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)

Previous studies have shown that sulfhydryl reagents can alter the facility of aqueous humor outflow but little is known about the sulfhydryl constituents of the aqueous outflow system or the effect of oxidants upon outflow facility. In the present study the concentration of glutathione (GSH) was measured in excised calf trabecular meshwork (TM) and found to be 0.40 mu mol/g wet wt (0.027 mu mol/mg protein). Oxidized glutathione was not detectable in the tissue. TM was found to have significant hexose monophosphate shunt activity as determined by measurement of the oxidation of 14C-1 and 14C-6-labeled glucose in tissue homogenates. The concentration of GSH in TM of enucleated calf eyes could be totally depleted by infusion of medium containing both diamide, which is an oxidant of GSH, and 1,3bis(2-chlorethyl)-1-nitrosourea (BCNU), which is an inhibitor of the enzyme glutathione reductase. The depletion of GSH was found to have no effect on the facility of aqueous outflow. Experiments were also done in which normal and TM GSH-depleted eyes were perfused with medium containing H202. Exposure to H202 produced no effect on outflow facility in the normal eyes but caused a 33% decrease in facility in eyes with the GSH-depleted TM. The results indicate that GSH may not participate directly in regulating aqueous humor outflow but is able to protect TM against H202-induced oxidative damage that would otherwise lead to a decrease in outflow facility.
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PMID:Glutathione in calf trabecular meshwork and its relation to aqueous humor outflow facility. 688 12

This study describes characteristics of a human bladder cancer cell line, SCaBER/R, selected for resistance to a mitomycin C (MMC) analogue BMY 25067. The SCaBER/R cell line was isolated by repeated 24 h exposures of the parental cells to 0.09 microM BMY 25067 (IC90, 24 h drug exposure) over a period of about 180 days. Approximately 2.2-fold higher concentration of BMY 25067 was required to kill 50% of the SCaBER/R cell line compared with parental cells (p < 0.001). The IC20 and IC90 values for BMY 25067 were also significantly higher in the SCaBER/R cell line than in SCaBER. Unlike most MMC resistant cell lines, the SCaBER/R cell line displayed a marked cross-resistance to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and lacked cross-resistance to cisplatin, doxorubicin or VP-16. The SCaBER/R cell line also displayed a marked cross-resistance to the parent drug (MMC) and BMY 25282, another analogue of MMC. NADPH cytochrome P450 reductase activity, an enzyme implicated in bio-reductive activation of MMC, did not differ significantly in these cells. DT-diaphorase activity, another MMC activation enzyme, was significantly lower in the SCaBER/R cell line when compared to the SCaBER cells. These results suggest that relatively lower sensitivity of SCaBER/R cell line to MMC and BMY 25067 may result from impaired drug activation. Cellular levels of glutathione (GSH) and GSH-transferase (GST), which have been suggested to affect the cytotoxicity of MMC, were comparable in SCaBER and SCaBER/R cell lines. BMY 25067 induced DNA interstrand cross-links (DNA-ISC) could not be detected in either of the cell lines even at drug concentrations which produced a significant cell kill. These findings suggest that (a) cellular resistance to BMY 25067 in the SCaBER/R cell line may be due to impaired drug activation, and (b) the nature of the cytotoxic produced by BMY 25067 may be different from that of MMC.
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PMID:Characterization of a human bladder cancer cell line selected for resistance to BMY 25067, a novel analogue of mitomycin C. 765 43

