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PubMed2003

Effects of flavonoids on glutathione and glutathione-related enzymes in cisplatin-treated L1210 leukemia cells.

Connections between the ability of quercetin (Qu)and galangin (Ga) to differentially modulate cis-Pt-induced apoptosis and their effects on glutathione system of murine L1210 leukemia cells were studied. The results showed that total glutathione (GSHt) level is increased significantly (cca 123% of control level), both in cells treated with 10 microM Qu and in cells treated with 4 microM cis-Pt and 10 microM Qu in combination. 10 microM Ga had no effect on GSHt content. Activities of glutathione S-transferase (GST) and glutathione reductase (GR) were not changed significantly when 10 microM flavonoids were used. Significant inhibition of GR activity was observed when flavonoids were used in concentrations higher than 25 microM. The presented data indicate that Qu change the redox state of the cells that is implicated in regulation of apoptosis, due to its ability to increase the GSHt level, and thus may potentiate cis-Pt-induced apoptosis of L1210 cells.

Animals↗
PubMed2004

Protective effects of taurine on glutathione and glutathione-dependent enzymes in ethanol-fed rats.

Ethanol, by its property of generating free radicals during the course of its metabolism, alters redox homeostasis and causes damage to cell structure and function. This study investigated the effect of taurine on ethanol-induced experimental toxicity in rats. Ethanol was administered chronically to rats for 28 days. This resulted in significant increases in the activities of transaminases, alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT) and bilirubin in plasma. The activities of glutathione peroxidase (GPx), glutathione-S-transferase (GST) and the contents of glutathione (GSH) and thiols in plasma and tissues were significantly reduced as compared to control animals. Simultaneous administration of taurine along with ethanol prevented the leakage of enzymes into circulation and restored glutathione and tissue thiols. The activities of antioxidant enzymes were normalized. We propose that taurine may have a bioprotective effect on ethanol-induced toxicity.

Animals↗
PubMed1985

Studies on tissue distribution of glutathione and on activities of glutathione-related enzymes after carbon tetrachloride-induced liver injury.

After an initial decrease following CCl4-application (1.0 ml/kg bodyweight, i.p.), in the liver of male Wistar rats, values of reduced glutathione (GSH) are at a maximum 6 and 12 h after treatment. Oxidized glutathione (GSSG) increases up to 24 h after intoxication. Malondialdehyde (MDA) is at a low level, when GSH is high. Glutathione peroxidase has a clear initial increase of activity, but otherwise shows only slight deviations from control values. Cytosolic and microsomal glutathione-S-transferases reach minimum values at 6 and 12 h, respectively. The histochemical demonstration of GSH reveals an uneven distribution in the liver lobule, with higher amounts of reaction products in the periphery. With increasing time after intoxication the typical lobular distribution pattern changes and the accumulation of GSH reaction products becomes patchy. Other parts, however, remain rather normal. 12 h after intoxication most of the hepatic lobules are relatively free of GSH, while the content of the central venules and sublobular veins is strongly stained. Lipid histochemistry shows a fat accumulation already 3 h after CCl4. Central lobular cells are particularly affected. Biochemical and histochemical results are discussed with respect to the regional differences.

Animals↗
PubMed1996

[Glutathione and enzymes associated with glutathione metabolism in adriamycin nephropathy].

Recent data have shown the protective effect of thiol groups on the progression of adriamycin-induced experimental nephropathy, in which reactive oxygen metabolites have been postulated to play an important role. To gain greater insight in the role of glutathione (GSH) in adriamycin-induced nephrosis, we studied changes in reduced GSH level and its associated enzymes in kidney tissue of rats undergoing chronic renal failure produced by i.v. infections of adriamycin (2 x 2 mg/kg b.w.). Kidney damage was characterized by increases in relative kidney weight and BUN levels. The results obtained revealed a 15% drop in renal GSH level in adriamycin-treated animals associated by a similar decrease in the gamma-glutamylcysteine synthetase activity. The activities of kidney glutathione reductase (GR) and glutathione peroxiase (GSH-Px) which are critical constituents of GSH-redox cycle, were significantly decreased (23 an 26%, respectively) in response to adriamycin treatment. Rat kidney glutathione-S transferase and gamma-glutamyl transpeptidase activities were not affected in adriamycin induced nephrosis. We propose that the impairment of renal antioxidant defense, characterized by combined drop in GSH, GR and GSH-Px levels, could permit enhanced free radical induced kidney damage in adriamycin-induced nephropathy.

