri et al, J. Biol. Chem. 271, 16193-16198 (1996)) may provide the missing evidence for these conformational changes. Possible ways to test this hypothesis are discussed.

Carboxylic Acids↗
PubMed1989

Identification of the glutathione conjugate of 4-nitroquinoline 1-oxide formed in the reaction catalyzed by murine glutathione transferases.

The product of the enzyme-catalyzed conjugation of glutathione and 4-nitroquinoline 1-oxide was isolated and its structure determined by MS and NMR. The results indicate that the cysteine sulfur of glutathione replaces the nitro group of 4-nitroquinoline 1-oxide in the reaction with the formation of 4-(glutathion-S-yl)-quinoline 1-oxide. No evidence was found for the binding of glutathione to any other position of 4-nitroquinoline 1-oxide or through any group other than the cysteine sulfur.

4-Nitroquinoline-1-oxide↗
PubMed1997

Cellular glutathione peroxidase knockout mice express normal levels of selenium-dependent plasma and phospholipid hydroperoxide glutathione peroxidases in various tissues.

Selenium-dependent cellular glutathione peroxidase (GPX1) knockout [GPX1(-)] mice were derived from 129/SVJ x C57BL/6 hybrid mice by microinjecting C57BL/6 blastocysts with recombinant embryonic stem cells carrying a target mutation in the GPX1 gene. Experiment 1 was conducted to determine the effects of the GPX1 knockout on the susceptibility of mice to dietary vitamin E and Se deficiency and on the expression of the Se-dependent plasma glutathione peroxidase (GPX3) and phospholipid hydroperoxide glutathione peroxidase (GPX4), and the Se-independent glutathione S-transferase (GST). Eleven GPX1(-) and 11 control mice (5 wk old, six males and five females) were fed a Se-deficient, Torula yeast basal diet (0.02 mg Se/kg, no supplemental vitamin E) or the basal diet supplemented with 0.5 mg Se/kg (as Na2SeO3) for 13 wk. Experiment 2 was conducted to determine the effect of the GPX1 knockout on the total Se concentration in the liver of Se-adequate mice. Six GPX1(-) and four control mice (5 wk old, half males and females) were fed the basal diet supplemented with 0.2 mg Se/kg and 15 mg of all-rac-alpha-tocopheryl acetate/kg for 5 wk. There was no difference in body weight gain or apparent susceptibility to dietary vitamin E and Se deficiency between the GPX1(-) and control mice. Knockout of GPX1 resulted in almost complete abolishment of GPX1 activity in various tissues, but had no effect on the GPX3 or GPX4 mRNA level and activity or the GST activity in several tissues at either level of dietary Se. The liver total Se concentration in the Se-adequate GPX1(-) mice was only 42% of that in the controls (P < 0. 0001). These results indicate that GPX1 is expressed independently of GPX3 or GPX4 and represents approximately 60% of the total hepatic Se in Se-adequate mice.

Animals↗
PubMed2004

S-(2,3-dichlorotriazinyl)glutathione. A new affinity label for probing the structure and function of glutathione transferases.