Interferon-gamma (IFN-gamma) has been shown to exacerbate tumor necrosis factor alpha (TNF alpha)-induced hepatotoxicity in vivo as well as act synergistically with TNF alpha in a variety of biological actions. In the present study we have examined interactions of IFN-gamma with TNF alpha and the role of nitric oxide synthase (NOS) activity in the generation of an intracellular oxidant stress in isolated mouse hepatocytes. Exposure to either IFN-gamma or TNF alpha significantly increased NOS activity. In combination, TNF alpha and IFN-gamma markedly increased NOS activity beyond that expected for a merely additive effect. IFN-gamma potentiated TNF alpha-induced effects on the hepatocyte glutathione pool, increasing the extent of GSH depletion and GSSG efflux. Furthermore, IFN-gamma exacerbated TNF alpha-induced ATP depletion. Exposure to both TNF alpha and IFN-gamma resulted in significant cytotoxicity in hepatocytes, whereas neither cytokine alone produced any toxicity. TNF alpha-induced cytotoxicity in hepatocytes pretreated with 1,3-bis (chloroethyl)-1-nitrosourea (BCNU, a glutathione reductase inhibitor) was potentiated by IFN-gamma. TNF alpha/IFN-gamma-induced GSSG efflux was prevented when hepatocytes were treated with the antioxidant mannitol. Furthermore, mannitol reduced the extent of ATP depletion as well as cytotoxicity induced by TNF alpha and IFN-gamma in either BCNU- or non-BCNU-treated hepatocytes. In contrast, mannitol abolished cytotoxicity in BCNU-treated cells exposed to TNF alpha alone. Thus, mannitol provides significant protection against deleterious oxidative effects induced by IFN-gamma and TNF alpha. However, IFN-gamma also appears to potentiate the deleterious effects of TNF alpha, at least in part, by mechanisms other than an increase in oxygen radical generation. Using the methylated analog of arginine, NG-monomethyl-L-arginine, to inhibit NOS activity, it was demonstrated that TNF alpha/IFN-gamma-induced ATP depletion, GSSG efflux, and cytotoxicity were not dependent upon the stimulation of NOS. Furthermore, significant increases in NOS activity did not occur until after 4 hr of exposure to either cytokine, whereas GSSG efflux and ATP depletion occurred during the first 4 hr of incubation. Taken together, these results indicate that IFN-gamma acts synergistically with TNF alpha, resulting in the potentiation of an intracellular oxidative stress, inhibition of energy metabolism, and cytotoxicity. However, these events do not appear to be related to an increase in NOS activity.
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PMID:Cytokine toxicity and induction of NO synthase activity in cultured mouse hepatocytes. 768 42

The effect of doxorubicin (DOX) on heart cell glutathione (GSH)-based enzyme systems was investigated in a rat heart myocyte model. Cellular levels of GSH decreased commensurate with viability following exposure to DOX or to the unrelated alkaloidal cardiotoxin emetine. GSH depletion by L-buthionine sulfoximine (L-BSO) did not alter myocyte viability nor doxorubicin (DOX) dose-response. The nitrosourea carmustine (BCNU), which impairs GSH reductase activity, also did not alter DOX cardiotoxicity. Doxorubicin significantly increased glutathione-S-transferase (GST) activity in a time-dependent fashion. In contrast, selenium-dependent glutathione peroxidase activity was reduced by 50%. These findings demonstrate that lowered GSH or GSH reductase levels do not enhance DOX cardiotoxicity in vitro and suggest that DOX may be a substrate for GST.
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PMID:Effect of doxorubicin on glutathione and glutathione-dependent enzymes in cultured rat heart cells. 784 48

Glutathione (GSH) contributes to the detoxification of anticancer drugs through the operation of specific glutathione S-transferases (GST) and innate, or acquired, overexpression of this enzyme family has been frequently observed in tumor cell lines. In the GMA32 line of Chinese hamster fibroblasts, we showed that GSH starvation produced by exposing cells to buthionine sulfoximine (BSO) increased the toxicity of chlorambucil and melphalan, but not that of N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU), cisplatine and doxorubicin. This indicates that efficient mechanisms of detoxification using GSH operate for chlorambucil and melphalan, but not for the other drugs in these cells. We then showed that GSH depletion could be selectively and transiently induced in the mu GST overexpressing cell line derived from GMA32, HC474, by exposing cells to substrates specific to the overexpressed isozyme. Exposing cells to such a substrate, trans-stilbene oxide, does not alter the sensibility of GMA32 cells to melphalan and chlorambucil, but increases that of HC474 cells to these drugs, to an extent comparable to that obtained with BSO. This observation highlights the possibility of exploiting GST overexpression, a frequent feature of tumor cells, to selectively sensitize these undesirable cells to anticancer drugs.
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PMID:A glutathione depletion selectively imposed on mu glutathione S-transferase overproducing cells increases nitrogen mustard toxicity. 785 20