Animals↗
PubMed1997

Glutathione and glutathione metabolizing enzymes in tissues and blood of breast cancer patients.

Many reports indicate that glutathione and enzymes cooperating with it are important in neoplastic processes. Glutathione (GSH) concentrations and glutathione S-transferase (GSH STr) and glutathione peroxidase (GSH-Px) activities were determined in breast cancer tissue and adjacent healthy tissues, as well as in blood of 28 patients. There were considerable differences in the investigated parameters among individual patients. Therefore we analyzed the paired samples of normal and cancerous tissues from the same individual. In 68% of the patients the activities of GSH-Px and in 85% patients those of GSH STr were found to be higher in the tumor than in the normal tissue. GSH concentration in 48% tumor samples were higher and in 44% lower than in corresponding normal tissues. Statistically significant correlation was found between GSH-Px and GSH STr in normal (r = 0.51, p < 0.005) and in cancer tissues (r = 0.64, p = 0.001). Correlation coefficient between GSH Px activity in normal and corresponding cancer tissues was r = 0.71 (p < 0.001), however this correlation in the case of GSH STr was much lower but still significant (r = 0.38, p < 0.05). No significant correlation in the determined parameters was found between erythrocytes or plasma and normal or cancer tissues.

Adult↗
PubMed1987

Amino acids, glutathione, and glutathione transferase activity in the brains of patients with Alzheimer's disease.

We measured the contents of amino acids and related amino compounds in autopsied brain from 22 patients with Alzheimer's disease (AD) and in cortical biopsy specimens from 2 other patients. The diagnosis of AD was established neuropathologically in all 24 patients by the presence of both neurofibrillary tangles and neuritic plaques in neocortex. The mean contents of gamma-aminobutyric acid (GABA), and of the GABA dipeptide homocarnosine, were significantly reduced in frontal and occipital cortices and in hippocampus of the autopsied brains of AD patients compared to control patients without neurological disease. However, GABA contents were normal in frontal cortex in biopsy samples from 2 patients. Phosphoethanolamine contents were significantly reduced at autopsy in frontal and occipital cortex, and in the substantia innominata. We found no evidence of a deficiency of glutamate, aspartate, or taurine in AD brain, as has been claimed. Glutathione contents and glutathione transferase activities were normal in frontal cortex and substantia innominata. The mechanism of neuronal death in patients with AD is unlikely to involve either insufficient synthesis of glutathione or failure to conjugate free radicals with glutathione.

Adolescent↗
PubMed1992

Erythrocyte membrane transport of glutathione conjugates and oxidized glutathione in the Dubin-Johnson syndrome and in rats with hereditary hyperbilirubinemia.

The Dubin-Johnson syndrome is manifested by conjugated hyperbilirubinemia and pigment accumulation in hepatocellular lysosomes. The TR-rat model is a phenotypic model of the Dubin-Johnson syndrome and is characterized by defective ATP-dependent transport of a group of nonbile acid organic anions, including glutathione-S-conjugates and oxidized glutathione, across the bile canaliculus. Similar ATP-dependent transport mechanisms have been described in erythrocytes. Intact erythrocytes and inverted erythrocyte membrane vesicles from Dubin-Johnson patients, TR-rats and appropriate controls were studied with regard to ATP-dependent transport of dinitrophenyl glutathione and oxidized glutathione. No significant differences were observed, indicating that the erythrocyte and canalicular ATP-dependent transporters for these substrates are functionally and potentially genetically distinct.

Adenosine Triphosphate↗
PubMed1991

The three-dimensional structure of class pi glutathione S-transferase in complex with glutathione sulfonate at 2.3 A resolution.

