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)

Prolonged exposure to mutagenic substances is strongly associated with an individual's risk of developing colorectal cancer. Clinical investigation of oltipraz as a chemopreventive agent is supported by its induction of the expression of detoxication enzymes in various tissues, and its protective activity against the formation of chemically induced colorectal tumors in animals. The goals of the present study were: to determine if oltipraz could induce detoxicating gene expression in human tissues; to identify effective non-toxic doses for more extensive clinical testing; and to establish a relationship between effects in the colon mucosa and those in a more readily available tissue, the peripheral mononuclear cell. 24 evaluable patients at high risk for colorectal cancer were treated in a dose-finding study with oltipraz 125, 250, 500, or 1,000 mg/m2 as a single oral dose. Biochemical analysis of sequential blood samples and colon mucosal biopsies revealed increases in glutathione transferase activity at the lower dose levels. These effects were not observed at the higher doses. More pronounced changes were observed in detoxicating enzyme gene expression in both tissues at all doses. Peripheral mononuclear cell and colon mRNA content for gamma-glutamylcysteine synthetase (gamma-GCS) and DT-diaphorase increased after dosing to reach a peak on day 2-4 after treatment, and declined to baseline in the subsequent 7-10 d. The extent of induction of gene expression in colon mucosa reached a peak of 5.75-fold for gamma-GCS, and a peak of 4.14-fold for DT-diaphorase at 250 mg/m2 ; higher doses were not more effective. Levels of gamma-GCS and DT-diaphorase correlated closely (P < or = 0.001) between peripheral mononuclear cells and colon mucosa both at baseline and at peak. These findings demonstrate that the administration of minimally toxic agents at low doses may modulate the expression of detoxicating genes in the tissues of individuals at high risk for cancer. Furthermore, peripheral mononuclear cells may be used as a noninvasive surrogate endpoint biomarker for the transcriptional response of normal colon mucosa to drug administration.
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PMID:Modulation of gene expression in subjects at risk for colorectal cancer by the chemopreventive dithiolethione oltipraz. 878 84

The effect of culture medium on glutathione (GSH) dependent detoxification defence system of primary cultured hepatocyte from either male or female rats was studied. Intracellular reduced (GSH) and oxidized glutathione (GSSG), and six GSH-related enzyme activities, including GSH peroxidase (GSH Px), GSH reductase (GSH Rd), cytosolic GSH S-transferase (cGST), microsomal GSH S-transferase (mGST), gamma-glutamyl transpeptidase (GTP), and gamma-glutamylcysteine synthetase (GCS), were investigated during a 6-day culture. Media free of fetal bovine serum (FBS) and with 2.5 or 10% FBS were used. Whatever the medium, there was an initial decrease of intracellular GSH and GSSG, a threefold increase of GSH at day 3 and fourfold increase of GSSG at day 4, later decreasing to their original level at day 6. The activities of all six GSH-related enzymes of male and female hepatocytes remained relatively stable during the first 72h, then gradually decreased to 50-80% of initial activities. With the exception of cGST, time-course profiles of other enzyme activities were not significantly different among various media. In both sexes, higher cGST activity was maintained for cells cultured in the presence of FBS. Results of immunoblotting analysis of cytosolic GST isozymes indicate that the placental form of GST (Yp) was markedly increased after plating and the extent of increase of Yp was higher in the presence of FBS. Despite the culture medium, the level of GST isoform Ya was maintained steadily for 6 days, however, Yb was maintained during the first 3 days and then decreased. In terms of the gender difference, GSH Px and GTP activities of hepatocytes from females were significantly greater than of males over the entire culture period. Results indicate that FBS seems not to be absolutely essential in maintaining GSH level and most of the GSH-related enzyme activities in rat hepatocytes. Furthermore, GSH levels and GSH-related enzyme activities of hepatocytes from female rats were similar to those from male rats.
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PMID:Glutathione and glutathione-related enzyme activities of male and female rat hepatocytes under various culture conditions. 891 40

We investigated the effect of glutathione (GSH)-dependent antioxidant system against hydrogen peroxide (H2O2) formation in oxygen-induced embryopathy. Exposure of rat embryos to a high concentration of oxygen (20%) during early neurulation (day 9 to 10) significantly increased the incidence of neural tube defects compared with control embryos (10% vs 0%, p < 0.01) exposed to a low O2 concentration (5%). The concentration of GSH in 20% O2-exposed embryos was significantly reduced compared with that in control embryos (10.68 +/- 0.72 vs 12.34 +/- 0.65 nmol/mg protein, p < 0.001). The activity of gamma-glutamylcysteine synthetase (gamma-GCS), the rate-limiting GSH synthesizing enzyme increased in 20% O2-exposed embryos (24.83 +/- 0.71 vs 21.00 +/- 0.94 microunits/mg protein). Increased activity of gamma-GCS was associated with increased expression of gamma-GCS mRNA. Substantial increases were also observed in the activities of glutathione peroxidase (GPX) and glutathione S-transferase (GST) in 20% O2-exposed embryos. The formation of intracellular H2O2, measured by flow cytometer using 2',7'-dichlorofluorescein diacetate (DCFH-DA), increased in isolated embryonic cells of 20% O2-exposed embryos. The addition of buthionine sulfoxamine (BSO), a specific inhibitor of gamma-GCS, to culture media exposed to 20% O2 produced a marked decrease in the concentration of GSH in association with a further increase in the incidence of embryonic malformations (24.4% vs. 10%, P < 0.01). The addition of 2.0 mM GSH ester to culture media exposed to 20% O2 prevented the development of embryonic malformations through the restoration of normal GSH contents and reduction of H2O2. Our results demonstrated that oxygen-induced embryonic malformations were induced by increased production of H2O2 in the presence of an immature free radical scavenger system. We suggest that impaired responsiveness of the GSH dependent antioxidant system against oxidative stress plays a crucial role in oxygen-induced embryopathy.
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PMID:Oxygen-induced embryopathy and the significance of glutathione-dependent antioxidant system in the rat embryo during early organogenesis. 898 Oct 36