Glutathione (GSH) is an endogenous thiol that detoxifies active oxygen and reactive species formed during intermediary metabolism and drug detoxification. Compounds with a range of potential toxicities were tested for their abilities to affect GSH reductase and GSH S-transferase activities, which are each components of the two principal detoxification pathways in which GSH participates. A high performance liquid chromatographic method for determining oxidized and reduced GSH was modified to assay GSH reductase activity. With this method it was possible to demonstrate that ethacrynic acid, which inhibits GSH S-transferase, also inhibits the activity of GSH reductase. Inhibition of GSH reductase by ethacrynic acid was similar to that seen with carmustine (BCNU). GSH reductase activity was not affected by cis- or transplatin, buthionine sulfoximine, other loop diuretics, cyclosporine A or aminoglycosides. Cyclosporine inhibited GSH S-transferase at 50 microM and higher concentrations. These results support a role for GSH-mediated detoxification mechanisms in ethacrynic acid- and cyclosporine-associated cytotoxicity, which may mediate their toxicities and their potential as adjunctive agents in antineoplastic therapy. A better understanding of the mechanism of their toxicity can greatly extend the clinical usefulness of these agents, as this toxicity is the basis of both their therapeutic and antitherapeutic actions.
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PMID:Inhibition of glutathione-related enzymes and cytotoxicity of ethacrynic acid and cyclosporine. 785 28

N,N'-bis(2-chloroethyl)-N-nitro-sourea (BCNU) is a potent inhibitor of glutathione reductase (GSSG-Red) activity in both tissues and cells. We examined the effects of treating alveolar type II cells with BCNU and found that a marked decrease in cellular GSSG-Red activity occurred in these cells associated with a time-dependent increase in cellular glutathione (GSH) concentrations. The increase in GSH was not found to be related to changes in cellular gamma-glutamyl transpeptidase activity, gamma-glutamylcysteine synthetase activity, nor increased intracellular transport of cystine. When the BCNU-exposed cells were incubated with hydrogen peroxide to produce oxidant stress, the cells exhibited increased susceptibility to oxidant damage when compared with controls, despite the fact that cellular concentrations of GSH were markedly elevated.
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PMID:Induction of intracellular glutathione in alveolar type II pneumocytes following BCNU exposure. 790 72

1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) resistance has been mostly studied in vitro. In an attempt to better understand BCNU resistance in the in vivo situation, we compared the principal drug-metabolizing enzyme systems in two L1210 leukemia lines, one sensitive and one resistant to BCNU (L1210/BCNU), passaged in vivo in mice. The following enzymes were assayed by immunoblotting: cytochromes P-450 (1A1/1A2, 2B1/2B2, 2C8-10, 2E1, 3A), epoxide hydrolase (EH) and glutathione S-transferase (GST-alpha, -mu and -pi). The following enzymes and cofactors were assayed fluorometrically or spectrophotometrically: 1-chloro-2-4 dinitrobenzene-GST (CDNB-GST), total glutathione (GSH), UDP-glucuronosyltransferase, beta-glucuronidase, sulfatase and sulfotransferase. Results showed that cytochrome P-450 1A1/1A2 was the only isoenzyme detected in both L1210 and L1210/BCNU. CDNB-GST activity was significantly higher in L1210/BCNU compared with L1210. The isoenzyme GST-alpha was more abundant in L1210/BCNU compared with L1210, whereas GST-pi was expressed less in the BCNU-resistant leukemia line. GST-mu was not detected in either L1210 leukemia lines. GSH levels were similar in the two L1210 lines. No significant difference was observed between the two leukemia lines for the conjugative enzymes UDP-glucuronosyltransferase and sulfotransferase, whereas their corresponding hydrolytic enzymes beta-glucuronidase and sulfatase were about two-fold lower in the BCNU-resistant leukemia line. Epoxide hydrolase was 1.3-fold higher in L1210/BCNU compared with L1210 and this level was about three-fold higher than in mouse liver. In conclusion, these studies showed the presence of cytochrome P-450 1A1/1A2 in the two L1210 leukemia lines studied, and indicated noteworthy differences between the two leukemia lines for many enzyme systems such as GST, beta-glucuronidase, sulfatase and epoxide hydrolase. These data are of importance to better understand the mechanisms of drug resistance to nitrosoureas in vivo.
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PMID:Principal drug-metabolizing enzyme systems in L1210 leukemia sensitive or resistant to BCNU in vivo. 796 9

