Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “GLUTATHIONE”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 415 records · Page 23Linked to original sources
PubMed2007

Glutathione and glutathione-linked enzymes in normal human aortic smooth muscle cells: chemical inducibility and protection against reactive oxygen and nitrogen species-induced injury.

Substantial evidence suggests a crucial role for glutathione (GSH) and GSH-linked enzymes in protecting against oxidative vascular disorders. However, studies on the chemical inducibility of these antioxidant defenses and their protective effects on oxidant injury in normal human vascular cells are currently lacking. Accordingly, this study was undertaken to investigate the inducibility of GSH, glutathione reductase (GR), glutathione peroxidase (GPx), and glutathione S-transferase (GST) by the chemoprotective agent, 3H-1,2-dithiole-3-thione (D3T) in cultured normal human aortic smooth muscle cells (HASMCs). HASMCs expressed measurable levels/activities of GSH, GR, GPx, and GST. Incubation of HASMCs with low micromolar concentrations of D3T resulted in a marked elevation in total cellular GSH content and GR activity. The protein and mRNA expression of gamma-glutamylcysteine ligase (GCL) and GR were also upregulated by D3T. In addition, D3T caused significant increases in mitochondrial GSH content and GR activity. In contrast, neither cellular GPx nor GST activity was altered after D3T treatment. Pretreatment of HASMCs with D3T afforded remarkable protection against reactive oxygen and nitrogen species (ROS/RNS)-mediated cell injury. Depletion of cellular GSH by pretreatment with buthionine sulfoximine (BSO), an inhibitor of GSH biosynthesis led to marked potentiation of the ROS/RNS-induced cell injury. Moreover, co-treatment of HASMCs with BSO was found to completely abolish the D3T-mediated GSH elevation, and remarkably reverse D3T cytoprotection against the ROS/RNS-elicited injury. Taken together, this study demonstrates that both GSH/GCL and GR in normal HASMCs are inducible by D3T, and that upregulation of GSH biosynthesis appears to be the predominant mechanism underlying D3T-mediated cytoprotection against ROS/RNS-elicited injury to human vascular smooth muscle cells.

Antineoplastic Agents↗
PubMed1995

Distribution of glutathione and glutathione-related enzyme systems in mitochondria and cytosol of cultured cerebellar astrocytes and granule cells.

The cellular and regional distribution of glutathione (GSH) and GSH-related enzyme systems involved in cellular defense against reactive oxygen species and electrophilic xenobiotics in the nervous system has been extensively studied. However, little is known about the subcellular distribution of GSH systems in brain tissue and cultured neural cells. The present study investigates the distribution of mitochondrial and cytosolic GSH and GSH-related enzymes in cultured cerebellar astrocytes and granule cells, and compares them with levels in the adult rat cerebellum. Cytosolic GSH levels and cytosolic activities of glutathione reductase (GR), glutathione peroxidase (GPX) and glutathione-S-transferase (GST) in astrocytes were 57, 153, 245, and 92% higher than those found in granule cells, respectively. In contrast, granule cells contained significantly higher mitochondrial GSH levels than astrocytes. Granule cells also demonstrated comparable mitochondria/cytosolic concentrations of GSH and GR, GPX and GST activities to those observed in the cerebellar tissue, whereas ratios in astrocytes were markedly lower. Although in vitro treatments with 100 microM ethacrynic acid depleted both cytosolic and mitochondrial GSH in cultured astrocytes and granule cells in a time-dependent fashion, cellular GSH in granule cells was more resistant to the GSH-depleting agent than astrocytes. These results suggest that although GSH and GSH-related enzymes are abundant in cytosolic compartments of astrocytes, mitochondrial pools are relatively small. Since brain mitochondria are sites of significant hydrogen peroxide generation, the mitochondrial localization of GSH and its associated enzymes in neural cells provide important defenses against toxic oxygen species in the nervous system. Differences in subcellular distribution of GSH systems in individual neural cell types may provide a basis for selective cellular and/or subcellular expression of neurotoxicity.

Animals↗
PubMed2003

Glutathione and glutathione-related enzymes in colorectal cancer patients.

