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PubMed2004

The influence of fasting on liver sulfhydryl groups, glutathione peroxidase and glutathione-S-transferase activities in the rat.

Sulfhydryl groups, glutathione peroxidase (GPx) and glutathione-S-transferase (GST) are important elements of the antioxidant defence in the organism. The efficacy of their antioxidant action is influenced by many factors. In this work, the effect of fasting on total, protein-bound and nonprotein sulfhydryl groups and on the activity of liver and serum GPx and GST in rats were determined. Male Wistar rats were divided into two groups: non-fasted and 18-hour fasted. In fasted animals liver content of nonprotein sulfhydryl groups (represented predominantly by reduced glutathione; GSH) was diminished by 22% in comparison to non-fasted group, whereas total and protein-bound -SH groups were unaffected. The activity of liver and serum GPx was unchanged in food deprived rats. In these animals the activity of GST in serum was reduced by 26%. Fasting had no significant effect on the activity of GST in the liver. Our results demonstrate that in rats deprived of food for 18 hours liver and serum GPx and GST are not involved in protection against action of reactive oxygen species formed during fasting. The observed drop in the content of liver nonprotein sulfhydryl groups without concomitant rise in the activity of GPx and GST indicates that this effect may be due to augmented degradation of GSH, its potentiated efflux from hepatocytes and formation of conjugates with intermediates arising as a result of reactive oxygen species action.

Animals↗
PubMed1998

Determination of glutathione transferase (GSTT1-1) activities in different tissues based on formation of radioactive metabolites using 35S-glutathione.

A new system has been developed to determine enzyme activities of glutathione transferase theta (GSTT1-1) based on radiometric product detection resulting from the enzymic reaction of methyl chloride with 35S-labelled glutathione. In principle, the method is universally applicable for determination of glutathione transferase activities towards a multiplicity of substrates. The method distinguishes between erythocyte GSTT1-1 activities of human 'non-conjugators', 'low conjugators' and 'high conjugators'. Application to cytosol preparations of livers and kidneys of male and female Fischer 344 and B6C3F1 mice reveals differential GSTT1-1 activities in hepatic and renal tissues. These ought to be considered in species-specific modellings of organ toxicities of chlorinated hydrocarbons.

Animals↗
PubMed2001

Effects of zinc chloride on glutathione and glutathione synthesis rates in various lung cell lines.

Zinc-mediated toxicity has been linked to cellular glutathione (GSH) contents. In this study, effects of zinc on cellular GSH content, glutathione reductase (GR) activity, and GSH synthesis were investigated. In all cell lines tested, decreases in cellular GSH content and GR activity as well as an increase in oxidized glutathione (GSSG) were found after incubation of cells with zinc chloride. These effects were dose- and time-dependent. Changes in GR activities were earliest affected and were most marked compared with the other parameters examined. Decrease of enzyme activity was not due to a decrease in the cosubstrate NADPH. In A549 and L2 cells, initial increases in GSH synthesis rates occurred up to about 175% of control. Later, GSH synthesis decreased to levels below controls. In 16Lu cells, GSH synthesis decreased after 2 h of zinc exposure. No transient increase was found in this cell line. Measurement of ATP content did not show any influence of zinc on cellular ATP. Lactate dehyrogenase leakage, a marker of a clear cytotoxic effect, occurred after 6 h of zinc treatment in the non-malignant cells examined, and after 16 h in malignant A549 cells. We assume the inhibition of GR activity and the associated increase of GSSG could possibly represent a main zinc-mediated toxic cellular effect.

Animals↗
PubMed1985

Synthesis and characterization of the oxygen and desthio analogues of glutathione as dead-end inhibitors of glutathione S-transferase.

The oxygen analogue, gamma-L-Glu-L-SerGly (GOH) and desthio analogue, gamma-L-Glu-L-AlaGly (GH) have been synthesized by a simple three step procedure involving active ester coupling of N-t-BOC-alpha-(4-nitrophenyl)-L-glutamate to L-SerGly and L-AlaGly, respectively. The two peptides are excellent dead-end inhibitors of isozymes 3-3 and 4-4 of rat liver glutathione S-transferase. At low fixed concentrations of 1-chloro-2,4-dinitrobenzene (CDNB) GOH and GH are linear competitive inhibitors of isozyme 3-3 vs glutathione with KI values of 13.0 and 116 microM, respectively. Both peptides are non-competitive (mixed-type) inhibitors vs CDNB when glutathione is the fixed substrate. Similar results are obtained with both peptides and isozyme 4-4. The results rule out ordered or ping-pong kinetic mechanisms where the electrophile adds first.