The three-dimensional structure of class pi glutathione S-transferase from pig lung, a homodimeric enzyme, has been solved by multiple isomorphous replacement at 3 A resolution and preliminarily refined at 2.3 A resolution (R = 0.24). Each subunit (207 residues) is folded into two domains of different structure. Domain I (residues 1-74) consists of a central four-stranded beta-sheet flanked on one side by two alpha-helices and on the other side, facing the solvent, by a bent, irregular helix structure. The topological pattern resembles the bacteriophage T4 thioredoxin fold, in spite of their dissimilar sequences. Domain II (residues 81-207) contains five alpha-helices. The dimeric molecule is globular with dimensions of about 55 A x 52 A x 45 A. Between the subunits and along the local diad, is a large cavity which could possibly be involved in the transport of nonsubstrate ligands. The binding site of the competitive inhibitor, glutathione sulfonate, is located on domain I, and is part of a cleft formed between intrasubunit domains. Glutathione sulfonate is bound in an extended conformation through multiple interactions. Only three contact residues, namely Tyr7, Gln62 and Asp96 are conserved within the family of cytosolic glutathione S-transferases. The exact location of the binding site(s) of the electrophilic substrate is not clear. Catalytic models are discussed on the basis of the molecular structure.

Amino Acid Sequence↗
PubMedDate not supplied

Concentration of glutathione and expression of glutathione peroxidases 1 and 4 in fresh sperm provide a forecast of the outcome of cryopreservation of human spermatozoa.

Oxidative stress imbalance potentially leads to damage of the structure of the cell and macromolecules such as plasma membrane components, proteins, and DNA. The plasma membrane of the sperm cell, which has high levels of polyunsaturated fatty acids, renders it particularly sensitive to free radical-mediated attacks. The freezing and subsequent thawing of sperm is a physically stressful process carried out during routine procedures in assisted reproduction techniques, which results in a highly variable and unpredictable reduction in the number of motile sperm cells. Subsequently, oxidative status can positively or negatively affect the motility, viability, and fertilizing capacity of thawed sperm. These effects are counteracted by various oxidative defense enzymes and anti-oxidants such as glutathione peroxidase isoforms GPx1 and GPx4, glutathione reductase (GR), and cellular glutathione (reduced) (GSH). In this way, oxidative status could represent a predictive marker of sperm quality following the freeze-thaw process. This study was based on 56 human sperm samples. We observed direct positive and negative relationships between the postthaw motile sperm recovery rate and GPx1 and GPx4 expression and activity, on the one hand, and GSH concentrations, on the other. No correlation was found between this recovery rate and GR or basic semen parameters. Predictive values clearly demonstrate that, among the molecules analyzed, the most accurate diagnoses result when analyses are conducted for GPx1 and GPx1 messenger RNA expression, GPx1 and GPx4 enzymatic activity, and GSH concentration. In conclusion, a reserve of glutathione, together with GPx expression, is necessary to eliminate free radicals using GSH or a like structural protein and seems to be essential for a good postthaw recovery. These molecules can be employed as indicators of postthaw sperm quality.

Cryopreservation↗
PubMed2000

Determining glutathione and glutathione disulfide using the fluorescence probe o-phthalaldehyde.

Because of the importance of glutathione (GSH) and glutathione disulfide (GSSG) in cellular signal transduction, gene regulation, redox regulation, and biochemical homeostasis, accurate determination of cellular glutathione levels is critical. Several procedures have been developed, but many suffer from overestimating GSSG or from cellular substances interfering or competing with GSH determination. Assays based on HPLC, with enzymatic reduction of GSSG by glutathione reductase and NADPH, appear to be valid but are limited in sample throughput and availability of equipment. The fluorescence probe o-phthalaldehyde (OPA, phthalic dicarboxaldehyde) reacts with GSH and has a high quantum yield, yet its use has been limited due to unidentified interfering and fluorescence-quenching substances in liver. This paper describes assay conditions under which these limitations are avoided. By using a phosphate-buffered assay at lower pH, interference with nonspecific reactants is minimal. Since enzymatic reduction is not possible due to the reaction of OPA with NAD(P)H and other stronger reducing agents, leading to an overestimation of GSSG levels, dithionite was used to reduce GSSG. High sample throughput combined with sensitive (20-pmol limit of detection) and accurate determination of GSH and GSSG using OPA is achievable with any monochromatographic spectrofluorometer. Sample preparation and storage conditions are described that return the same levels of GSH and GSSG for at least 4 weeks.