In recent years much attention has been focused on the role of glutathione (GSH) and GSH-related enzymes such as glutathione peroxidase (GSH Px), glutathione reductase (GSH Red), and glutathione S-transferase (GST) in the inhibition of free radical-induced carcinogenesis. In this study, erythrocyte GSH levels and activities of GSH Px, GSH Red, and GST were determined in patients with colorectal tumors (n = 20, mean age 54.5 +/- 8.3 yr). Erythrocyte GSH Red and GST activities were significantly higher in patients with colorectal tumors. Erythrocyte GSH levels and GSH Px activities were found to be significantly decreased in the patients. When the patients were classified based on their clinical grading (Dukes classifications), there was no significant difference in studied parameters between Dukes B and Dukes C. Our results suggest that oxidative stress may play an important role in colorectal tumorigenesis and that these events have no effect on the clinical grading of the colorectal tumor.

Aged↗
PubMed1995

Glutathione, glutathione utilizing enzymes and thioltransferase in platelets of insulin-dependent diabetic patients: relation with platelet aggregation and with microangiopatic complications.

Reduced glutathione (GSH) and activity of GSH related enzymes play a key role in defence against oxygen free radicals, whose production is, as known, raised in patients affected by diabetes mellitus, and at the same time they may contribute to the process of platelet aggregation. The purpose of this study was to evaluate GSH levels and activity of glutathione peroxidase (GSH-Px), glutathione reductase (GSSG-Red), glutathione transferase (GSH-Tr), glucose-6-phosphate-dehydrogenase (G6PDH), and thioltransferase (TT) in platelets of insulin-dependent diabetic patients in fair metabolic control (mean glycated haemoglobin: 6.5%), as related to presence of retinopathy, neuropathy or nephropathy and to platelet aggregation by arachidonic acid (AA) in vitro. Mean effective dose (ED50) of AA was on average significantly lower in the group of insulin-dependent diabetic patients (0.41 +/- 0.02 mM (SEM), n = 46) as compared with that of control subjects strictly matched for age, sex and weight (0.77 +/- 0.02, n = 51; P = 0.0001). Mean platelet GSH as well as the activity of GSH related enzymes expressed as geometric mean (95% confidence intervals) were similar in diabetic patients and in controls, except for GSSG-Red whose activity was significantly higher in diabetic subjects (28.5 (14.4-57.5) mU 10(-9) platelets vs. 20.3 (8.7-56) mU 10(-9) platelets; P = 0.01). In the diabetic group TT was reduced when compared with healthy controls (3.8 (0.9-12.2) mU 10(-9) platelets vs. 6 (1.6-26.1) mU 10(-9) platelets; P = 0.04).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2005

Effect of melatonin on lipid peroxidation, glutathione and glutathione-dependent enzyme activities in experimental otitis media with effusion in guinea pigs.

Melatonin plays a role in the prevention of oxidative damage. In the present study, we investigated whether the increased oxidative stress in experimental otitis media with effusion (OME) induced by histamine is reflected in erythrocytes and middle ear effusion fluid. Lipid peroxidation in effusion fluid was measured to determine the effects of melatonin on oxidative stress. Erythrocyte and middle ear effusion malondialdehyde (MDA) levels, erythrocyte glutathione (GSH) levels and glutathione peroxidase (GPx), glutathione reductase (GRd) and glutathione-S-transferase (GST) activities were measured in three groups of six guinea pigs each at 3 hr after the injection of 0.1 mL of histamine (or saline) into the middle ear. In erythrocyte and middle ear effusion samples, MDA levels showed a significant increase in guinea pigs with experimental OME group when compared with the control animals. Erythrocyte GPx, GST, GRd activities and GSH levels significantly reduced in experimental OME guinea pigs when compared with the control and melatonin-treated animals. Erythrocyte GPx activity also significantly increased after melatonin treatment when compared with the control group. These findings suggest that reactive oxygen species play a role in histamine-induced OME. Pretreatment with melatonin increases antioxidant enzyme activities and reduced formation of MDA, an indicator of lipid peroxidation, in histamine-induced OME.

Animals↗
PubMed1991

[Glutathione levels and the activity of the enzymes of glutathione metabolism in erythrocytes of patients with acute cholecystitis].

