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)

Glutathione (GSH) and GSH-related enzymes, glutathione reductase (GR), gamma-glutamyl cysteine synthetase (gamma-GCS), gamma-glutamyl transpeptidase (gamma-GTP), glutathione S-transferase (GST) and adenosine triphosphatase (ATPase) enzymes were analysed to study the effect of busulfan on the defence mechanisms of the lens. All these enzymes were found to increase significantly except GSH which showed only 7.9% increase as compared to controls in precataractous stage. These results affirm that busulfan is capable of evoking a response from the enzymes involved in the various pathways of GSH enabling the lens to prolong its clarity. The cataractous lenses showed significant decrease in all these parameters. Here, the impairment of the defense mechanism (GST, GR) and the total ATPase may be attributed to the cumulative action of the drug which can react with -SH groups of these enzymes, ultimately causing opacification.
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PMID:Glutathione and glutathione-related enzymes in busulfan treated rat lens. 191 43

Glutathione-depleted hepatocytes, by incubation with diethylmaleate (DEM) or phorone (2,6-dimethyl-2,5-heptadiene-4-one), i.e., substrates of the GSH S-transferases (EC 2.5.1.18), showed rates of gluconeogenesis from various precursors significantly lower than controls; however the rate of glucose synthesis from fructose was similar to that of controls. Isolated hepatocytes from rats pretreated with those substrates 1 h before isolation to deplete hepatic glutathione (GSH) also showed a decrease of the rate of gluconeogenesis from lactate plus pyruvate. Incubation of hepatocytes with L-buthionine sulfoximine, a specific inhibitor of gamma-glutamyl-cysteine synthetase (EC 6.3.2.2), resulted in a decreased rate of gluconeogenesis from lactate plus pyruvate only when GSH values were lower than 1 mumol/g cells. Freeze-clamped livers from GSH-depleted rats showed a higher concentration of malate and glycerol 3-phosphate, indicating that GSH depletion probably affects phosphoenolpyruvate carboxykinase and glycerol-3-phosphate dehydrogenase activities. Several indicators of cell viability, such as lactate dehydrogenase leakage, malondialdehyde accumulation, ATP concentration, or urea synthesis from different precursors, were not affected by GSH depletion under the experimental conditions used here. Besides, the GSH/GSSG ratio remained unchanged in all cases.
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PMID:Effects of glutathione depletion on gluconeogenesis in isolated hepatocytes. 402 24

The effects of the synthetic dibromo-pyrethroid insecticide deltamethrin on some hepatic phase I and II enzyme activities were studied in rat liver. The animals were treated with daily doses of 5 and 10 mg/kg of both pure insecticide or its commercial formulation (Decis), administered i.p. in corn oil for 7 days. The following enzyme activities were studied: NADPH-cytochrome-P450 reductase, aryl-hydrocarbon hydroxylase, aminopyrine N-demethylase, glutamyl cysteine synthetase, glutathione S-transferase, glutathione peroxidase, peroxisomal acyl-CoA oxidase, catalase, and urate oxidase. Both deltamethrin and its commercial formulation were effective in modifying the activities of several of these hepatic xenobiotic-metabolizing enzymes. However, some differences in enzyme modifications were found between treatment with pure or commercial deltamethrin, the latter being more active. This effect could be ascribed to additives, solvents, and chemical intermediates present in the Decis formulation. These results suggest that exposure to this deltamethrin commercial formulation could be more dangerous than exposure to deltamethrin alone, both in terms of its hepatotoxicity and/or alterations in the hepatic biotransformation of other occupational/environmental xenobiotics.
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PMID:Studies on hepatic xenobiotic-metabolizing enzymes in rats treated with insecticide deltamethrin. 747 74