The present study examined the effects of S-(N-methylcarbamoyl)glutathione (SMG), S-(N-methylcarbamoyl)-L-cysteine (L-SMC) and some analogs of these S-linked conjugates of methyl isocyanate (MIC) on the activity of glutathione reductase (GR) in freshly isolated rat hepatocytes and on the levels of reduced and oxidized glutathione (GSH and GSSG) in exposed cells. Both SMG and its monoethyl ester (0.5 mM) were found to inhibit GR weakly, although L-SMC proved to be an effective inhibitor of the enzyme (60 +/- 4% activity remaining after a 4-hr incubation at 0.5 mM). The cysteine adduct (SCC) of 2-chloroethyl isocyanate (CEIC) was a strong inhibitor of GR (27 +/- 1% activity remaining after a 1-hr incubation at 0.1 mM) and was essentially equipotent with the antitumor agent N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU). L-SMC depleted intracellular GSH in a time- and concentration-dependent manner up to 2 hr of incubation, beyond which time GSH levels began to recover. Exposure of cells to the enantiomeric conjugate, D-SMC, led to a similar concentration- and time-dependent inhibition of GR and fall in intracellular GSH, but in this case the depletion of GSH was extensive and was sustained throughout the 5-hr incubation period. Only a small amount (less than 10%) of the GSH that was lost from cells exposed to SMC was recovered in the medium, indicating that SMC did not cause efflux of GSH (most of the free cysteine released during breakdown of SMC was recovered in the medium). Experiments with hepatocytes exposed for 5 hr to SCC (0.1 mM) demonstrated that GSSG levels were elevated by 32 +/- 5% relative to controls. Collectively, these results indicate that carbamate thioester conjugates of MIC and CEIC inhibit GR, probably via release of the free isocyanate at the cell surface, which then penetrates the hepatocyte. The inhibitory effects of the isocyanates on GR, coupled with their propensity to react spontaneously with GSH, combine to deplete significantly intracellular stores of GSH.
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PMID:Effect of carbamate thioester derivatives of methyl- and 2-chloroethyl isocyanate on glutathione levels and glutathione reductase activity in isolated rat hepatocytes. 806 46

Glutathione (GSH) and glutathione S-transferases (GSTs) play an important role in the protection of cells against toxic effects of many electrophilic drugs and chemicals. Modulation of cellular GSH and/or GST activity levels provides a potentially useful approach to sensitizing tumor cells to electrophilic anti-cancer drugs. In this study, we describe the interactions of four representative alkylating agents (AAs), melphalan, 4-hydroperoxy-cyclophosphamide (4HC), an an activated form of cyclophosphamide, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), and cisplatin, with GSH and GST in the human breast cancer cell line MCF-7. Depletion of cellular GSH pools by approximately 80% by treatment of the cells with the GSH synthesis inhibitor buthionine sulfoximine (BSO) sensitized the tumor cells to each AA to a different extent, with dose-modifying factors of 2.39, 2.21, 1.64, and 1.27 observed for melphalan, 4HC, cisplatin, and BCNU, respectively. Treatment of the cells with the GST inhibitor ethacrynic acid (EA) failed to show any significant effects on the cytotoxicity of these AAs. However, EA did potentiate the cytotoxicity of melphalan when given in combination with BSO, an effect that may be due to a more complete depletion of cellular GSH levels by the combined modulator treatment. Following a 1-hr exposure to cytotoxic-equivalent concentrations of these AAs, GSH levels decreased substantially in the case of 4HC and BCNU, but increased by 30-50% in the case of cisplatin and melphalan. BSO pretreatment largely blocked this effect of cisplatin and melphalan on cellular GSH, while it further enhanced the GSH-depleting activity of both 4HC and BCNU. On the basis of these results, it is concluded that (a) GSH affects the cytotoxicity of different AAs to different extents, (b) basal GST expression in MCF-7 cells does not play a major role in AA metabolism, (c) EA can potentiate the enhancing effect of BSO on melphalan cytotoxicity in MCF-7 cells, and (d) depletion of cellular GSH by pretreatment with BCNU or cyclophosphamide may correspond to a useful strategy for enhancing the anti-tumor activity of other AAs given in a sequential combination.
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PMID:Role of cellular glutathione and glutathione S-transferase in the expression of alkylating agent cytotoxicity in human breast cancer cells. 814 7


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