It is shown that in acute cholecystitis patients versus chronic cholecystitis ones and donors, the total glutathione in blood is lower while the activity of glutathione metabolism enzymes in red blood cells inhibited. Enzymological findings correlate with clinical symptoms of intoxication. Surgery aggravates disturbed activity of the enzymes. Conventional conservative therapy is not effective in normalizing the enzymes activity either. A good therapeutic response can be achieved by a directed transport of antibiotics in autologous blood ghosts which promotes recovery of normal activity of glutathione metabolism enzymes, routine glutathione level, early stabilization of hepatocytic membranes beneficial for surgical patients.

Acute Disease↗
PubMed1994

Thymic peptides increase glutathione level and glutathione disulfide reductase activity in vascular endothelial cells.

The glutathione redox cycle plays an important role in antioxidant and detoxification mechanisms. We recently reported that a calf thymic peptide (TP) protected vascular endothelial cells from oxidant injury induced by hydrogen peroxide. Using electrophoresis and amino acid sequencing analysis, we have now shown that TP consists of two peptides. The fast-moving peptide has 9 amino acid residues at the NH2 terminal and accounts for 92% of total quantity, while the other peptide has 18 amino acid residues at the NH2 terminal and amounts to 8%. The present study investigated the effect of TP on glutathione redox cycle. Confluent monolayers of bovine pulmonary artery endothelial cells (PAEC) were incubated with TP (12.5-100 micrograms/mL) for 24-48 h. TP caused a dose-dependent increase in glutathione (GSH) level and glutathione disulfide reductase activity but no significant change in GSH peroxidase activity. Exposure of PAEC to an organic oxidant t-butyl hydroperoxide (tBHP) resulted in decreased GSH level, increased lipid peroxidation, and elevated leakage of intracellular lactate dehydrogenase. Preincubation of PAEC with TP prevented these changes induced by tBHP. The data suggest that the antioxidant effect of TP may be due, at least in part, to its modulation of the GSH redox cycle in vascular endothelial cells. TP may thus be considered a new antioxidant with novel activities in addition to being an immune regulator.

Amino Acid Sequence↗
PubMed1982

Inhibition of glutathione excretion, bile flow, and alterations of the glutathione status by 4-nitrosophenetol during perfusion of rat livers.

(1) Hemoglobin-free single-pass perfusion of isolated rat livers was carried out with various concentrations of 4-nitrosophenetol (NOPt). (2) NOPt, up to 2 mumol/min/g liver wet wt., was reduced by the liver with formation of N-hydroxy-4-phenetidine (NHOHPt), 4-phenetidine (NH2Pt), phenacetin and polar metabolites. (3) Three per cent of NOPt was irreversibly bound to liver proteins after a load of 20 mumol/g liver wet wt. After 30 min perfusion, 0.2 mumol of liver glutathione was lost by 1 mumol NOPt infused. (4) Bile flow and glutathione release by the bile decreased rapidly during NOPt perfusion. (5) Glutathione release of the livers into venous effluent was diminished by NOPt and was stimulated only slightly by t-butylhydroperoxide (BOOH). Because BOOH reduction and glutathione peroxidase were not altered and intracellular glutathione disulfide (GSSG) levels were elevated, inhibition of the GSSG excretory mechanism is assumed.

Animals↗
PubMed1994

Alteration of the erythrocyte glutathione redox balance by N-acetylcysteine, captopril and exogenous glutathione.

The effect of the thiol containing compounds N-acetylcysteine and captopril on glutathione metabolism in human erythrocytes has been investigated non-invasively using 1H spin echo NMR. N-Acetylcysteine was found to increase the reduced form of glutathione while captopril increased the oxidized form, but no changes in the total glutathione concentration were observed. Incubation of the cells with buthionine sulphoximine to inhibit de novo glutathione synthesis did not affect the response. The results show that these compounds act by altering the redox balance of glutathione rather than by stimulating its synthesis, and that their mechanisms of action are different, and not simply due to the presence of the thiol group.

Acetylcysteine↗
PubMed1992

Reactions of glutathione and glutathione radicals with benzoquinones.