Induced-acetaldehyde toxic effects on gluatathione [GSH] metabolism and sulfhydryl (SH) groups in liver and in brain of female albino rats with reference to age was studied. The total -SH groups were decreased whereas the specific activities of glutathione-S-transferase [GST] and glutathione peroxidase [GPo] were increased in acetaldehyde treated rats. However, the specific activity levels of glutathione reductase [GR] and gamma-glutamylcysteine synthetase [gamma-GCS] were decreased. In general, acetaldehyde induced changes in the specific activities of the enzymes that increase with increasing age.
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PMID:Age-related metabolic effects of acetaldehyde on rats with reference to detoxification enzymes and sulfhydryl groups. 898 6

A recent finding in epidemiological and laboratory studies suggests that the ratio of selenium to glutathione is lower in breast cancer subjects than its control counterparts. Selenium, an antioxidant and anticarcinogen, can modify the status of glutathione and some associated enzymes by blocking peroxidation of lipids in membranes of cancer subjects. Studies were conducted using female albino rats of Wistar strain bearing mammary tumor induced by 7,12-dimethylbenz(a) anthracene to assess the biological role of selenium on some antioxidant enzymes associated with the maintenance of glutathione status. For induction of mammary tumor, 25 mg DMBA in a 1 ml emulsion of sunflower oil and physiological saline was injected subcutaneously to each rat. One group in each of control and tumor bearing rats, were fed 5 mg sodium selenite/kg diet from the day of tumor induction for 24 weeks. Increase in the reduced glutathione concentration was preceded by significant increase in the oxidized glutathione as well as in the activities of gamma-glutamylcysteine synthetase, glutathione peroxidase, glutathione reductase, glutathione S-transferase, and glucose-6-phosphate dehydrogenase by selenium administration in rats bearing tumor. However, selenium administration to rats bearing tumor decreased the activity of gamma-glutamyl transpeptidase. These observations clearly demonstrate the influence of dietary selenium supplementation in correcting abnormal changes in glutathione turnover and some associated enzymes in tumor induced rats.
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PMID:Influence of selenium on glutathione and some associated enzymes in rats with mammary tumor induced by 7,12-dimethylbenz(a)anthracene. 909 65

This study was designed to elucidate the mechanisms of cisplatin (CDDP) resistance using two human ovarian cancer cell lines, KF and TYK, and two CDDP-resistant lines, KFr and TYK/R, derived from the former lines. KFr and TYK/R showed about 3-fold higher resistance to the cytotoxic effects of CDDP than their parental lines. They also showed a significant increase in sensitivity to not only etoposide, but also (+)-(4S)-4, 11-diethyl-4-hydroxy-9-[(4-piperidino -piperidino)carbonyloxy]-1H -pyrano[3',4':6,7]inodolizino[1,2-b]quinoline-3,14(4H, 12H)-dione hydrochloride trihydrate (CPT-11). Cellular CDDP accumulation levels in KFr and TYK/R were decreased from those of the parental cells. By contrast, the cellular glutathione (GSH) content in KFr cells was 1.7-fold higher than that in KF, whereas TYK/R cells had a 40% lower content than TYK cells. Cellular mRNA levels of drug-resistance-related genes, such as DNA topoisomerase (topo) I and topo II, glutathione S-transferase-pi (GST-pi), gamma-glutamylcysteine synthetase (gamma-GCS), and metallothionein (hMT) genes, were compared between drug-sensitive KF or TYK and KFr or TYK/R. KFr cells had 8.5- and 24.7-fold higher mRNA levels of gamma-GCS and topo II genes than KF cells while KFr had only a slight increase in GST-pi mRNA level as compared with KF. By contrast, TYK/R cells had 2.9- and 1.7-fold higher hMT and topo I mRNA levels than TYK cells. Acquisition of CDDP resistance in human ovarian cancer cells thus appeared to be related mainly to expression of gamma-GCS, topo II and hMT genes, and partly to that of topo I and GST-pi genes, in addition to a decrease in CDDP accumulation.
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PMID:Altered expression of gamma-glutamylcysteine synthetase, metallothionein and topoisomerase I or II during acquisition of drug resistance to cisplatin in human ovarian cancer cells. 911 51

