Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1260386 (GSH)
 38,102 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cutaneous protection against ultraviolet B (UVB) radiation damage by endogenous glutathione (GSH) was evaluated in the epidermis of the hairless mouse by measuring the influence of GSH depletion on sunburn cell (SBC) formation. Cellular GSH exerts antioxidant effects and recent studies have suggested a role for oxygen radicals in the production of SBC. Hairless mice (Skh/h 1) received oral treatment with buthionine S,R-sulfoximine (BSO), an irreversible inhibitor of gamma-glutamylcysteine synthetase, to deplete cutaneous GSH; 4 d later their ears were exposed to UVB radiation. BSO treatment significantly reduced GSH levels in the epidermis to 10-15% of control levels. Twenty-four hours after UVB exposure, SBC counts in the ears of animals with and without BSO treatment were measured, and those exposed to UVB were found to have increased. Greater numbers of SBC were found in the ears of BSO-treated mice exposed to 15 or 20 mJ/cm2 UVB, than in non-BSO-treated mice exposed to the same UVB doses. At higher UVB doses, there were no statistically significant differences between the groups. The results show that endogenous GSH provides the epidermis with measurable protection against injury by low or moderate UVB doses.
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PMID:Effect of glutathione depletion on sunburn cell formation in the hairless mouse. 204 72

The role of intracellular glutathione (GSH) against the genotoxicity of azathioprine (AZA) was examined by the use of rat hepatocytes and alkaline and neutral elution techniques. Treatment of hepatocytes with AZA for 3 h induced DNA fragmentation in alkaline conditions but not in neutral conditions. A dose-dependent increase in DNA single-strand breaks was observed with the treatment of AZA ranging from 0.3 mM to 1.0 mM with concomitant cytotoxicity. However, neither 6-mercaptopurine, which is a major metabolite of AZA, nor 6-mercaptopurine riboside, an active form of the former, induced the DNA damage at the same concentrations. Moreover, the elution rate of DNA fragmentation, even at low dose of AZA that is not cytotoxic, significantly increased in the presence of buthionine sulfoximine, which is a selective inhibitor of gamma-glutamylcysteine synthetase; i.e., depletion of GSH in hepatocytes enhanced the DNA damage by AZA. Thus, AZA has been proved to be genotoxic, and the genotoxicity is likely to be protected by GSH present in hepatocytes, suggesting that GSH depletion potentiates the carcinogenic effect of AZA.
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PMID:Modulation of genotoxicity of azathioprine by intracellular glutathione in hepatocytes. 206 52

The proliferative response of splenocytes to concanavalin A (Con A) is significantly lower in aged than in young rats. The addition of reduced (GSH) but not oxidized (GSSG) gamma-glutamylcysteinyl-glycine (glutathione) in vitro totally reverses the defective proliferative response of splenocytes from aged rats. The inhibitor of gamma-glutamylcysteine synthetase, buthionine sulfoximine, abrogates the in vitro proliferation of splenocytes from young rats activated with Con A, and this effect is significantly reversed by addition of GSH. The enhancing effects of GSH on proliferation of Con A-activated splenocytes of both young and old rats are apparent as early as 24 h and are still evident as late as 72 h in culture. Both cysteine and 2-mercaptoethanol are able to mimic the effect of GSH in causing a greater increase in Con A-induced proliferative responses of splenocytes from old rats (eightfold) as compared to young animals (threefold). Although 2-mercaptoethanol increases expression of membrane-bound transferrin receptors on both Con A-activated splenocytes and T lymphocytes, this alone does not account for the greater enhancement of Con A-induced proliferation of splenocytes from old as compared to young rats. These data are consistent with the hypothesis that the glutathione peroxidase-dependent detoxification system is defective in T lymphocytes of aged rats.
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PMID:Glutathione augments in vitro proliferative responses of lymphocytes to concanavalin A to a greater degree in old than in young rats. 226 15