The reactions of glutathione (GSH) and glutathione radicals with a series of methyl-substituted 1,4-benzoquinones and 1,4-benzoquinone have been studied. It was found that by mixing excess benzoquinone with glutathione at pH above 6.5, the products formed were complex and unstable. All of the other experiments were carried out at pH 6.0, where the main product was stable for several hours. Stopped-flow analysis allowed the measurement of the rates of the rapid reactions between GSH and the quinones, and the products were monitored by High Performance Liquid Chromatography (HPLC). The rates of the reactions vary by five orders of magnitude and must be influenced by steric factors as well as changes in the redox states. It was observed that simple hydroquinones were not formed when the different benzoquinones were mixed with excess GSH and suggests that the initial reaction is addition/reduction rather than electron transfer. In the presence of excess quinone, the hydroquinone of the glutathione conjugate is oxidized back to its quinone. The rates of the reaction were measured. By using the technique of pulse radiolysis, it was possible to measure the reduction of the quinones by GSSG.- and the oxidation of hydroquinones by GS(.). It is proposed that the appearance of GSSG in reactions of quinones with glutathione could be due to oxidation of the hydroquinone by oxygen and the subsequent superoxide or H2O2 promoting the oxidation of GSH to GSSG.

Benzoquinones↗
PubMed2001

Glutathione uptake after intraperitoneal administration and glutathione radiopharmacology after rectal administration, in mice.

Glutathione is a biologic aminothiol radioprotector. Hydrolysis of exogenous glutathione takes place in the extracellular compartment and leads to two metabolites: gamma-glutamylcysteine and glycine. In healthy mice, after an intraperitoneal administration of glutathione, all organs absorb the gamma-glutamylcysteine and the glycine with variable kinetics according to their enzymatic equipment. The rectal administration of glutathione in mice previously irradiated at the pelvic region, increases the availability of glutathione in the rectum and in other organs at a distant from the irradiation site. This contribution could be used to protect the rectum and the uterus during therapeutic irradiation.

Administration, Rectal↗
PubMed1998

Transport of glutathione conjugate in erythrocytes from aged subjects and susceptibility to oxidative stress following inhibition of the glutathione S-conjugate pump.

The aim of the present study was to investigate the effect of donor aging on the glutathione conjugate transport in erythrocytes and whether it plays a role in the resistance to oxidative stress of the erythrocytes of aging subjects. In our comparative study on intact erythrocytes of healthy aging and young adults, in which 2,4-dinitrophenyl-S-glutathione (DNP-SG) was used as model glutathione S-conjugate, we found that the efflux of DNP-SG remained unchanged in the aged subjects. This result suggests that the detoxification function is maintained against the chemical stress employed in erythrocytes of aging subjects. In the assay conditions used, which were optimized to obtain maximal inhibition of glutathione S-conjugate transport, our results also indicated that the susceptibility of erythrocytes to in vitro lipid peroxidation generated by cumene hydroperoxide was enhanced by pretreatment with DNP-SG inhibitors in both age groups. However, the difference in susceptibility was not a function of aging. Further, the results suggested that inhibition of glutathione S-conjugate pump may impair cellular protection of the erythrocytes against oxidative damage.

Adult↗
PubMedDate not supplied

S-(2-hydroxy-3-buten-1-yl)glutathione and S-(1-hydroxy-3-buten-2-yl)glutathione are in vivo metabolites of butadiene monoxide: detection and quantitation in bile.

Administration (ip) of butadiene monoxide, a toxic metabolite of 1,3-butadiene, to rats caused the appearance of two new biliary peaks when analyzed by HPLC chromatography. These peaks were isolated and identified as the regioisomeric glutathione conjugates, S-(2-hydroxy-3-buten-1-yl)glutathione (I) and S-(1-hydroxy-3-buten-2-yl)glutathione (II), by comparison of their HPLC retention times and fast atom bombardment mass spectra to those of synthetic standards. S-(4-Hydroxy-2-buten-1-yl)glutathione, a rearrangement product formed during chemical synthesis or storage of I, was not detected. Whether butadiene monoxide was given at a dose of 14.3 or 143 mumol/kg, the amount of conjugates excreted in 30 min was at least 85% of that excreted in 120 min. Conjugate excretion in 60 min did not exhibit saturation when the butadiene monoxide dose was varied between 14.3 and 286 mumol/kg; the total amount of the butadiene monoxide dose excreted as combined I and II averaged only 7.6 +/- 4.2% (mean +/- SD, n = 12), with approximately a 3:1 ratio of isomers I:II being excreted at all butadiene monoxide doses. Whereas these results indicate a role for glutathione S-transferase-catalyzed reactions in butadiene monoxide metabolism in vivo, biliary excretion of I and II can only account for a small fraction of the butadiene monoxide dose given.

