Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.5.1.18 (glutathione S-transferase)
22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In a P-glycoprotein-negative cell line, GLC4-Adr90, a 75-fold acquired Adriamycin (Adr) resistance coincided with a reduced cellular Adr level, an increased detoxifying capacity (glutathione (GSH) and glutathione S-transferase (GST) elevated), and a reduced topoisomerase-II (topo-II) activity compared with the parent cell line GLC4. The effect on Adr resistance of buthionine sulfoximine (BSO, GSH synthesis inhibitor), was studied alone or in combination with verapamil (drug-efflux inhibitor), docosahexaenoic acid (membrane lipid domain affector), ethacrynic acid (GST inhibitor), aphidicolin (DNA-polymerase-alpha inhibitor) or novobiocin (NOV, topo-II inhibitor). Cytotoxicity was tested using a microculture tetrazolium assay. In GLC4-Adr90, BSO and NOV increased Adr-induced cytotoxicity 12.9-fold and 1.8-fold respectively. The combination of BSO plus NOV showed an additive effect, decreasing the Adr resistance factor from 75 to 2.7. Combination of modulators of Adr resistance directed at different resistance mechanisms appears promising in vitro.
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PMID:Combined in vitro modulation of adriamycin resistance. 168 Aug 15

The effects of GSH depletion in a human breast cancer cell line and a multi-drug resistant subline (ADRr) were determined in a number of experimental conditions. The ADRr cells contained lower GSH concentration which cannot be explained solely on the basis of differences in cell kinetics, and yet the rate-limiting synthetic enzyme gamma-glutamylcysteine synthetase was increased 2-fold. Inhibition of GSH synthesis by BSO resulted in more rapid and more pronounced GSH depletion in ADRr compared to the wild-type cells, suggesting that enhanced GSH utilization and efflux in the resistant cells account for the lowered basal concentration. In addition, the gamma-glutamyl moiety salvage enzyme gamma-glutamyltranspeptidase was reduced markedly in the ADRr cell line. Since these cells have overexpression of the efflux pump protein P-glycoprotein, we examined the effects on cellular GSH of inhibition of the pump's function by verapamil. We found that verapamil significantly depleted cellular GSH. In a rat mammary carcinoma cell line selected in Adriamycin for multi-drug resistance, a similar molecular phenotype has been described including diminished cellular GSH concentration. Verapamil treatment of these cells also resulted in significant depletion of cellular GSH. These results are consistent with the recent report that combined treatment of BSO and verapamil has an additive effect on cytotoxicity. It is likely that decreased basal GSH concentration is due to oxidation and conjugation of it in reactions catalyzed by the enhanced peroxidase and GST found in these cells.
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PMID:Glutathione depletion in human and in rat multi-drug resistant breast cancer cell lines. 199 9

Relative to the rat and most other species tested, the mouse is resistant to the carcinogenic effects of aflatoxin B1 (AFB). Previous investigations in our laboratory demonstrated that mouse liver cytosol has 52 times greater hepatic glutathione S-transferase (GST) activity toward the AFB-epoxide, compared with rat liver cytosol. To determine the importance of GST-mediated detoxification of the AFB-epoxide in the mouse in vivo, we examined the effects of glutathione (GSH) depletion on the covalent binding of AFB to hepatic DNA in control and 2(3)-butyl-4-hydroxyanisole (BHA)-treated mice. Male Swiss-Webster mice were fed control or 0.75% BHA diet for 14 days. Depletion of hepatic GSH was accomplished with D,L-buthionine-S-sulfoximine (BSO, 0.6 g/kg in saline) and diethyl maleate (DEM, 0.75 ml/kg), administered by ip injection at 2 and 1.5 hr, respectively, prior to administration of 3H-AFB (0.25 mg/kg, ip in DMSO). The combined BSO-DEM treatment depleted hepatic GSH by 97 and 70% in control and BHA-treated mice, respectively. In mice receiving the control diet, GSH depletion was associated with a 30-fold increase in the covalent binding of AFB to hepatic DNA. AFB-DNA binding in mice treated with dietary BHA alone was reduced to 54% of control. In BHA-treated mice, BSO-DEM treatment increased AFB-DNA binding by 62%. Dietary BHA increased hepatic S-9 mediated activation of AFB to the AFB-epoxide by eightfold in both control and BSO-DEM mice. BHA also increased GST activity toward the AFB-epoxide by 52 and 68% in control and BSO-DEM mice, respectively. The BSO-DEM treatment alone had no significant effect on the in vitro biotransformation of AFB. These results support the hypothesis that GST is the principal determinant of species differences in susceptibility to AFB-induced hepatocarcinogenicity. The results also support the hypothesis that BHA may protect against the toxic and carcinogenic effects of xenobiotics in part by preventing the depletion of hepatic GSH.
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PMID:Effects of modulation of hepatic glutathione on biotransformation and covalent binding of aflatoxin B1 to DNA in the mouse. 313 27