S-(2,3-Dichlorotriazinyl)glutathione (SDTG) was synthesized and shown to be an effective alkylating affinity label for recombinant maize glutathione S-transferase I (GST I). Inactivation of GST I by SDTG at pH 6.5 followed biphasic pseudo-first-order saturation kinetics. The biphasic kinetics can be described in terms of a fast initial phase of inactivation followed by a slower phase, leading to 42 +/- 3% residual activity. The rate of inactivation for both phases exhibits nonlinear dependence on SDTG concentration, consistent with the formation of a reversible complex with the enzyme (K(d) 107.9 +/- 2.1 micro m for the fast phase, and 224.5 +/- 4.2 micro m for the slow phase) before irreversible modification with maximum rate constants of 0.049 +/- 0.002 min(-1) and 0.0153 +/- 0.001 min(-1) for the fast and slow phases, respectively. Protection from inactivation was afforded by substrate analogues, demonstrating the specificity of the reaction. When the enzyme was inactivated (42% residual activity), approximately 1 mol SDTG per mol dimeric enzyme was incorporated. Amino-acid analysis, molecular modelling, and site-directed mutagenesis studies suggested that the modifying residue is Met121, which is located at the end of alpha-helix H"'(3) and forms part of the xenobiotic-binding site. The results reveal an unexpected structural communication between subunits, which consists of mutually exclusive modification of Met residues across enzyme subunits. Thus, modification of Met121 on one subunit prevents modification of Met121 on the other subunit. This communication is governed by Phe51, which is located at the dimer interface and forms part of the hydrophobic lock-and-key intersubunit motif. The ability of SDTG to inactivate other glutathione-binding enzymes and GST isoenzymes was also investigated, and it was concluded that this new reagent may have general applicability as an affinity reagent for other enzymes with glutathione-binding sites.

Affinity Labels↗
PubMed2000

Effect of pineal indoles on activities of the antioxidant defense enzymes superoxide dismutase, catalase, and glutathione reductase, and levels of reduced and oxidized glutathione in rat tissues.

Male Sprague-Dawley rats were randomly divided into four groups. Two of the groups received a single intraperitoneal injection of melatonin and 5-methoxytryptamine (5 mg/kg body weight), respectively, at 9 PM. One group received an intraperitoneal injection of 5-methoxytryptophol (5 mg/kg body weight) at 9 AM. The remaining group received alcoholic saline (vehicle) and served as the control. All rats were sacrificed 90 min after injection and the livers, kidneys, and brains were dissected. The activities of superoxide dismutase, catalase, and glutathione reductase in the organs were measured. It was found that both melatonin and 5-methoxytryptamine were approximately equipotent in enhancing the activities of superoxide dismutase and glutathione reductase in the kidney and liver, while 5-methoxytryptophol displayed a weaker effect. Both melatonin and 5-methoxytryptamine augmented the level of reduced glutathione in the kidney and liver, while 5-methoxytryptophol did so only in the kidney. All three pineal indoles increased the activity of superoxide dismutase and lowered the ratio of oxidized to reduced glutathione in the brain.

5-Methoxytryptamine↗
PubMed1981

Effect of glutathione deficiency on the pool of CoA-glutathione mixed disulfide in Escherichia coli.

The formic acid extracts of several glutathione-deficient strains of Escherichia coli have been assayed for the presence of the mixed disulfide of CoA and glutathione, CoASSG. Strains deficient in gamma-glutamyl-cysteine synthase (EC 6.3.2.2) produced only CoA dimer. Strains deficient in glutathione synthase (EC 6.3.2.3) produced the mixed disulfide of CoA and the gamma-glutamylcysteine dipeptide. The pool size of total CoA in the cell did not change significantly even in the absence of glutathione.

Coenzyme A↗
PubMed1991

Glutathione and glutathione-related enzymes in human cataractous lenses.

Glutathione and its related enzymes were measured for normal and cataractous human lenses. Glutathione decreased progressively with the development of cataracts. This decrease was more pronounced in the nucleus than in the capsule-epithelia of cataractous lenses. Glutathione reductase in nuclear extracts was relatively unchanged during cataract progress, while glutathione synthetase was significantly low in the advanced stages of cataracts. gamma-Glutamylcysteine synthetase was not measurable in the nuclei of cataractous lenses.

Aged↗
PubMed1993

Changes in blood selenium and glutathione concentrations and glutathione peroxidase activity in human pregnancy.

