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PubMed2002

Protein denitration/modification by glutathione-S-transferase and glutathione peroxidase.

Peroxynitrite (PN)-pretreated histone III-S (NH) and reduced glutathione (GSH)-treated NH (NH(GSH)) were incubated with glutathione-S-transferase (GST) and glutathione peroxidase (GPX). Western blot analysis revealed decreased 3-nitrotyrosine immunoreactivity for NH(GSH), but not for NH. Additionally, increased nitrate was noted as an end product of these enzymatic reactions. The findings imply that GSH-treatment of NH may facilitate its conformational change in favor of subsequent enzymatic denitration and/or modification, which could be vital in relieving cellular oxidative stress and regulating NO/PN-mediated signal transduction cascade.

Animals↗
PubMed1999

Elevation of glutathione level and activation of glutathione-related enzymes affect virus infection in tobacco.

The effects of two chemicals, L-2-oxothiazolidine-4-carboxylic acid (OTC) and (S)-carvone, were investigated on the development of necrotic symptoms and on the virus concentration in tobacco mosaic virus (TMV)-infected tobacco plants. OTC treatments markedly increased the cellular glutathione (GSH) levels in tobacco leaf discs. In addition, OTC pretreatment considerably decreased both the number of necrotic lesions and the virus content in TMV-infected leaf discs. The monoterpene (S)-carvone increased only slightly the GSH content of leaf tissues and caused lipid peroxidation. (S)-carvone dramatically induced the activity of glutathione S-transferase and to a lesser extent elevated also the activities of ascorbate peroxidase and glutathione reductase. Treatments with (S)-carvone strongly reduced the number and size of necrotic lesions, but did not influence the virus concentration. The results show that increased levels of GSH and activities of GSH-related enzymes by OTC and (S)-carvone reduce necrotization of virus-infected tissues. However, virus multiplication and lesion formation do not necessarily correlate: virus multiplication is suppressed only by substantially elevated GSH contents.

Ascorbate Peroxidases↗
PubMed1996

Effect of oltipraz, alpha-tocopherol, beta-carotene and phenethylisothiocyanate on rat oesophageal, gastric, colonic and hepatic glutathione, glutathione S-transferase and peroxidase.

Four anticarcinogens (oltipraz, alpha-tocopherol, beta-carotene and phenethylisothiocyanate [PEITC]) were studied with respect to their effects on oesophageal, gastric, colonic and hepatic (i) glutathione (GSH) content, (ii) glutathione S-transferase (GST) enzyme activity, (iii) GST isoenzyme levels, and (iv) glutathione peroxidase (GPx) enzyme activity in male Wistar rats. GST enzyme activity was significantly increased in oesophagus (1.9X) and colon (1.2X) by PEITC and in liver (1.4X) by oltipraz. GST Alpha was doubled in the liver by oltipraz, alpha-tocopherol and PEITC. GST Mu levels were increased by beta-carotene and PEITC in stomach and liver, by oltipraz in liver and by alpha-tocopherol in stomach. PEITC induced colonic GST Pi levels (1.3X). GSH content was induced in liver by oltipraz (1.4X) and alpha-tocopherol (1.2X) and in colon by PEITC (1.6X). Each of the anticarcinogens tested increased GPx activity at one or more sites: Se-dependent and total GPx activities were induced in 31.3% and 37.5% of all possibilities, respectively. Major induction in total GPx was found in stomach by alpha-tocopherol (1.8X). In conclusion our data demonstrate that dietary administration of oltipraz, PEITC, alpha-tocopherol and beta-carotene, may exert chemopreventive effects in the digestive tract of the rat by enhancing GST, GPx, and, to a lesser extent, GSH levels.

Animals↗
PubMed1997

The effect of ethyldeshydroxy-sparsomycin and cisplatin on the intracellular glutathione level and glutathione S-transferase activity.