Nitrosocimetidine (NC) and 1-methyl-2-nitro-1-nitrosoguanidine (MNNG) are closely related N-nitrosamidines. NC is the nitrosated derivative of cimetidine (Tagamet), an orally administered compound used extensively in the treatment of gastric ulcers. MNNG is a potent carcinogen capable of initiating tumors close to the site of administration and used experimentally to produce stomach cancer. It has become evident that the primary metabolic fate of both of these agents is denitrosation. We have discovered an activity in the cytosol fraction of hamster liver which is capable of denitrosating these nitrosamidines with an efficiency approaching 100%. The activity is heat sensitive and requires reduced glutathione as a cofactor. Inhibition of the denitrosating activity with compounds which inhibit in parallel the conjugation of glutathione with 1-chloro-2,4-dinitrobenzene (CDNB) provides evidence that the activity is glutathione transferase. One molecule of reduced glutathione is consumed in each denitrosation event. Nitrite is formed as denitrosation proceeds with a yield equivalent to 25-50% of the denitrosated product produced. Glutathione disulfide is a minor reaction product, representing 3% of the denitrosation product yield in the MNNG case and 12% in the NC case. Thus far in our survey of N-nitrosamines, N-nitrosamides and N-nitrosamidines, only the nitrosamidines appear to be vulnerable to the cytosolic denitrosating activity. In an attempt to evaluate the importance of the glutathione-dependent reaction in the intact hamster, we have depleted glutathione by pretreatment with the commonly used agents diethyl maleate (DEM) and L-buthionine-S,R-sulfoximine (L-BSO). Nitroso compound was administered i.v. and the circulating blood levels of intact and denitrosated compound 5 min after dosing quantified. NC- and MNNG-derived methylation of organ DNA was also monitored. Pretreatment had no effect on the cytosolic denitrosating or CDNB-conjugating activities. L-BSO pretreatment had no apparent effect on the denitrosative metabolism of NC or MNNG. With DEM pretreatment we obtained clear indications of a decreased rate of denitrosation and observed a 10-fold increase in MNNG-derived liver DNA methylation. The differential effects of these pretreatments are taken as an indication that DEM-sensitive processes other than those requiring glutathione dominate N-nitrosamidine denitrosation in the hamster.
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PMID:Evidence for cytosolic glutathione transferase-mediated denitrosation of nitrosocimetidine and 1-methyl-2-nitro-1-nitrosoguanidine. 367 6

Induction of Phase II enzymes of the [Ah] gene battery by L-buthionine (S,R)-sulfoximine (BSO) and other agents was examined in mouse hepatoma Hepa-1c1c7 cells. BSO, a nonelectrophilic inhibitor of gamma-glutamylcysteine synthetase (GCS), is routinely used to examine the toxicological implications of GSH depletion. Exposure to BSO for 24 h produced a 75-85% depletion of GSH levels, proportional to the inhibition of GCS activity, as well as small increases in the UDP-glucuronosyltransferase (UGT, 60%) and glutathione transferase (GST, 30%) enzyme activities in Hepa-1 wild-type (wt) cells. However, for the NAD(P)H:menadione oxidoreductase (NMO1) and cytosolic aldehyde dehydrogenase class 3 (AHD4) enzyme activities, BSO produced larger increases (110% and 170%, respectively). The mechanisms of NMO1 and AHD4 induction were examined further. In Hepa-1 wt cells, NMO1 and AHD4 activities were increased by the aromatic hydrocarbon inducer 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and by the electrophile tert-butylhydroquinone (tBHQ), known inducing agents for these enzymes. However, NMO1 and AHD4 were induced in Ah receptor nuclear translocation-defective mutant (c4) cells by BSO and tBHQ, but not by TCDD, suggesting that the induction by BSO and tBHQ is not Ah receptor-mediated. In wt cells, N-acetylcysteine produced a concentration-dependent increase in intracellular cysteine levels, but not GSH levels, in the absence or presence of BSO. Furthermore, N-acetylcysteine had no effect on NMO1 activity under any conditions examined, suggesting that GSH levels per se, rather than change in overall thiol status, might be mediating increased NMO1 activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Enzyme induction by L-buthionine (S,R)-sulfoximine in cultured mouse hepatoma cells. 757 30