We have examined the toxicity of trans-platinum (trans-diamminedichloroplatinum II) to heme and hemoprotein metabolism in the kidney of glutathione (GSH)-depleted rats and compared it with that produced by cis-platinum. Unlike cis-platinum treatment (7.0 mg/kg, i.v.) which caused after 7 days significant increases in cytochromes P450 and b5, and a marked decrease in porphyrin content of the kidney, trans-platinum alone (7 mg/kg, i.v.) did not elicit notable changes in these variables when measured 1 or 7 days after treatment. Also, cis-platinum treatment significantly altered the heme degradation pathway by increasing the activity of heme oxygenase and decreasing that of biliverdin reductase; trans-platinum treatment did not elicit a response in these activities. However, when rats were given the inhibitor of GSH synthesis, D,L-buthionine-S,R-sulfoximine (BSO), the subsequent administration (2 hr later) of trans-platinum produced, in 1 day, the spectrum of responses that were mediated by cis-platinum after 7 days. In the kidneys of rats treated with BSO plus trans-platinum the concentration of platinum measured only about 50% of that detected in the kidneys of rats treated with trans-platinum alone. In the liver, trans-platinum by itself or in combination with BSO was ineffective in altering the measured variables of heme metabolism. The possibility that similarity between cis-platinum and trans-platinum plus BSO may extend to systems other than heme metabolism, e.g. GSH synthesis and degradation, was examined. cis-Platinum caused significant inhibition of both renal gamma-glutamyl synthetase and gamma-glutamyl transpeptidase after 7 days, but not after 1 day. Twenty-four hours after treatment, BSO + trans-platinum caused inhibition of gamma-glutamylcysteine synthetase activity, whereas this activity in animals treated with BSO alone had returned to control values. At this time point, neither oxidized glutathione (GSSG)-reductase nor gamma-glutamyl transpeptidase activity was affected by trans-platinum + BSO treatment. The findings suggest that GSH constitutes an important defense mechanism against trans-platinum alteration of heme metabolism and may play a role in cellular accumulation of the drug in an inactive complex. It is proposed that BSO treatment, despite resulting in a diminished intracellular concentration of trans-platinum, allows reaction of the metal complex with target molecules by virtue of its ability to deplete GSH.
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PMID:Promotion of trans-platinum in vivo effects on renal heme and hemoprotein metabolism by D,L-buthionine-S,R-sulfoximine. Possible role of glutathione. 233 13

The effect of carbon monoxide (CO) on pulmonary glutathione-S-transferase (GST) activity was investigated using the isolated perfused rabbit lung (IPRL) preparation. CO at a concentration of 7.5% did not alter the conjugation of glutathione (GSH) with 1,2-epoxy-(p-nitrophenoxy)propane (ENP) in the IPRL. The rate of GSH conjugate formation with ENP was not altered when the lung was exposed to a selective inhibitor of gamma-glutamylcysteine synthetase, buthionine sulfoximine (0.1 mM), but was significantly diminished (P less than 0.01) by co-administration of GST inhibitor cibacron blue (1 microM) with ENP. These results indicate that the rabbit lung actively conjugates GSH with ENP and that this reaction may be decreased by specific inhibitors of GST. However, the rate of GSH conjugation is not affected by CO ventilation in the IPRL.
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PMID:Glutathione conjugation in the isolated perfused rabbit lung: the effects of carbon monoxide, buthionine sulfoximine and cibacron blue. 235 70

Depletion of glutathione (GSH) by treatment of mice with buthionine sulfoximine (BSO), an effective inhibitor of gamma-glutamylcysteine synthetase, markedly enhanced (about 10-fold) the lethal and renal toxicity of mercuric chloride. The lethal toxicity of HgCl2 was prevented by administration of GSH monoester; this was observed in mice pretreated with BSO and given a low dose of HgCl2, and also in untreated mice that were given a much higher dose of HgCl2. In contrast, administration of GSH did not protect. Since administered GSH is not transported effectively into cells, whereas GSH monoester is transported and split intracellularly to GSH, the findings indicate that protection against HgCl2 requires intracellular GSH. The experimental approaches used here suggest that cellular GSH is a major determinant of sensitivity to HgCl2 toxicity, and also that administration of GSH esters may be useful for prevention of HgCl2 toxicity.
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PMID:Cellular glutathione as a determinant of sensitivity to mercuric chloride toxicity. Prevention of toxicity by giving glutathione monoester. 238 41

Resistance to antineoplastic drugs is a major problem in the clinical management of cancer. Previous studies have demonstrated that the cytotoxicity of certain anticancer drugs is increased by lowering the glutathione (GSH) levels with buthionine sulfoximine (BSO), a specific inhibitor of gamma-glutamylcysteine synthetase. In this study we report that the resistance to doxorubicin, an anthracycline antibiotic and the most active agent in the treatment of breast cancer, can be partially reversed by exposing MCF-7 doxorubicin-resistant breast tumor cells (MCF-7/ADRR) to minimally cytotoxic doses of BSO. We found that the BSO treatment (50 microM, 48 h) of MCF-7/ADRR cells resulted in 80 to 90% depletion in total GSH concentrations. The toxicity of doxorubicin, as determined by growth inhibition and clonogenic assays, was significantly potentiated in the BSO-treated GSH-depleted cells relative to control breast tumor cells, and a dose-modifying factor of 5 to 7 was observed. Since the cytotoxicity of doxorubicin has been associated with its ability to undergo enzymatic activation and to form hydroxyl (OH) radicals in this cell line, we also quantitated the OH formation in the BSO-treated and untreated MCF-7/ADRR cells using electron spin resonance spintrapping techniques. These results show that doxorubicin stimulated at least 2-fold more OH formation in the tumor cells after GSH levels were decreased by 90%. These results indicate that GSH plays an important role in modulating doxorubicin-induced OH formation via the scavenging of hydrogen peroxide by glutathione peroxidase and thus partially protects MCF-7/ADRR cells from the cytotoxic effect of doxorubicin.
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PMID:Potentiation of doxorubicin cytotoxicity by buthionine sulfoximine in multidrug-resistant human breast tumor cells. 253 60