Animals↗
PubMed1985

Glutathione S-transferases catalyzed conjugation of 1,4-disubstituted butanes with glutathione in vitro.

Rat liver glutathione S-transferases catalyzed the conjugation of 1,4-diiodobutane with glutathione in vitro. The reaction followed saturation kinetics and was dependent on the concentration of the enzyme, substrate and glutathione in the incubation media. S-Benzylglutathione inhibited the enzymatic conversion of 1,4-diiodobutane to product. The cyclic sulfonium compound, gamma-glutamyl-beta-(S-tetrahydrothiophenium) alanyl-glycine was identified as the product of this conjugation reaction. This product was stable under physiological conditions in presence of rat liver cytosol but rapidly and quantitatively decomposed at pH greater than or equal to 12 to give tetrahydrothiophene.

Animals↗
PubMed1986

Inhibition of glutathione peroxidase and glutathione transferase in mouse liver by misonidazole.

The mechanisms of toxicity and sensitization by the radiosensitizer misonidazole [1-(2-nitro-1-imidazolyl)-3-methoxy-2-propanol] are not well understood. We report here on the inhibition of total glutathione peroxidase (GSHPx), selenium-dependent glutathione peroxidase (selenium-GSHPx) and glutathione transferase (GSHTx) activities by misonidazole. Mouse liver cytosol GSHPx and selenium-GSHPx were inhibited in vitro with 0.5 mM misonidazole. On administration of the drug intraperitoneally (800 mg/kg) to mice, it was found that GSHPx, selenium-GSHPx, and GSHTx were inhibited in homogenate, cytosol, and microsomal fractions of mouse liver. GSHPx was depressed in all fractions up to 60-70% of control values, with maximum depression occurring in the cytosol and homogenate fractions in less than 2 hr. Recovery of activity was slower in the microsomes. In general, the pattern of depression of selenium-GSHPx was parallel to that of GSHPx except in microsomes, where GSHPx is minimal. Quantitatively, selenium-GSHPx was least affected. GSHTx was inhibited 70-80% of control values in cytosol and homogenate with recovery by 24 hr, whereas a second period of depression occurred at 24 hr in the microsomes. The inhibition of peroxide-metabolizing enzymes may lead to elevation of intracellular peroxide levels, contributing to the radiosensitizing effect and/or toxicity of misonidazole.

Animals↗
PubMed1989

Glutathione conjugation of nitro compounds by monkey glutathione S-transferases.

The distribution in Japanese monkey tissues of glutathione S-transferase activity toward some aromatic nitro compounds was examined by measuring the release of the nitro group as nitrite ion. The activity was especially high in liver, kidney and small intestine when compounds such as 4-nitroquinoline N-oxide, 5-nitrofurfural diacetal and o-dinitrobenzene were used as substrates. The nitrite-releasing activity of the major enzyme purified from rhesus monkey liver was also tested on fifty-two nitro compounds including nineteen nitrofuran derivatives. Among the thirty-three nitro compounds other than the nitrofuran derivatives tested as substrates, the purified enzyme showed activity only toward o-dinitrobenzene, 4-nitroquinoline N-oxide, 3,4-dinitrobenzoic acid, p-dinitrobenzene, 2,5-dinitrobenzoic acid, 2,5-dinitrophenol, tetra-chloronitrobenzene and 2,4-dinitrobenzoic acid. The crude supernatant fraction of rhesus monkey liver showed activity in substrate specificity roughly similar to that of the purified enzyme. On the other hand, among at least ten carcinogenic 2-substituted 5-nitrofran derivatives tested, 4,6-diamino-2-(5-nitro-2-furyl)-s-triazine, 5-nitro-2-furaldehyde semicarbazone, N-[[3-(5-nitro-2-furyl)-1,2,4-oxadiazol-5-yl]methyl] acetamide, and N-[5-(5-nitro-2-furyl)-1-3,4-thiadiazol-2-yl)acetamide were shown to be enzymatically conjugated with reduced glutathione. Among the other nine 2-substituted 5-nitrofuran derivatives tested, six compounds could be the substrates of the enzyme, and 5-nitrofurfural and 5-nitrofurfural diacetal were especially good substrates. There was, however, little apparent correlation between their carcinogenicity and susceptibility to glutathione S-transferase. The bulky substituents at position 2 appeared to decrease the susceptibility of these nitrofuran derivatives to the enzyme. Both Vmax and Km values of the purified enzyme varied greatly among the substrates, and the optimum pH fell between 7.5 and 9.0 in most cases.

Animals↗
PubMed1991

Distribution of glutathione peroxidases and glutathione reductase in rat brain mitochondria.