MCF-7 human breast cancer cells possess high levels of O6-alkylguanine-DNA alkyltransferase and moderate levels of glutathione, and are more resistant to chloroethylnitrosoureas (CNUs) than cells with low levels of either molecule. The role of each as a component of CNU resistance was assessed using O6-benzylguanine (O6-bG) or O6-methylguanine (O6-mG) to deplete the alkyltransferase and L-buthionine sulfoxamine (L-BSO) to deplete glutathione. O6-bG and O6-mG potentiated 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) cytotoxicity, resulting in a dose modification factor of 5.4 and 2.3, respectively, which reflected the more potent inhibitory effect of O6-bG. L-BSO alone had little effect on the survival of MCF-7 cells following BCNU exposure, but when combined with O6-mG, BCNU cytotoxicity was additive, yielding a dose modification factor of 3.2. O6-bG or O6-mG and L-BSO acted independently, as neither class of inhibitor affected the other's mechanism of CNU resistance. Furthermore, MCF-7 cells overexpressing GST mu were not more resistant to BCNU than the parent cell line in either the presence or absence of O6-bG or L-BSO. These results indicate that on a relative basis in MCF-7 cells, the alkyltransferase is the cell's first line of defense against CNUs. This suggests that therapeutic trials based on O6-bG-induced biochemical modulation of CNU resistance may increase the efficacy of these chemotherapeutic agents against human malignant cells and that L-BSO may have little additive effect when used with these agents.
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PMID:Combined depletion of O6-alkylguanine-DNA alkyltransferase and glutathione to modulate nitrosourea resistance in breast cancer. 806 41

Cross-resistance presents an obstacle in cancer chemotherapy. Cadmium is a potential carcinogen whose exposure has been shown in epidemiological and laboratory experiments to cause lung cancer. Cadmium also induces various forms of resistance in human lung carcinoma cells. This resistance may be shared by antineoplastic agents, which should be a concern for chemotherapy of cadmium-induced lung cancer. In the present study, two subpopulations of human lung carcinoma A549 cells with a different magnitude of resistance to cadmium toxicity were shown to have a parallel resistance to the cytotoxic action of Adriamycin (ADR), an important anticancer drug. Several factors were examined to investigate the mechanism(s) for the cross-resistance, including cellular metallothionein and glutathione (GSH) concentrations, glutathione S-transferase activity, mdr1 expression, and antioxidant enzyme activities including superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase. Only cellular GSH content was elevated consistently in the cadmium/ADR-resistant cells relative to the cadmium/ADR-sensitive cells. Treatment with buthionine sulfoximine, a specific inhibitor of GSH synthesis sensitized both cell lines to ADR only when the cellular GSH levels were depleted to about 5% of control. This BSO treatment, however, did not affect cell viability. Further study revealed that the cadmium/ADR-resistant cells have a greater capacity in recovery of cellular GSH content following BSO treatment. The results demonstrate that cross-resistance to ADR exists in cadmium-resistant human lung carcinoma A549 cells, and enhanced GSH synthesis capacity, rather than elevated levels of cellular GSH, may be related to this resistance.
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PMID:Decreased sensitivity to adriamycin in cadmium-resistant human lung carcinoma A549 cells. 911 95