In addition to its participation in a variety of other biochemical reactions, glutathione (GSH) is a major antioxidant. It is regularly generated intracellularly from its oxidized form by glutathione reductase activity that is coupled with a series of interrelated reactions. Synthesis of GSH also takes place intracellularly by a two-step reaction, the first of which is catalyzed by rate-limiting gamma-glutamylcysteine synthetase activity. Intracellular substrates for GSH are provided both by direct amino acid transport and by a gamma-glutamyl transpeptidase reaction that salvages circulating GSH by coupling the gamma-glutamyl moiety to a suitable amino acid acceptor for transport into the cell. Although the liver is a net synthesizer of circulating GSH, organs such as the kidney salvage GSH through the gamma-glutamyl transpeptidase reaction. Intracellular GSH may be consumed by GSH transferase reactions that conjugate GSH with certain xenobiotics. Elevation of cellular GSH levels in cultured cells in response to hyperoxia or electrophilic agents such as diethylmaleate is coupled with an increase in activity of the Xc- transport system for the amino acids cystine and glutamate. Strategies may be developed for protection against oxidant injury by enhancement of transport systems for precursor amino acids of GSH or by providing substrate that circumvents feedback inhibition of GSH synthesis.
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PMID:Regulation of cellular glutathione. 257 74

We have previously reported that the iron-loading of mice, by feeding them carbonyl iron, caused an elevation of hepatic glutathione concentration and an increase in glutathione excretion from the liver (Kawabata, T., Ogino, T. and Awai, M. (1989) Biochim. Biophys. Acta 1004, 89-94). To elucidate the mechanism of glutathione elevation, hepatic cysteine concentration and gamma-glutamylcysteine synthetase (L-glutamate: L-cysteine gamma-ligase (ADP-forming), EC 6.3.2.2) activity were measured and possible changes in cysteine metabolism were also compared between iron-loaded and control mice. Hepatic cysteine concentration was higher in iron-loaded mice (185 +/- 12 nmol/g wet wt.) than in the controls (164 +/- 8 nmol/g wet wt.), and gamma-glutamylcysteine synthetase activity was also elevated in iron-loaded mice (34.3 +/- 3.2 nmol/mg protein per min) compared with the controls (28.6 +/- 3.8 nmol/mg protein per min). A comparison of the metabolic pathways with intravenously injected [35S]cysteine showed that organ distribution of the isotope was not significantly different, and also the rate of [35S]cysteine uptake into the hepatic glutathione fraction exhibited no difference between the two groups of mice. This shows that hepatic cysteine turnover may not be different between the two groups of mice. Since hepatic cysteine concentration was higher in iron-loaded mice, the apparently equal turnover of hepatic cysteine suggests that GSH synthesis may be elevated in iron-loaded mice. The high gamma-glutamylcysteine synthetase activity is suggested to stimulate GSH synthesis in iron-loaded mice.
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PMID:Stimulation of glutathione synthesis in iron-loaded mice. 257 72

A single intraperitoneal injection of DL-buthionine-S,R-sulfoximine (BSO) (4 mmol/kg) to overnight-starved rats caused a 70% inhibition of hepatic gamma-glutamylcysteine synthetase and induced a decrease in liver-reduced glutathione (GSH) for several hours. There was, however, no difference in hepatic lipid peroxidation, as assessed by malondialdehyde accumulation, between the control and BSO groups. During acute ethanol intoxication (5 g/kg), hepatic lipid peroxidation was increased by approx. 40% within 6 hr. Hepatic [GSH] was also significantly decreased by ethanol. The effect of ethanol on GSH level was not observed in rats pretreated with BSO, though the ethanol-induced enhancement of hepatic lipid peroxidation was potentiated by the BSO pretreatment. Under these conditions there were no apparent effects on blood concentrations of ethanol and acetaldehyde nor on activities of hepatic alcohol dehydrogenase, aldehyde dehydrogenase, glutathione-dependent detoxifying enzymes, superoxide dismutase or catalase. These results suggest that, although a decrease (by BSO) in GSH by itself does not alter the degree of endogenous lipid peroxidation, it is associated with a potentiation of the enhancement of hepatic lipid peroxidation caused by acute ethanol intoxication.
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PMID:Buthionine sulfoximine inhibition of glutathione biosynthesis enhances hepatic lipid peroxidation in rats during acute ethanol intoxication. 257 68


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