Animals↗
PubMed2000

The effects of carbamazepine and valproic acid on the erythrocyte glutathione, glutathione peroxidase, superoxide dismutase and serum lipid peroxidation in epileptic children.

Some epileptic drugs may change antioxidant enzyme activities in humans and experimental animals. Recent studies suggest that membrane lipid peroxidation may be causally involved in some forms of epilepsy, and the differences are reported in free radical scavenging enzyme levels. GSHpX, SOD, GSH are important parameters of antioxidant defence mechanisms. This study was undertaken to evaluate the effects of valproic acid and carbamazepine (CBZ) therapy on erythrocyte glutathione (GSH), glutathione peroxidase (GSHpX), superoxide dismutase (SOD) and lipid peroxidation. During the treatment with VPA or CBZ, the erythrocyte GSHpX and GSH levels of epileptic children were significantly changed as compared to those of health control subjects. The mean levels of serum lipid peroxidation and erythrocyte superoxide dismutase were not statistically different from controls. The methods used for investigation of glutathione peroxidase, superoxide dismutase, glutathione and serum lipid peroxidation were all based on spectrophotometric measurement.

Adolescent↗
PubMed2000

Endogenous glutathione-binding proteins of insect cell lines: characterization and removal from glutathione S-transferase (GST) fusion proteins.

After affinity purification on immobilized glutathione, insect-cell-derived glutathione S-transferase (GST) fusion proteins contain variable amounts of protein contaminants of about 23-24 kDa. We have isolated these glutathione-binding proteins from the widely used Sf9 and Hi5 insect cell lines and characterized them by LC-MS and N-terminal sequencing. Based on the observation that these proteins have higher affinity for glutathione than GST fusions, we have found that by using differential elution conditions the amount of such contaminants in GST fusion preparations can be strongly reduced directly during the affinity purification step. The main interest of these results is that they are not restricted to a specific construct, but rather they seem to apply to various insect-cell-derived GST fusions.

Animals↗
PubMed2005

Induction of glutathione S-transferase and glutathione by toxic compounds and elicitors in reed canary grass.

Treatment of read canary grass leaves with phenol, 4-chlorophenol, naphthalic anhydride and phenylethylisothiocyanate increased glutathione S-transferase activity by 1.4-2.4-fold (control 17 U g(-1) DW). Benzothiadiazole, beta-aminobutyric acid and salicylic acid increased activity by 1.3-1.8-fold. Total glutathione pool was increased by the toxic compounds by 1.2-2-fold and by the elicitors 1.4-1.6-fold (control 593 nmol g(-1) DW). Unlike the other compounds, benzothiadiazole and salicylic acid did not decrease the redox state. Benzothiadiazole acted synergistically with chlorophenol on glutathione S-transferase and glutathione levels and counteracted the decrease in redox state caused by the xenobiotic. Reed canary grass thus has a strong potential to neutralize toxic compounds, which may be further enhanced by elicitors.

Aminobutyrates↗
PubMed1988

Micromethods in single muscle fibers. 2. Determination of glutathione reductase and glutathione peroxidase.

This paper extends the previous study for systems which control intracellular oxidative events in muscle and describes procedures suitable to assay glutathione peroxidase (GSHPx), glutathione reductase (GR), and total glutathione (GSH + GSSG) after fiber typing of individual muscle fibers. In human skeletal muscle, both GR and GSHPx activities were relatively low when compared to those of other tissue. No difference was found among fiber types (I, IIA, and IIB) with regard to GR activity, but in contrast GSHPx activity was significantly lower in type IIB fibers than in the other types. These results suggest that type IIB fibers may have a reduced ability to cope with hydroperoxides generated during oxidative stress, which, in turn, could lead to increased damage to membrane structures by lipid peroxidation or oxidation of sensitive intracellular thiol (-SH) enzymes by hydrogen peroxide. The Km of skeletal muscle GR for GSSG was 27 microM and for NADPH was 22 microM. If one assumes approximately 95% of total glutathione is present in the reduced state, then GSSG concentration would be of the order of 0.3 mmol/kg and under these conditions skeletal muscle GR would be efficient in all muscle fiber types.