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

The antischistosomal agent oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione] has been shown to inhibit chemically induced carcinogenesis in a variety of animal models. Of greatest interest is its unique ability to protect several target organs from structurally diverse carcinogens. Molecular and biochemical studies suggest that oltipraz affords cellular protection by inducing the expression of a battery of Phase II detoxification enzymes. Induction of glutathione S-transferase, gamma-glutamylcysteine synthetase and DT-diaphorase has been observed in human tissues following the administration of a single oral dosage of oltipraz. Preclinical and clinical data continue to support the development of oltipraz as a chemopreventive agent for clinical usage.
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PMID:Chemopreventive activity of oltipraz. 959 27

The critical role of the glutathione S-transferase (GST) multigene family in cellular protection in combination with the large interindividual variability in the expression of these enzymes has prompted an investigation of their importance in cancer prevention and susceptibility. Previous preclinical and clinical studies from this laboratory have established an association between decreased GST activity and increased risk for colorectal cancer. Based upon the increased incidence of colon malignancies among patients with ulcerative colitis, GST activity has been examined in a mouse model of induced colitis. Significant decreases (50% of controls) in the GST activity of colon tissue were observed during the establishment and progression of colitis. These data suggested that depletion of cellular protection may be an important event in the carcinogenic progression of ulcerative colitis. The ability of the dithiolthione oltipraz to induce GST expression within the murine colon has been demonstrated. Use of chemopreventive regimens to induce phase 2 detoxication enzyme expression represents a promising strategy for the prevention of cancer. Clinical studies revealed that the GST activity of blood lymphocytes from individuals with either a personal or family history of colorectal cancer or a personal history of colon polyps was decreased significantly when compared to that of healthy controls. Phase 1 clinical evaluation of oltipraz has demonstrated its ability to induce GST activity as well as the level of transcripts encoding gamma-glutamylcysteine synthetase (gamma-GCS) and DT-diaphorase in the colon mucosa of individuals at increased risk for colorectal cancer. The observed correlation between the posttreatment response in blood lymphocytes and colon mucosa suggested that blood lymphocytes may be used in future trials as a surrogate biomarker of the responsiveness of colon tissue to chemopreventive regimens.
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PMID:Glutathione S-transferases--biomarkers of cancer risk and chemopreventive response. 967 68

In this study, the role of glutathione S-transferase (GST) P1-1, the cellular reduced glutathione (GSH) status, and ATP-dependent efflux pumps in the cellular glutathione-dependent biotransformation of thiotepa and transport of the main metabolite monoglutathionylthiotepa in relation to cytotoxicity was studied in control and GST-P1-1-transfected MCF-7 cell lines. It was demonstrated that an enhanced cellular level of GST-P1-1 leads to an enhanced formation of monoglutathionylthiotepa, which is transported out of the cell into the medium. Monoglutathionylthiotepa was able to reversibly inhibit the activity of purified GST-P1-1, but only at nonphysiological concentrations, indicating that feedback inhibition of GST by its metabolites is not a relevant process in vivo. The GST activity, cellular GSH level, and/or ATP-dependent efflux of monoglutathionylthiotepa were modulated using ethacrynic acid, D,L-buthionine-S,R-sulfoximine, probenecid, and verapamil to understand the interplay between GSTs, glutathione conjugation, and efflux of glutathione conjugates in more detail. Inhibition of the GSH biosynthesis by D,L-buthionine-R,S-sulfoximine, a specific inhibitor of gamma-glutamylcysteine synthetase, significantly reduced the glutathione conjugation of thiotepa and potentiated the cytotoxicity of thiotepa. Pretreatment of cells with ethacrynic acid resulted in decreased formation of monoglutathionylthiotepa as a result of inhibition of GST in the GST-P1-1 transfectant. In addition, the intracellular amount of monoglutathionylthiotepa increased in both of the cell lines on exposure to ethacrynic acid, indicating that transport of the glutathione conjugate was partially inhibited by the glutathione conjugate of ethacrynic acid. Transport activity of monoglutathionylthiotepa could also be inhibited by probenecid and verapamil, inhibitors of organic anion transport, without influencing the biotransformation capacity of the cells. It was demonstrated that inhibition of glutathione conjugate efflux by probenecid and verapamil leads to enhanced cytotoxicity, which indicates that besides thiotepa, monoglutathionylthiotepa is also cytotoxic for the cells. Only enhanced biotransformation and subsequent transport of the glutathione conjugate into the medium (which occurs with the GST-P1-1 transfectant) results in enhanced viability. Therefore, it was concluded that only enhanced biotransformation of thiotepa represents a real detoxification pathway when the resulting conjugate is transported out of the cells. Altogether, the results indicate that it is not the overexpression of GST per se but the interplay between GSH/GST and glutathione conjugate efflux pumps that results in increased resistance to alkylating anticancer drugs such as thiotepa.
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PMID:Glutathione-dependent biotransformation of the alkylating drug thiotepa and transport of its metabolite monoglutathionylthiotepa in human MCF-7 breast cancer cells. 978 13


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