Whole-blood and plasma selenium (Se) concentrations, red blood cell and plasma glutathione peroxidase activities, and red blood cell glutathione concentrations were investigated in 49 healthy pregnant women. Mean whole-blood and red blood cell Se concentrations started to decline after the 16th week and plasma Se after the 26th week of pregnancy. The lowest values were noted just before delivery. Negative correlations were found between the gestational age and both whole-blood and plasma Se concentrations: (r = -0.560 (p < 0.001) and r = -0.553 (p < 0.001), respectively. Plasma and red blood cell glutathione peroxidase activities started to decrease after the 20th and 30th week of pregnancy, respectively, and before delivery were significantly lower (p < 0.001) than during the 10th week of pregnancy. The red blood cell glutathione concentration increased significantly just before delivery. These results seem to confirm the supposition that in pregnant women with low or even moderate blood Se concentrations the requirement for the element significantly increases.

Adult↗
PubMed1984

Glutathione peroxidase, superoxide dismutase, and glutathione S-transferase activities in human lung.

Glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and glutathione S-transferase activities were measured in lung tissue obtained from 7 patients receiving resectional surgery because of localized lung tumors. Human-lung-soluble fractions were also fractionated on Sephadex G-150-S columns, and GSH-Px activity was measured using hydrogen peroxide and cumene hydroperoxide as substrates to investigate the presence of non-selenium-dependent GSH-Px activity. The amount of SOD activity was found to be similar to the amount of activity present in rat lung. Glutathione S-transferase activity was 3 times greater in human lung than that in rat lung. Selenium-dependent GSH-Px activity was much lower in human lung than that in rat lung (less than 30%), and no evidence of non-selenium-dependent glutathione peroxidase activity was found in human lung using gel filtration techniques. We conclude that human lung differs from rat lung in some antioxidant enzymatic defense mechanisms, and that selenium deficiency could result in marked decreases in the ability of human lung to detoxify organic hydroperoxides.

Animals↗
PubMed2000

Erythrocyte superoxide dismutase and glutathione peroxidase activities, and malondialdehyde and reduced glutathione levels in schizophrenic patients.

There is abundant evidence that free radicals are involved in membrane pathology in the central nervous system and that they may play a role in neuropsychiatric disorders, including schizophrenia. In this study, we investigated erythrocyte superoxide dismutase and glutathione peroxidase activities as antioxidant enzymes, malondialdehydes as a sign of lipid peroxidation, and reduced glutathione levels in schizophrenic patients. Activities of superoxide dismutase and levels of malondialdehyde in erythrocytes were greater in all patients (n=48) and in patients with acute (n=16) and chronic schizophrenia (n=32) (p<0.001 for all patients and chronic patient group; p<0.05 for acute patient group). The activities of glutathione peroxidase were lower in patients (p<0.05 for all patients and acute patient group; p=0.051 for chronic patient group) compared with the control group. Mean erythrocyte reduced glutathione was lower in patients than in controls (p<0.05). In the patient group, erythrocyte superoxide dismutase activity was positively correlated with scales and duration of disease and erythrocyte malondialdehyde concentration. These data reveal that antioxidative defense mechanisms might be impaired in schizophrenic patients.

Adolescent↗
PubMed1981

Effect of styrene on hepatic mixed function oxidases, glutathione content and glutathione-s-transferase activity in rats.

Effect of styrene administration (250, 450 and 900 mg/kg orally for 7 consecutive days) on hepatic mixed function oxidase (MFO) enzyme activities, glutathione content and glutathione-S-transferase activity were observed. Activity of aryl hydrocarbon hydroxylase and aniline hydroxylase was significantly enhanced at higher doses of styrene (450 and 900 mg/kg). A significant lowering of glutathione content accompanied with the inhibition of glutathione-S-transferase activity was also noticed at the highest dose of styrene (900 mg/kg).

Aniline Hydroxylase↗
PubMed1986

Activity of glutathione peroxidase and glutathione reductase in the human lens related to age.

Lenses from 42 eye bank eyes were assayed for glutathione peroxidase and glutathione reductase activities. The activity of glutathione peroxidase, when considered as a function of age, was lowest in the neonate lens, increasing with age to reach maximal values in young adult lenses, and thereafter progressively decreasing with ages greater than 40 years. Glutathione reductase activity was little affected by age when expressed as activity per lens, per gram lens or per mg soluble protein, indicating that activity of this enzyme did not increase with lens size as would a representative lenticular protein. However, the activity of this enzyme per gram lens was among the highest of any species yet examined.