Fluorescence↗
PubMed1990

Automated assays for superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase activity.

Automated assays for catalase, glutathione peroxidase, glutathione reductase, and superoxide dismutase are presented. The assay for catalase is based on the peroxidatic activity of the enzyme. The glutathione peroxidase and reductase assays measure the consumption of NADPH following the reduction of t-butyl hydroperoxide and oxidized glutathione, respectively. The assay for superoxide dismutase is based on the reduction of cytochrome c. All assays utilize the Cobas FARA clinical automated analyzer and provide considerable time savings over the manual assays.

Animals↗
PubMed1994

Alpha,beta-unsaturated carbonyl compounds: inhibition of rat liver glutathione S-transferase isozymes and chemical reaction with reduced glutathione.

Five different alpha,beta-unsaturated carbonyl compounds displayed different reactivities with regard to inhibition of alpha- and mu-class isozymes of rat liver glutathione S-transferases and the chemical reaction with glutathione. Only (E)-2-octenal and (E)-3-nonen-2-one exhibited significant levels of inhibition for each of the rat liver GST isozymes examined. The (E)-2-octenal was more effective as an inhibitor of the alpha-class of isozymes when compared to the mu-class, whereas the (E)-3-nonen-2-one showed a greater degree of inhibition of the mu-class of isozymes relative to the alpha-class. Isozyme 1-1 demonstrated the greatest degree of inhibition with (E)-2-octenal (IC50 = 5.89 microM) of all inhibitor/isozyme combinations. The Ki values for (E)-2-octenal and (E)-3-nonen-2-one toward selected alpha- and mu-class of rat liver glutathione S-transferase isozymes were determined and both of these compounds competitively inhibited all five of the rat liver glutathione S-transferase isozymes examined. The Ki values obtained for these two compounds were significantly different for each of the isozymes except for isozyme 4-4. With the alpha-class of rat liver GST isozymes, (E)-3-nonen-2-one showed a larger Ki value than (E)-2-octenal. Whereas, with the mu-class, (E)-2-octenal exhibited a larger Ki value than (E)-3-nonen-2-one. The rate constants of the forward reaction (k+1), as well as the equilibrium constants (Kd) were determined and the rate constants of the reverse reaction (k-1) were calculated.

Aldehydes↗
PubMed1987

The isolation of a fetal rat liver glutathione S-transferase isoenzyme with high glutathione peroxidase activity.

A previously uncharacterized glutathione S-transferase isoenzyme which is absent from normal adult rat livers has been isolated from fetal rat livers. The enzyme was purified using a combination of affinity chromatography, CM-cellulose column chromatography and chromatofocusing. It is composed of two non-identical subunits, namely, subunit Yc (Mr 28,000) and a subunit (Mr 25,500) recently reported by us to be uniquely present in fetal rat livers and which we now refer to as subunit 'Yfetus'. The enzyme which we term glutathione S-transferase YcYfetus has an isoelectric point of approx. 8.65 and has glutathione S-transferase activity towards a number of substrates. The most significant property of the fetal isozyme is its high glutathione peroxidase activity towards the model substrate cumene hydroperoxide. We suggest that this isozyme serves a specific function in protecting fetuses against the possible teratogenic effects of organic peroxides.

Amino Acids↗
PubMed1992

Cellular glutathione (GSH) and glutathione S-transferase (GST) activity in human ovarian tumor biopsies following exposure to alkylating agents.

In vitro studies have suggested that elevated levels of the thiol glutathione (GSH) may be associated with acquired alkylating agent resistance, but there is currently little data on the relationship between elevated GSH and glutathione S-transferase levels and clinical alkylating agent resistance. In this study, GSH and glutathione S-transferase levels have been determined in 23 human ovarian tumor samples obtained prior to the onset of combination chemotherapy, and in 23 samples obtained after the development of acquired chemoresistance. GSH levels were 10-fold greater in human ovarian tumor cells obtained after alkylating agent resistance developed, than in biopsy samples obtained prior to treatment. No significant changes in the expression of total glutathione S-transferases were seen in relation to prior drug exposure.

Antineoplastic Combined Chemotherapy Protocols↗