The distribution of glutathione reductase (GR), glutathione peroxidase (GPx) and phospholipid hydroperoxide glutathione peroxidase (PHGPx) in isolated rat brain mitochondria was investigated, using a fractionation procedure for the separation of inner and outer membranes, contact sites between the two membranes and a soluble fraction mainly originating from the mitochondrial matrix. The data indicate that GR and GPx are concentrated in the soluble fraction, with a minor portion of the two enzymes being associated with the contact sites. PHGPx is localized largely in the inner membrane. The possible functional significance of these findings is discussed.

Animals↗
PubMed1980

Glutathione and glutathione S-transferases in the Salmonella mammalian-microsome mutagenicity test.

Levels of the tripeptide glutathione (GSH) and the activity of glutathione S-transferases were investigated in S9 fractions of rats and mice and in Salmonella typhymurium tester strains TA1535, TA100, TA1538 and TA98. The S9 and Salmonella typhimurium tester strains had high levels of glutathione. Compared with S9, the activity of GSH S-transferases was lower in the bacteria. However, electrophiles such as 1-chloro-2,4-dinitrobenzene (CDNB), diethyl maleate and styrene oxide were effectively bound to bacterial GSH. The mutagenicity of the direct mutagen CDNB was drastically lowered in presence of S9 fractions but not in presence of microsomes. A comparable decrease was obtained when microsomal supernatant, which contains GSH and GSH S-transferases, was added to the microsomes. Addition of GSH in excess completely abolished mutagenicity of CDNB. These results demonstrate that the conjugation of electrophiles with GSH mediated by the S9 fraction or the bacterial tester strains represents an important detoxication mechanism which may influence the results obtained with the Salmonella typhimurium mammalian-microsome mutagenicity test.

Animals↗
PubMed1983

Non-selenium-dependent glutathione peroxidase activity in rat lung: association with lung glutathione S-transferase activity and the effects of hyperoxia.

To determine if non-selenium-dependent glutathione peroxidase (Non-Se GSH-Px) activity is present in rat lung, we fractionated rat lung soluble fractions from rats fed a selenium-deficient or control diet and measured glutathione peroxidase activity with both cumene hydroperoxide and hydrogen peroxide as substrates. We also measured glutathione S-transferase (GSH S-transferase) activity in the fractions with 1-chloro-2,4-dinitrobenzene as substrate. Non-Se GSH-Px activity was present (about 34% of total GSH-Px activity), and the peak present in the gel filtration chromatogram coeluted with the GSH S-transferase peak. We then measured GSH S-transferase activity in lung-soluble fractions from rats exposed to room air or 85% O2 for 5 days. Lung GSH S-transferase activity was increased in the oxygen-exposed animals when compared to the air-exposed controls. The increase in GSH S-transferase activity could represent the induction of lung non-Se GSH-Px activity.

Animals↗
PubMed1994

Relationship of glutathione and glutathione-S-transferase to cisplatin sensitivity in human head and neck squamous carcinoma cell lines.

Factors controlling glutathione metabolism may govern sensitivity to chemotherapeutic agents such as cisplatin. Using a battery of cell lines derived from previously untreated head and neck squamous cell carcinomas, we examined cisplatin resistance relative to (a) glutathione-S-transferase (GST)-pi gene amplification and expression, (b) basal and inducible GST-total and GST-pi enzymatic activity, and (c) cellular levels of reduced glutathione (GSH). Using Southern blot analysis and northern blot hybridization, no relationship between GST-pi gene amplification, mRNA expression and drug resistance could be identified. Despite the capacity of cisplatin to induce GST enzyme activity, the response was variable and unrelated to cisplatin responsiveness. However, an inverse relationship between GSH levels and cisplatin sensitivity was identified. To further clarify these effects, cells were treated with S-allyl cysteine (SAC), a thioallyl derivative isolated from garlic (Allium sativum), which altered cellular GSH in a biphasic manner. Pretreatment with SAC to lower cellular GSH levels followed by exposure to cisplatin significantly enhanced the cytotoxic effects of cisplatin, while SAC alone had no effect on cell growth.

Carcinoma, Squamous Cell↗
PubMed1977

The influence of dietary selenium and vitamin E on glutathione peroxidase and glutathione in the rat.