Adolescent↗
PubMedDate not supplied

Circadian rhythms in glutathione and glutathione-S transferase activity of rat liver.

The experiments were conducted to examine the existence of circadian rhythms in glutathione concentration and glutathione S-transferase activity in the liver of the rat. In animals synchronized to a 12:12 h light-dark cycle and fasted at 6 different time points to allow exactly 24 h of fasting, both, glutathione concentration and glutathione S-transferase activity show diurnal variation with a maximum during the light period and a minimum at night. On the other hand the hepatic protein level was maximal during the light period and decreased to its lowest level during the dark period. The implications of such oscillations in the circadian rhythms of toxicological or therapeutical effects of many xenobiotic agents are clear.

Analysis of Variance↗
PubMed1976

Glutathione peroxidase activity and glutathione concentration in genetically dystrophic mice.

The present studies were conducted to determine whether inherited muscular dystrophy in the 129/ReJ-dy mouse was associated with differences in specific activity, substrate availability, or apparent Km of glutathione peroxidase. The results indicate that glutathione peroxidase is elevated in skeletal muscle of mice with genetic muscular dystrophy when the activity is expressed on a protein basis. This elevation precedes the development of severe paralysis since muscles from the fore legs showed increased enzyme activity as early as the more severely affected hind legs. There was no difference in glutathione peroxidase activity in tissues other than skeletal muscle. GSH concentration was elevated in muscle and normal in other tissues of dystrophic mice, showing that adequate substrate was available to the enzyme. The apparent Km for cumene hydroperoxide was also similar for muscle of normal and dystrophic mice. This report provides further evidence that mice with dystrophia muscularis have a functional glutathione peroxidase system in all tissues including skeletal muscle, and that a defect in this in vivo protective system is apparently not a contributing factor in the pathology of the disease.

Aging↗
PubMed2002

[Plasma selenium concentration, glutathione peroxidase and glutathione S-transferase activities in patients with chronic liver diseases].

The effects exerted on hepatocytes by alcohol metabolites, drugs or other toxins and also hepatotropic viruses lead to chronic liver diseases. Reactive oxygen species (ROS) have been implicated in a number of pathologies, including different types of liver diseases. Organism has developed several mechanisms to counteract or prevent reactive oxygen species effects. These include enzymes such as: glutathione peroxidase (GSH-Px) with selenium (Se) in the active site and glutathione S-transferase (GST). Measurement of GST, compared with alanine aminotransferase (AIAT), has been advocated as a superior marker of hepatocellular damage. The aim of this study was to assess selenium concentration, glutathione peroxidase and glutathione S-transferase activities in plasma of patients with various types of liver diseases. The study population consisted of 54 patients and 25 healthy volunteers. The patients were divided into two groups according to etiology of the disease. Plasma selenium concentration was reduced in patients with cirrhosis, as compared to controls, irrespective of etiology and activity of AIAT. Plasma GSH-Px activity was significantly lower in both groups of patients with normal AIAT activity, whereas it was higher in both groups with activity of AIAT higher than 40 U/l. GST activity was higher only in post-viral group in patients with high AIAT activity. Impaired intestinal absorption and distribution of selenium among plasma proteins have been suggested as possible mechanism of reduced selenium concentration. Changes in the activities of glutatthione-dependent enzymes in plasma may arise from increased formation of reactive oxygen species or from release of these enzymes from injured hepatocytes to plasma.

Adult↗
PubMed1991

Specificity of isozymes of murine hepatic glutathione S-transferase for the conjugation of glutathione with L-phenylalanine mustard.