Since previous studies from this laboratory have suggested that glutathione S-transferase (GST) 8-8 of rat belongs to a distinct subgroup of GST isozymes which may be involved in the detoxification of the products of lipid peroxidation (Zimniak et al., J. Biol. Chem. 269, 992-1000, 1994), during the present studies we examined the effect of iron-induced lipid peroxidation on the expression of GST 8-8 in rat liver. Rats treated with 100 mg/kg body wt iron showed a significant increase in lipid peroxidation in liver. This was accompanied by a concomitant increase in the expression of GST 8-8 in liver as observed in isoelectrophoretic analysis of rat liver GSTs, and an increase in GST activity toward 4-HNE, a toxic product of lipid peroxidation toward which GST 8-8 displays high specific activity. Western blot studies using polyclonal antibodies specifically recognizing GST 8-8 also indicated that, among the GST isozymes of rat liver, GST 8-8 was preferentially induced upon iron treatment. These findings were further confirmed by purifying and quantitating GST 8-8 protein from the controls and iron-treated rats. Significant differences in the specific activities of GST 8-8 purified from the controls and iron-treated rats were observed, indicating that more than one GST isozyme related to GST 8-8 may be present in rat liver. This observation is consistent with the observed heterogeneity in mouse mGSTA4-4 which is an ortholog of rat GST 8-8. Iron treatment also caused significant increase in GSH levels probably because of de novo synthesis as indicated by an increase in gamma-glutamyl cysteine synthetase activity. The results of these studies suggest that GST 8-8, and possibly other related GST isozymes, may play an important role in defense mechanisms against lipid peroxidation.
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PMID:Iron-induced lipid peroxidation in rat liver is accompanied by preferential induction of glutathione S-transferase 8-8 isozyme. 787 79

A cis-diamminedichloroplatinum (II) (CDDP)-resistant cell line (NOS2CR) demonstrated 7.4-fold greater resistance to CDDP compared with the parental cell line (NOS2) established from a patient with serous cystadenocarcinoma of the ovary. We investigated the role of enzyme systems associated with glutathione (GSH) in these cell lines. The GSH content was almost identical in both cell lines. Preincubation with 50 microM DL-buthionine-S, R-sulfoximine (BSO), an inhibitor of gamma-glutamyl cysteine synthetase, for 24 hr reduced the IC50 in both NOS2 and NOS2CR cells. Glutathione-S-transferase pi (GST-pi) activity and mRNA level in NOS2CR cells were higher than in NOS2 cells. However, gamma-glutamyltranspeptidase (GGT) activity in NOS2CR cells was 2.4-fold less than in NOS2 cells. The GST activity and mRNA level in both cell lines were constant when the cells were exposed to CDDP. Exposure to CDDP for 48 hr increased the GGT mRNA level 4.4 and 1.8 times in NOS2 and NOS2CR cells, respectively, compared with no exposure. By exposure to CDDP for 48 hr, the GGT activities in NOS2 and NOS2CR cells were increased 1.6-and 2.5-fold, respectively, compared with no exposure. The above data provide the first evidence that GGT activity and GGT mRNA are induced by CDDP in human carcinoma cell lines.
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PMID:Glutathione related enzymes in cis-diamminedichloroplatinum (II)-sensitive and-resistant human ovarian carcinoma cells. 790 18

The effect of genetic obesity and phenobarbital treatment on hepatic conjugation pathways was evaluated in the obese Zucker rat. Acetaminophen pharmacokinetic parameters were examined in vivo after a 30-mg/kg acetaminophen intravenous bolus dose in the presence and absence of phenobarbital treatment. Glucuronidation and glutathione conjugation pathways were studied in vitro in obese and lean Zucker rats after phenobarbital treatment. Obese Zucker rats demonstrated a higher glucuronidation capacity as evidenced by a higher formation clearance of acetaminophen glucuronide and greater UDP-glucuronosyltransferase (UDPGT) activity toward acetaminophen and p-nitrophenol compared with lean controls. Sulfate and glutathione conjugation pathways were not affected by genetic obesity. Obese Zucker rats possessed a higher total hepatic glutathione content due to greater liver weight. Phenobarbital treatment enhanced glucuronidation of acetaminophen and structurally related compounds (i.e., p-nitrophenol) similarly in both phenotypes, but the treatment failed to induce morphine UDPGT in the obese Zucker rat. No effect of phenobarbital was observed on sulfate conjugation, gamma-glutamyl cysteine synthetase activity or hepatic glutathione content in obese or lean Zucker rats. Similar increases in glutathione transferase activities were observed in animals of both phenotypes after phenobarbital treatment. This study demonstrates that glucuronidation is enhanced in genetically obese rats, whereas phenobarbital causes normal induction of several enzymes of the glucuronidation and glutathione conjugation pathways in the obese Zucker rat. However, morphine UDPGT was not induced by phenobarbital, suggesting that obese Zucker rats may possess a defect in the induction of this enzyme similar to that already described for the CYP2B gene in this strain.
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PMID:Effect of genetic obesity and phenobarbital treatment on the hepatic conjugation pathways. 851 12