The effect of dietary selenium (Se) and vitamin E supplementation on tissue reduced glutathione (GSH) and glutathione peroxidase activity has been studied in the rat. Increasing Se intake by 0.4 ppm gave significantly higher enzyme levels in all tissues studied, an effect not influenced by vitamin E intake. Further increasing Se to 4 ppm gave higher enzyme levels in red blood cells only, while in liver there was a significant decrease in enzyme activity probably reflecting Se hepatotoxicity. In the absence of Se supplements increasing dietary vitamin E to 100 mg/kg diet significantly increased enzyme activity but this effect was modified by simultaneous Se supplementation. Se intake had no effect on GSH levels. Rats on a high vitamin E intake 500 mg/kg had a significantly higher tissue GSH level. Dietary Se had a sparing effect on vitamin E, rats supplemented with Se having significantly raised plasma vitamin E levels. These results confirm the role of selenium in glutathione peroxidase and also show that vitamin E influences the activity of the enzyme.

Animals↗
PubMed1989

Site-directed inactivation of human lung acidic glutathione S-transferase by 1-chloro-2,4-dinitrobenzene in the absence of glutathione.

Human lung acidic glutathione S-transferase is irreversibly inhibited by 1-chloro-2,4-dinitrobenzene (CDNB) in the absence of the co-substrate glutathione (GSH). The time-dependent inactivation is pseudo-first-order and demonstrates saturation kinetics, suggesting that inactivation occurs from an EI complex. The Ki was 0.14 mM; and kobs was 0.32 min-1 at 0.6 mM CDNB. The enzyme was protected against CDNB inactivation by GSH. The other two classes of glutathione S-transferase, the basic and near-neutral, are not significantly inactivated by CDNB. Incubation with [14C]CDNB indicated covalent binding to all three classes of transferase. One peptide fraction was found to be radiolabelled in both the basic and acidic transferases when these were incubated with [14C]CDNB and GSH, cleaved with cyanogen bromide, and chromatographed by HPLC. Incubation in the absence of GSH yielded one and two additional labelled peptide fractions for the basic and acidic transferases, respectively. Our results suggest that while CDNB arylates all three classes of human transferases, only the acidic transferase possesses a specific GSH-sensitive CDNB binding site, binding to which leads to time-dependent inactivation.

Binding Sites↗
PubMed1995

Strain- and sex-specific differences in the glutathione S-transferase class pi in the mouse examined by gradient elution of the glutathione-affinity matrix and reverse-phase high performance liquid chromatography.

A gradient elution with glutathione (GSH) from a GSH-Sepharose 6B affinity column separated the hepatic mouse glutathione S-transferases (GST) to the alpha-, mu- and pi-classes. The GST-dependent conjugation of atrazine and glutathione was catalyzed by a pi-class GST. The pi- and mu-classes were both identified by their respective specific substrates, and after reverse-phase HPLC, by N-terminal analysis of 19-35 of the amino acids. The alpha-class GST was associated with a high selenium-independent GSH peroxidase activity and the purified protein had a N-blocked terminal. Strain related differences in the pi-class GST of the CD-1, C57BL/6, DBA/2 and Swiss-Webster males were observed by PhastGel electrophoresis of the GSH affinity chromatograph separated fractions, reverse phase HPLC and by N-terminal amino acid sequence analysis.

Animals↗
PubMed1987

Effects of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) on the levels of glutathione and lipid peroxidation and the activity of glutathione reductase in liver and lung.

After subcutaneous injection of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) to rats, glutathione reductase activity in lung and liver diminished rapidly. The restoration of enzyme activity occurred more slowly in the lung than in the liver. The pattern for the time-course of total glutathione (GSH) levels was similar between lung and liver, except for a marked depression of hepatic levels 6 h after drug administration. The level of malondialdehyde (MDA) in lung was not affected by BCNU throughout the experimental period (3 days). However, the level in liver had increased significantly by 6 h after drug administration. These observations indicate that lipid peroxidation in lung was not induced by BCNU even when glutathione reductase activity was markedly diminished. In contrast, the lipid peroxidation in liver was induced by BCNU and was preceded by an early marked depression in total GSH.

Animals↗
PubMed1984

Effects of paraquat administration on longevity, oxygen consumption, lipid peroxidation, superoxide dismutase, catalase, glutathione reductase, inorganic peroxides and glutathione in the adult housefly.

The effects of oxidative stress in the adult male housefly were examined by the administration of 1 mM paraquat. Houseflies exhibit NADH and NADPH-diaphorase activity. Paraquat caused a significant decrease in life span, metabolic rate and the concentration of thiobarbituric acid-reactants. Concentrations of reduced glutathione and inorganic peroxides were increased by paraquat. Paraquat stimulated the activity of catalase but did not affect activities of superoxide dismutase and glutathione reductase. The levels of oxidized glutathione and the rate of fluorescent age pigment accumulation were unaffected by paraquat. Results indicate that paraquat toxicity does not result from lipid peroxidation.

Animals↗