Animals↗
PubMed1979

A steady-state-kinetic model for formaldehyde dehydrogenase from human liver. A mechanism involving NAD+ and the hemimercaptal adduct of glutathione and formaldehyde as substrates and free glutathione as an allosteric activator of the enzyme.

The steady-state kinetics of formaldehyde dehydrogenase from human liver have been explored. Non-linearities were obtained in v-versus-v[S] plots. It was necessary and sufficient to consider two reactants of the equilibrium mixture of formaldehyde, glutathione and their hemimercaptal adduct for a complete description of the kinetics. A random sequential reaction scheme is proposed in which adduct and beta-NAD+ are the substrates. In addition, glutathione can bind to an allosteric regulatory site and only the glutathione-containing enzyme is considered productive. Various alternative reaction models were examined but no simple alterative was superior to the model chosen. The discrimination was largely based on results of non-linear regression analysis. Several S-substituted glutathione derivatives were tested as activators or inhibitors of the enzyme, but all were without effect. Thio-NAD+, nicotinamide--hypoxanthine dinucleotide and 3-acetylpyridine-adenine dinucleotide could substitute for beta-NAD+ as the nucleotide substrate. alpha-NAD+ and ADP-ribose were competitive inhibitors with respect to beta-NAD+ and non-competitive with glutathione and the adduct. When used simultaneously, the inhibitors were linear competitive versus each other, indicating a single nucleotide-binding site or, if more than one, non-co-operative binding sites.

Aldehyde Oxidoreductases↗
PubMed1987

Identification of a novel glutathione transferase in human skin homologous with class alpha glutathione transferase 2-2 in the rat.

Six forms of glutathione transferase with pI values of 4.6, 5.9, 6.8, 7.1, 8.5 and 9.9 have been isolated from the cytosol fraction of normal skin from three human subjects. The three most abundant enzymes were an acidic Class Pi transferase (pI 4.6; apparent subunit Mr 23,000), a basic Class Alpha transferase (pI 8.5; apparent subunit Mr 24,000) and an even more basic glutathione transferase of Class Alpha (pI 9.9; apparent subunit Mr 26,500). The last enzyme, which was previously unknown, accounts for 10-20% of the glutathione transferase in human skin. The novel transferase showed greater similarities with rat glutathione transferase 2-2, another Class Alpha enzyme, than with any other known transferase irrespective of species. The most striking similarities included reactions with antibodies, amino acid compositions and identical N-terminal amino acid sequences (16 residues). The close relationship between the human most basic and the rat glutathione transferase 2-2 supports the classification of the transferases previously proposed and indicates that the similarities between enzymes isolated from different species are more extensive than had been assumed previously.

Amino Acids↗
PubMed2002

Genetic polymorphisms of glutathione S-transferase A1, the major glutathione S-transferase in human liver: consequences for enzyme expression and busulfan conjugation.