Ethyldeshydroxy-sparsomycin (EdSm) is a ribosomal protein synthesis inhibitor which synergistically enhances the antitumor activity of cisplatin against L1210 leukemia in vivo. Because cellular glutathione (GSH) and glutathione S-transferases (GST) are reported to interfere with the antitumor activity of cisplatin, we analyzed the effect of EdSm and cisplatin on GSH and GST activity in selected tumor cells. For this purpose we used three murine leukemia tumors with different sensitivities towards EdSm and cisplatin: L1210-WT, sensitive to both drugs, L1210-Sm, resistant to EdSm, and L1210-CDDP, resistant to cisplatin. No significant differences were detectable between these three cell lines regarding the population doubling time, the cell size, and the cellular level of protein and glutathione. Neither of the resistant L1210 subclones showed P-glycoprotein expression. Drug exposure, however, changed the intracellular dynamics. Exposure to EdSm strongly decreased the amount of cellular protein, decreased the overall GST activity and led to GSH depletion, whereas exposure to cisplatin induced a rise in the amount of protein, in GSH, and in the total GST activity. These effects are dose-dependent and correlate well with the sensitivity of the tumor cells for EdSm or cisplatin. In addition, exposure to EdSm lowered the V(max) of GST in L1210-WT and L1210-Sm; however, in L1210-CDDP both the V(max) and the K(m) were increased. That this was not a direct effect of EdSm on GST was shown in a cell-free system, where EdSm did not influence the GST activity nor could it act as a substrate for GST. Our results suggest that the synergistic combination of EdSm and cisplatin might be explained by EdSm switching off the cellular detoxification mechanism for cisplatin, i.e. by inhibition of de novo synthesis and subsequent depletion of GSH and GST.

Animals↗
PubMed1991

Comparative study on the influence of two 2-chloroethylnitrosoureas with different carbamoylating potential towards glutathione and glutathione-related enzymes in different organs of the rat.

The influence of two CNUs with similar alkylating but strongly different carbamoylating activity towards the glutathione system was investigated in different organs. Both CNUs influence the glutathione system of the bone marrow in a similar manner, irrespective of their carbamoylating potential. In contrast, glutathione reductase activity in the other organs was strongly decreased by the potent carbamoylator BCNU, whereas no or only minor effects were produced by its weakly carbamoylating counterpart HECNU. The results confirm that bone marrow toxicity of CNUs primarily results from alkylation and not from carbamoylation. Other organ-related toxic effects, however, are probably a result of carbamoylating reactions exerted by BCNU. This applies especially to lung toxicity that has been observed frequently as a major side effect in clinical trials with BCNU.

Alkylation↗
PubMed1993

Effects of liver damage induced by carbon tetrachloride on glutathione and glutathione-dependent enzymes in rat gastric mucosa.

The present study investigated the relationship between the concentration of the reduced form of glutathione (GSH) and GSH-dependent enzyme activities in the gastric mucosa during acute liver injury caused by carbon tetrachloride (CCl4) in rats. Transient decreases in glutathione S-transferase (GST) activity and in glutathione peroxidase (GSH-Px) activity was observed (p < 0.01). GSH concentration also decreased (p < 0.01) but then transiently increased (p < 0.05). Gamma-glutamyltransferase (GGT) activities in rats killed 6, 12, and 24 hr after exposure to CCl4 were all higher than in the control group (p < 0.01). There was a significant correlation between GSH concentration and GST activity (p < 0.05) and between GSH concentration and GSH-Px activity (p < 0.01). However, there was no correlation between GSH concentration and GGT activity. The gastric mucosa, as judged by light microscopy, was slightly more damaged in the rats exposed to CCl4 than in the control group. From the observed abnormalities of GSH and GSH-dependent enzymes in the gastric mucosa of the rats exposed to CCl4, changes in GSH content and GSH-related enzymes in gastric mucosa may be important in gastric protection during acute liver injury.

Animals↗
PubMed1993

Effects of carbon tetrachloride-induced chronic liver damage on glutathione and glutathione-dependent enzymes in rat gastric mucosa.

The present study investigated the relationship between the concentration of the reduced form of glutathione (GSH) and GSH-dependent enzyme activities in the gastric mucosa during chronic liver injury caused by carbon tetrachloride (CCl4) in rats. There were significant decreases in the mucosal GSH concentration and glutathione S-transferase (GST) activity as well as a significant increase in gamma glutamyltransferase (GGT) activity in rats exposed to CCl4 (all p < 0.001). However, no significant change was observed in glutathione peroxidase (GSH-Px) activity. A negative correlation was seen between the mucosal GSH concentration and GGT activity (p < 0.05) and a positive correlation between the GSH concentration and GST activity (p < 0.01). No correlation was noted between the GSH concentration and GSH-Px activity. Gastric mucosal damage, as evaluated by macroscopic observation and light microscopy, was more damaged in the rats exposed to CCl4 than in the control group. There was a significant correlation between histologic mucosal damage and GGT activity (p < 0.05) as well as a negative correlation between the number of macroscopic lesions and GSH and between the number of macroscopic lesions and GST (p < 0.01). From the observed abnormalities of GSH and GSH-dependent enzymes in the gastric mucosa of the rats exposed to CCl4, GSH content and the activities of GSH-dependent enzymes might play a role in the gastric mucosal defense mechanism during chronic liver injury.