The steady state expression of glutathione S-transferases (GSTs) at both the protein and mRNA level is reported for the 60 tumor cell lines that are used for the National Cancer Institute Drug Screening Program. Individual GST isozymes were separated, identified, and quantified (with reverse-phase calibration curves) through a novel high performance liquid chromatographic procedure. GSTP1 was the predominant isozyme and was found at quantifiable levels in all but two of the cell lines. This isozyme ranged from 0.03% to 2.7% of the total cytosolic protein. For the mu family, 90% of the lines had GSTM2, 68% had GSTM3, but only 28% were positive for the M1 phenotype. The M1 proportion is lower than would be expected from the standard M1 null phenotype for human populations. Isozymes of the alpha family were detected only at very low levels in 35% of the lines. Significant quantitative correlations among enzyme activity, total enzyme protein, and mRNA were shown for GSTP1. However, such relationships were not apparent for the mu or alpha families. Levels of glutathione (GSH), and the transcript levels of other enzymes involved in GSH homeostasis were determined. gamma-Glutamyl cysteine synthetase (gamma-GCS) was present in all cell lines, but did not correlate with levels of intracellular GSH. Glyoxalase-I and gamma-glutamyl transpeptidase, both involved in GSH salvage, were found in 100% and 70% of the cell lines, respectively. Using a pattern-matching computer program, COMPARE, we compared and correlated the arrays of mRNA and protein levels with the pattern of chemosensitivity or chemoresistance of the 60 cell lines with 175 agents constituting a standard agent database. This database is composed of compounds to which a putative mechanism of action has been assigned. Although Pearson correlation coefficients relating the target and drug patterns were generally modest, when the patterns for the enzyme protein and mRNA levels for GST pi were correlated to drug sensitivity patterns, the list of 30 agents most closely matching (for which P < 0.05) was enriched with alkylating agents. gamma-GCS also showed an enrichment of alkylating agents in the COMPARE correlations, indicating that high levels of gamma-GCS may be an important determinant of resistance. In contrast, none of the other enzymes or GSH had patterns of expression that resulted in an obvious correlation to the sensitivity or resistance of alkylating agents.
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PMID:Glutathione-associated enzymes in the human cell lines of the National Cancer Institute Drug Screening Program. 870 Jan 7