BACKGROUND: High-dose busulfan is widely used as part of conditioning regimens for patients who are undergoing hematopoietic stem cell or bone marrow transplantation. High plasma concentrations of busulfan have been linked to the occurrence of hepatic venoocclusive disease (VOD), a severe complication associated with a high mortality. Because conjugation with glutathione, the major route of biotransformation of busulfan, is predominantly catalyzed by the isozyme glutathione S-transferase A1 (GSTA1), we hypothesized that low expression or function of GSTA1 in liver caused by genetic polymorphisms may be the mechanism underlying VOD. METHODS: Immunoblot analysis of GSTA and measurement of busulfan-glutathione conjugation by liquid chromatography-mass spectrometry were performed in 48 normal human liver samples. To search for polymorphisms, the complete GSTA1 coding regions and the promoter fragment were sequenced. All results were compared by multivariate analysis. RESULTS: Absolute levels of GSTA protein and formation rates of busulfan-glutathione conjugate displayed a 7- and 8-fold range, from 240 to 1600 pmol/mg and 25 to 205 pmol/min per milligram of total cytosolic protein, respectively, and correlate (r2 = 0.49, P <.0001). A total of 8 single nucleotide polymorphisms (SNPs) of GSTA1 were identified, 1 of which was a silent mutation in exon 5 (A375G); all others were found in the promoter region. Haplotype analysis revealed the existence of 5 defined alleles. There was no significant relationship between any of the GSTA1 SNPs or haplotypes and either hepatic glutathione S-transferase A (GSTA) expression or GSTA1 function. CONCLUSIONS: The identified GSTA1 polymorphisms are not likely to be related to the VOD because they do not appear to be associated with changes in GSTA expression or function. Compared with other members of the GST family, GSTA1 displays surprisingly little variation.

Busulfan↗
PubMed1998

Glutathione metabolism and glutathione S-conjugate export ATPase (MRP1/GS-X pump) activity in cancer. I. Differential expression in human cancer cell lines.

Mg(2+)-dependent vanadate-sensitive glutathione S-conjugate ATPase (GS-X pump) activity is a common feature of some ATP-binding cassette (ABC) transporters, such as the multidrug resistance-associated protein (MRP1) gene product, that exports biologically active electrophiles after their conjugation with intracellular glutathione (GSH) from normal and cancer cells. Antitumor electrophiles (e.g. naturally occurring cyclopentenone prostaglandins and anticancer chemicals) can be intracellularly conjugated with GSH via a glutathione S-transferase catalyzed reaction and be eliminated through GS-X pumps thus threatening cancer chemotherapeutics. Since different sensitivities to antitumor electrophiles are shown by different cell types, the ability of several human cancer cell lines to produce and export S-(2,4-dinitrophenyl)-glutathione (DNP-SG) conjugate through the GS-X pump, using whole cells and inside-out membrane vesicle preparations, is investigated. Different cancer cell lines exhibited characteristically different GS-X pump activity. In particular, HEp-2 larynx carcinoma cells possess an elevated DNP-SG export rate through the GS-X pump compared with HeLa, K562, U937 or HL-60 cells, which exhibit the lowest activity. The differences in DNP-SG export rates are not due to decreased glutathione S-transferase activity or impaired de novo synthesis of GSH. The findings suggest that the GS-X pump may be involved in the modulation of the biological activity of both naturally occurring electrophiles and anticancer drugs. The differential expression of GS-X pumps may lead to an improved understanding of multidrug resistance and may be exploited in the development of new therapeutic strategies for the treatment of cancer patients.

Adenosine Triphosphatases↗
PubMed1987

Effect of selenium depletion and repletion on plasma glutathione and glutathione-dependent enzymes in the rat.

Selenium deficiency has several known biochemical effects. In the rat, these effects include loss of glutathione peroxidase (GSH-Px) activity, increased plasma glutathione concentration and increased liver glutathione S-transferase (GSH S-Tr) activity. The time course of the development of these changes in rats fed selenium-deficient diets and the time course of reversal of these changes in selenium-deficient rats fed graded levels of selenium were determined. As selenium deficiency was produced, liver cytosolic and plasma GSH-Px activities decreased first and were less than 5% of control when plasma glutathione concentration and liver GSH S-Tr activity began to increase. Elevated liver GSH S-Tr activity in selenium-deficient rats was corrected by refeeding selenium at the lowest level of supplementation (0.015 ppm) for 4 wk. GSH-Px activity required a supplementation of 0.10 ppm selenium for correction to control levels in 4 wk. Based on these studies a classification of the severity of selenium deficiency into mild, moderate and severe categories is proposed. In addition, the effect of dietary sulfur amino acid supplementation on plasma glutathione concentration was studied.

Amino Acids, Sulfur↗