Animals↗
PubMed2001

Methamphetamine causes depletion of glutathione and an increase in oxidized glutathione in the rat striatum and prefrontal cortex.

The administration of methamphetamine to experimental animals results in damage to dopaminergic neurons. The hypothesis that methamphetamine-induced neurotoxicity is mediated by reactive oxygen species was evaluated. It was found that acute administration of methamphetamine (5 and 15 mg kg(-1)) resulted in production of oxidative stress as demonstrated by decreased glutathione and increased oxidized glutathione levels in the rat striatum and prefrontal cortex. These changes in glutathione and oxidized glutathione levels were dose-dependent in striatum but not in prefrontal cortex. In conclusion, the results of present study provide further evidence in support of the notion that oxidative stress may play an important role in the methamphetamine-induced neurotoxicity.

Journal Article↗
PubMed2002

The effect of glutathione monoester (GME) on glutathione (GSH) depleted rat liver.

The effect of glutathione monoester (GME) on buthionine sulfoximine (BSO) mediated glutathione (GSH) depletion in rats was studied to understand the defensive role of intraperitoneally supplemented GSH. Administration of glutathione mono ester (GME) (at a dose of 5 mmole/kg body weight, twice a day for 30 days) significantly prevented the buthionine sulfoximine (at a dose of 4 mmole/kg body weight, twice a day for 30 days) induced alterations. This study suggests that glutathione mono ester is hepatoprotective and plays an important role in preventing lipid peroxidation, which leads to cytotoxic effects.

Journal Article↗
PubMed1999

Glutathione and glutathione-dependent enzymes in cancer drug resistance.

Genetic and biochemical evidence has demonstrated that glutathione and glutathione-dependent enzymes play a central role in cellular defence against toxic environmental agents. Modulation of cellular glutathione homeostasis can also have a profound effect on the sensitivity of cancer cells to a wide range of drugs used in chemotherapy. These effects are produced by multifactorial mechanisms that involve inactivation of toxic electrophiles by conjugation, modulation of cellular redox state, activation of drug transporter systems and regulation of cell signalling and repair pathways. New data demonstrating the importance of these pathways in cytoprotection and greater understanding of the mechanisms which regulate their function reveal a number of new targets for novel anti-cancer agents. It is critical, however, if these targets are to be exploited correctly that the dynamics of glutathione regulation are taken into account. Copyright 1999 Harcourt Publishers Ltd.

Journal Article↗
PubMed1988

The regulation of gelation of Phloem exudate from cucurbita fruit by dilution, glutathione, and glutathione reductase.

The average glutathione equivalent concentration in phloem exudate collected from squash fruit (Cucurbita moschata [Duchesne] Poir. var Butternut) and pumpkin fruit (Cucurbita pepo [L.] var Jack-o-lattern) was 1.02 and 0.60 millimolar, respectively. Glutathione reductase (EC 1.6.4.2) activity in phloem exudate from squash and pumpkin fruit averaged 0.48 and 1.74 micromole NADPH oxidized per minute per milliliter, respectively. Protein concentrations in fruit phloem exudates averaged 67 milligrams per milliliter for squash and 57 milligrams per milliliter for pumpkin. The phloem-specific P-proteins account for most of the protein content of exudate. Pure exudate from fruit does not gel for hours or days, but when diluted with neutral or alkaline aqueous solutions, exudate gels rapidly. Exudate solutions undergo biphasic pH changes with dilution. We suggest that P-protein undergoes conformational change upon dilution, exposing titratable groups and sulfhydryl residues. Oxidation of the latter forms the intermolecular disulfide bridges of the gel. The gelation of diluted exudate is regulated by factors (oxygen, pH, glutathione, NADPH) which affect the maintenance of reduced sulfhydryl residues and the activity of glutathione reductase. While these factors may also act in vivo to regulate redox conditions in phloem, their relationship to hypothetical sol/gel transitions or motile and nonmotile phases in the transport conduit is unknown.