Melatonin, the chief hormone secreted by the pineal gland, has been previously shown to inhibit human breast cancer cell growth at the physiological concentration of 1 nM in vitro. In this study, using the estrogen receptor (ER)-positive human breast tumor cell line MCF-7, we have shown that 10 microM L-buthionine-[S,R]-sulfoximine (L-BSO), an inhibitor of gamma-glutamylcysteine synthetase (the rate-limiting enzyme in glutathione synthesis), blocks the oncostatic action of 1 nM melatonin over a 5-day incubation, indicating that glutathione is required for melatonin action. The result was repeated with ZR75-1 cells, suggesting that the glutathione requirement is a general phenomenon among ER+ breast cancer cells. Addition of exogenous glutathione (1 microM) to L-BSO-treated groups restored the melatonin response in both cell lines. Further demonstration of the importance of glutathione was shown using the ER- breast tumor cell line HS578T, which is normally unresponsive to melatonin. Growth in this cell line was inhibited in the presence of 1 microM ethacrynic acid (an inhibitor of glutathione S-transferase) plus 1 nM melatonin, and this effect was blocked with 10 microM L-BSO. We also observed a steady decrease of intracellular glutathione in MCF-7 cells over a 5-day incubation, suggesting that these cells metabolize glutathione differently than do normal cells.
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PMID:Physiological melatonin inhibition of human breast cancer cell growth in vitro: evidence for a glutathione-mediated pathway. 915 84

We evaluated the effects of a panel of glutathione derivative (S-butyl, S-decyl, S-ethyl, S-heptyl, S-hexyl; S-methyl, S-nonyl, S-octyl, S-propyl and S-pentyl glutathiones) on glutathione-S-transferase activity in the cell lysates of a human lung cancer, PC-9. Glutathione derivatives inhibited glutathione-S-transferase activity in PC-9 cell lysates by up to 67%. When PC-9 cells were incubated with the IC50 concentration of adriamycin (200 nM) and with nontoxic concentrations (1 microM) of the glutathione derivatives, cytotoxicity ranged from -20% to +55% of the control levels. Enhancement of adriamycin toxicity by glutathione derivatives was significantly correlated with the inhibition of glutathione-S-transferase activity. S-decyl-glutathione, which was one of the most potent inhibitors of glutathione-S-transferase activity, significantly enhanced the adriamycin-induced antitumor effect in vivo. Findings suggest that some glutathione derivatives, including the S-decyl, S-octyl, and S-hexyl glutathiones, enhance adriamycin-induced cytotoxicity in part by inhibiting glutathione-S-transferase and that these agents may be useful as chemosensitizers for adriamycin therapy. In conclusion, the present results showed that some glutathione derivatives enhanced sensitivity of tumor cells to ADR by inhibiting GST activity. The use of BSO and EA as sensitizers to chemotherapy is currently being evaluated in clinical trials. The present data suggest that the use of GSH derivatives to modulate GST activity may improve the response to ADR.
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PMID:Glutathione derivatives enhance adriamycin cytotoxicity in a human lung adenocarcinoma cell line. 921 76

L-buthionine-S,R-sulfoximine (L-S,R-BSO) was enriched for the active L-buthionine-S-sulfoximine (L-S-BSO) diastereomer. Comparative analysis was performed to determine if this enriched form possessed an increased capacity to deplete glutathione (GSH), and to inhibit the proliferation of tumor cell lines and fresh human tumor samples. Increased activity was observed for the enriched preparation of L-S-BSO in direct proportion to its increased L-S-diastereomeric percentage. Significant antitumor activity towards melanoma, breast and ovarian carcinoma specimens was noted, with the greatest activity directed against malignant melanoma. The activity of BSO on melanoma specimens was found to be correlated with their melanin content, suggesting that free radicals generated during melanin synthesis may become cytotoxic after GSH-dependent scavenging has been eliminated by BSO treatment. The antimelanoma activity of melphalan and BCNU were found to be significantly enhanced in combination with L-S-BSO. With respect to the mechanism of L-S-BSO synergy with alkylators, L-S-BSO treatment of M14 and ZAZ human melanoma cell lines resulted in decreased GSH levels and glutathione S-transferase (GST) activity. Western and Northern blot analyses indicated that GST-mu was the predominant isozyme downregulated after L-S-BSO treatment. Both M14 and ZAZ cell lines selected for resistance to L-S-BSO also showed decreased levels of GST-mu expression. However, in drug free media GST enzyme activity returned to pre-treatment levels without altering the BSO-resistance status of the cell lines. We conclude that L-S-BSO may be an active agent in the treatment of melanoma, and that it may enhance alkylator activity on melanoma through depletion of GSH and down-regulation of GST expression. Purified L-S-BSO should be explored clinically as an active agent for the treatment of melanoma.
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PMID:Melanin content and downregulation of glutathione S-transferase contribute to the action of L-buthionine-S-sulfoximine on human melanoma. 967 61


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