Glutathione S-transferase (GST) isozymes play a central role in the protection of cells from cytotoxic chemicals and have a putative role in the intrinsic and acquired resistance of tumors to cytotoxic drugs. We have isolated and purified GST isozymes from mouse liver (M. Warholm et al., Biochemistry, 25: 4119-4125, 1986) and analyzed the metabolic products of the reaction of L-phenylalanine mustard (L-PAM) with glutathione in the presence of GST isozymes, using reverse phase high performance liquid chromatography. At pH 6.5, the spontaneous conjugation of L-PAM and glutathione is suppressed and the major product at 60 min is the monochloro, monohydroxyl derivative of L-PAM. Addition of neither class mu nor class pi isozymes to the reaction has any effect on the metabolism of L-PAM. Only isozymes of the alpha GST class catalyze the conjugation of L-PAM with glutathione. In this case, the major metabolite at 1 h is the monochloro, monoglutathionyl conjugate. Increasing the amount of mu or pi isozyme in the reaction mixture has no effect on the metabolism of L-PAM, whereas increasing the amount of alpha isozyme completely supplants hydrolysis with conjugation. Thus, increased levels of class alpha GST isozyme may represent a specific mechanism whereby cells can acquire resistance to nitrogen mustards.

Animals↗
PubMed1990

Alteration of endogenous glutathione peroxidase, manganese superoxide dismutase, and glutathione transferase activity in cells transfected with a copper-zinc superoxide dismutase expression vector. Explanation for variations in paraquat resistance.

Transfection of a human pSV2 (copper-zinc) superoxide dismutase expression vector into murine fibroblasts resulted in stable clones producing increased amounts of copper-zinc superoxide dismutase. A marked increase in endogenous glutathione peroxidase activity (up to 285%) and a smaller increase in glutathione transferase activity (up to 16%) also occurred. Manganese superoxide dismutase activity was decreased in all clones, whereas catalase and NADPH reductase activities were not affected. Alterations in glutathione peroxidase and manganese superoxide dismutase activities correlated with increases in copper-zinc superoxide dismutase activity. Whereas all clones were resistant to paraquat, a direct correlation between copper-zinc superoxide dismutase activity and resistance to paraquat did not exist. In agreement with previous reports clones expressing the highest copper-zinc superoxide dismutase activity did not display the highest resistance to paraquat. However, there was a direct correlation between the increase in glutathione peroxidase activity and paraquat resistance (p less than 0.002).

Animals↗
PubMed1988

Effect of endogenous glutathione, superoxide dismutases, catalase, and glutathione peroxidase on adriamycin tolerance of Chinese hamster ovary cells.

Based on the concept that activated oxygen species are causally involved in Adriamycin toxicity, endogenous antioxidant defenses are expected to be important determinants of cellular Adriamycin tolerance. We have tested this prediction by making use of an oxygen-resistant variant subline of Chinese hamster ovary cells (CHOr), which is characterized by increased levels of glutathione, copper- and zinc-containing superoxide dismutase, manganese-containing superoxide dismutase, catalase, and glutathione peroxidase. The levels of antioxidant defenses in wild-type CHO (CHOs) cells were within the range reported for human tumor cell lines, except for catalase, which was comparatively high. Oxygen-tolerant CHOr cells, which contained 4.3-fold more catalase activity than CHOs cells, were proportionally more resistant to H2O2, indicating that catalase activity in wild-type CHOs cells was still limiting H2O2 tolerance. The Adriamycin sensitivity of CHOs cells was compared to that of CHOr cells by clonogenic cell survival. After correcting for differential drug uptake in CHOs and CHOr cells, no significant difference in Adriamycin sensitivity could be detected. Furthermore, drug-induced cyanide-resistant oxygen consumption and electron spin resonance data indicated that both cell strains were equally efficient in reducing Adriamycin to its semiquinone radical and in generating activated oxygen species through oxidation-reduction cycling. These results indicate that Adriamycin tolerance of wild-type CHO cells, as determined by clonogenic cell survival, is not limited by endogenous glutathione, copper- and zinc-containing superoxide dismutase, manganese-containing superoxide dismutase, catalase, or glutathione peroxidase.

Animals↗