Journal Article↗
PubMed1991

Glutathione S-transferase-catalyzed conjugation of 9,10-epoxystearic acid with glutathione.

The possible role of glutathione S-transferases (GST) in detoxification of fatty acid epoxides generated during lipid peroxidation has been evaluated. Present studies showed that cytosolic human glutathione S-transferases belonging to alpha, mu, and pi classes isolated from human liver and lung catalyzed the conjugation of glutathione and 9,10-epoxystearic acid. The product of enzymatic reaction, i.e., conjugate of GSH and epoxystearic acid, was isolated and characterized. The Michaelis constant (Km) values of the alpha, mu, and pi classes of GSTs for 9,10-epoxystearic acid were found to be 0.47, 0.32 and 0.80 mM, respectively, whereas the maximal velocity (V max) values for the alpha, mu, and pi classes of GSTs were found to be 142, 256, and 52 mol/min/mol, respectively. These results indicate that even though 9,10-epoxystearic acid is a substrate for all the three classes of GSTs, the mu class isozymes have maximum activity toward this substrate and may preferentially metabolize fatty acid epoxides more effectively as compared to the other classes of GSTs.

Glutathione↗
PubMed1989

Glutathione and glutathione S-transferases in clones of cultured rat liver epithelial cells that express varying activity of gamma-glutamyl transpeptidase.

In rat chemical hepatocarcinogenesis models, the hepatocytes in the preneoplastic/neoplastic nodules characteristically demonstrate common biochemical changes including significant and often marked elevation in the cellular glutathione (GSH) content and in the activities of the enzymes gamma-glutamyl transpeptidase (GGT) and glutathione S-transferase (GST). Such consistent and concomitant biochemical changes may signify a common regulatory mechanism in the expression of these enzymes. We have utilized a panel of clonally derived rat liver epithelial cell lines that express varying activities of GGT to study the quantitative correlation between these three cellular components of the phase II drug metabolizing enzyme system. The results indicate that in confluent cultures, cells with high GGT activities have significantly higher cellular GSH content, and a linear correlation exists between the glutathione content and the logarithm of the GGT activity. In contrast, the basal activities of GST and GGT were not coordinately regulated. However, most of the chemical carcinogen-treated cell lines, regardless of their GGT activity, expressed higher GST activity than the normal parental rat liver epithelial cells. The basal expressions of both the Yb and Yp subunits of GST were also not correlated with the relative expression of GGT. Since GGT may play an important role in supplying the cells with the basic constituents for the synthesis of GSH and since GSH is an important cellular molecule in the protection of cells from toxic electrophiles, enhancement of GGT activity in preneoplastic/neoplastic nodules of chemical carcinogen-treated rats may represent a necessary biochemical adaptation for the induction of the "resistant" phenotype of these hepatocytes.

Animals↗
PubMed1995

Glutathione redox cycle-driven recovery of reduced glutathione after oxidation by tertiary-butyl hydroperoxide in preimplantation mouse embryos.

The purpose of this study was to determine whether mouse embryos at the two-cell to blastocyst stage have the capacity to reduce glutathione disulfide (GSSG) and to elucidate the mechanism that embryos utilize to recover from tertiary-butyl hydroperoxide (tBH)-induced oxidative stress. Experiments were conducted on embryos in vitro and tBH was used to induce oxidation of embryonic reduced glutathione (GSH). After derivatization of extracted embryo samples with dansyl chloride, GSH and GSSG were measured at picomole levels by fluorometric HPLC. Two-cell- and blastocyst-stage embryos were able to recover their GSH levels within 45 min after depletion of GSH by incubation in tBH for 15 min. Addition of 1,3-bis(2-chloroethyl)-1-nitrosourea to the culture medium blocked recovery of GSH and resulted in continued elevation of GSSG. Addition of buthionine sulfoximine (BSO) to the culture medium did not affect GSH levels in two-cell-stage embryos, but did reduce GSH levels in blastocysts by 1.5 h. Culture of two-cell embryos in the presence of BSO for 45 h decreased embryonic GSH content and percentage of embryos developing to the blastocyst stage. These results indicate that preimplantation mouse embryos have the capacity to reduce GSSG and suggest that under normal conditions, depletion and synthesis of GSH occur to a greater extent in the blastocyst than in the two-cell-stage embryo. A major protective role for glutathione reductase during specific stages of embryo development is indicated.

Animals↗
PubMed1999

5-(Pentafluorobenzoylamino)fluorescein: A selective substrate for the determination of glutathione concentration and glutathione S-transferase activity.

5-(Pentafluorobenzoylamino)fluorescein (PFB-F), a new thiol-reactive molecule was synthesized to improve the detection limits and specificity of the assays for glutathione S-transferase (GST) activity and glutathione (GSH). A rapid assay method to measure GSH concentration or GST activity and the simultaneous analysis of multiple samples is possible because the glutathione adduct, GS-TFB-F, is separated from PFB-F by thin-layer chromatography (TLC) and can be quantitated by a fluorescence scanner. The detection limits for GSH and for GST activity using TLC were found to be as low as 10 pmol/microl and 1 ng/microl using equine liver GST, respectively. Determination of GSH concentration or GST activity in bovine pulmonary artery endothelial (BPAE) cell lysates gave a linear response for samples corresponding to 500-2500 cells. PFB-F could also measure GST activities of GST fusion proteins and prove to be a suitable substrate for determining the activities of human GST isozymes and other sources of mammalian GST. The selectivity of PFB-F with GSH was proven by comparing trace amount of the adducts that formed with cysteine and beta-galactosidase to that formed with GSH. The HPLC profile of a reaction mixture where cell lysate was used in place of purified GST, also shows only two main peaks, corresponding to GS-TFB-F and unreacted PFB-F. The selectivity of PFB-F for GSH was further confirmed by exposing BPAE cells to dl-buthionine-[S,R]-sulfoximine (BSO). Our results of GS-TFB-F determination indicate that 12-, 24-, or 36-h incubations with BSO caused 2-, 6-, or 7.6-fold reductions in GSH levels, respectively.

Animals↗
PubMed1991

Glutathione and glutathione conjugate efflux from cultured liver cells.

Efflux of glutathione (GSH) and GSH-conjugates from cultured rat liver epithelial cell lines; the non-tumorigenic ARL-15C1 and the gamma-glutamyl transpeptidase containing, tumorigenic ARL-16T2, has been assessed under basal condition and during chronic treatment with 75 and 150 microM ethacrynic acid (EA). The intracellular level of GSH increased in proportion to EA concentration during chronic exposure. The rates of GSH and GSH-EA conjugate efflux increased with intracellular GSH in both ARL cell lines. Glutathione-S-transferase activity measured with EA as substrate increased over the experimental time course after treatment with 150, but not 75 microM EA. When intracellular GSH content was increased by treatment with the cysteine pro-drug, 2-L-oxothiazolidine 4-carboxylic acid, the rate of GSH efflux was increased, but not the rate of GS-EA conjugate export. Inhibition of gamma-glutamyl transpeptidase by acivicin (AT-125) increased the GSH and GS-EA conjugate efflux rate in ARL-16T2 cells by factors of approximately 2 and 15, respectively. Acivicin treatment of ARL-16T2 cells chronically treated with EA elevated GSH efflux rate by 10-fold and GS-EA efflux by 40-fold versus control samples. These studies show that GSH and GSH conjugate efflux are accomplished as independently regulated processes. Efflux of GSH is enhanced by increased intracellular GSH, but increase in the conjugate transport rate requires the presence of the GSH conjugate. The response of the efflux process to treatment with a chronic GSH depleting agent was identical in two cell lines in which the metabolic fate of glutathione is known to differ fundamentally.

Animals↗
PubMed1998

The relative effectiveness of human plasma glutathione peroxidase as a catalyst for the reduction of hydroperoxides by glutathione.

To reveal clues to the function of human plasma glutathione peroxidase (GPx), we investigated its catalytic effectiveness with a variety of hydroperoxides. Comparisons of hydroperoxides as substrates for plasma GPx based on the ratio of Vmax/Km were blocked by the limited solubility of the organic hydroperoxides, which prevented kinetic saturation of the enzyme at the chosen glutathione concentration. Therefore, we compared the hydroperoxides by the fold increase in the apparent first-order rate constants of their reactions with glutathione owing to catalysis by plasma GPx. The reductions of aromatic and small hydrophobic hydroperoxides (cumene hydroperoxide, t-amyl hydroperoxide, t-butyl hydroperoxide, paramenthane hydroperoxide) were better catalyzed by plasma GPx than were reductions of the more "physiological" substrates (linoleic acid hydroperoxide, hydrogen peroxide, peroxidized plasma lipids, and oxidized cholesterol).

Catalysis↗