Maintenance of cellular homeostasis is a critical survival trait in tumors when exposed to anticancer drugs. Because conjugation and elimination of drugs and their metabolites is dependent upon sequential and coordinated pathways, acquired drug resistance through a gradual adaptive response would rarely be expected to be the consequence of changes in the expression of one gene product. We have used a number of drug-resistant human cell lines to characterize those genes that are implicated in maintaining a resistant phenotype. Human HT29 colon cancer cells chronically exposed to ethacrynic acid (EA) [a glutathione (GSH) and glutathione S-transferase (GST) modulator] have acquired resistance to the drug. Commensurate with resistance, EA is more effectively conjugated to GSH and effluxed from the resistant cells. Using directed and random (differential display) approaches, a number of detoxification and/or protective gene products have been shown to be expressed at elevated levels. These include: gamma-glutamyl cysteine synthetase (gamma-GCS, the rate-limiting enzyme in GSH biosynthesis); GST pi (the enzyme catalyzing the conjugation reaction); multidrug resistance associated protein (MRP) (the membrane pump responsible for effluxing the conjugate from the cell interior). In addition, other gene products not directly linked with EA metabolism were induced, including dihydrodiol dehydrogenase (an alpha-ketoreductase) (30-fold), DT-diaphorase (threefold), and a transcriptional regulator SSP 3521 (threefold). HL60 cells resistant to a GSH paralog Ter199 also show increased expression of some of these gene products. Furthermore, an adriamycin-resistant human HL60 cell line also shows overexpression of GST pi, gamma-GCS, and MRP, but in addition has approximately 20-fold more DNA-dependent protein kinase catalytic subunit (DNA-PKcs). This enzyme is an early stress response gene that can phosphorylate and activate downstream transcription factors. Such overexpression could impact on the transcriptional control of the other detoxification gene products. Both adriamycin and a typical drug-GSH conjugate (APA-SG) are inhibitors of DNA-PK. Because cellular levels of these conjugates would presumably be a good indicator of stress, it would seem reasonable to speculate that DNA-PK may act as a receiver and transmitter of signals that are crucial to the drug-resistant phenotype. Additionally, this enzyme may prove to be a potentially important target for drug design based upon the inhibitory activity of GSH conjugates.
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PMID:Importance of glutathione and associated enzymes in drug response. 940 35

We investigated the role of glutathione (GSH) and antioxidant enzymes in menadione-resistance by using K300 cells (menadione-resistant cells) and parental P19 cells (menadione-sensitive cells). We found that acquisition of resistance was associated with elevations in glutathione content and DT-diaphorase activity. The activity of glutathione S-transferase (GST) was significantly decreased, while the activities of glutathione peroxidase, glutathione reductase, catalase, and superoxide dismutase in K300 cells were maintained at the same levels as compared to the parental P19 cells. Using reactive oxygen species (ROS)-sensitive fluorescence dye 2,7- dichlorodihydrofluorescein diacetate (DCFH/DA), we demonstrated that K300 cells are characterized by reduced cellular ROS as compared to the parental P19 cells during menadione's action. Menadione depleted glutathione to a small extent in the K300 cells, but a rapid depletion was observed in P19 cells. Pretreatment of K300 cells with dicumarol, a DT-diaphorase inhibitor, or buthionine sulfoximine (BSO), an inhibitor of gamma-glutamyl cysteine synthase, sensitized the cells to menadione. BSO treatment was less effective than dicumarol treatment in reversing menadione resistance in K300 cells. These results strongly support the belief that DT-diaphorase plays a central role in protecting cells against menadione-induced oxidative stress by decreasing the ROS formation.
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PMID:The roles of glutathione and antioxidant enzymes in menadione-induced oxidative stress. 1111 72

The mechanisms by which acute administration of methapyrilene, an H(1)-receptor antihistamine causes periportal necrosis to rats are unknown. This study investigated the role of the hepato-biliary system in methapyrilene hepatotoxicity following daily administration of 150 mg/kg per day over 3 consecutive days. Biliary metabolites of methapyrilene were tentatively identified. In male Han Wistar rats administration of methapyrilene significantly increased hepatic reduced glutathione (GSH) to 140% of control levels 24 h following the last dose. There were no significant changes in the activities of glutathione-related enzymes, glutathione peroxidase (GPx) and reductase (GSH), glutathione S-transferase (GST), and gamma-glutamyl cysteine synthetase (gamma-GCS) over 3 days of methapyrilene administration. Methapyrilene treatment resulted in no significant increase in excretion of biliary oxidized glutathione (GSSG), a sensitive marker of oxidative stress in vivo, following the third dose. [3H]Methapyrilene-derived radioactivity was detected in bile, to a greater extent than in feces, indicating that methapyrilene and/or metabolites underwent enterohepatic recirculation. Cannulation and exteriorization of the bile duct (to interrupt enterohepatic recirculation) afforded some protection against the hepatotoxicity, assessed by clinical chemistry and histopathology. Liquid chromatography-mass spectrometry (LC-MS) analysis of bile indicated the presence of unmetabolized methapyrilene, methapyrilene O-glucuronide and desmethyl methapyrilene O-glucuronide. These data demonstrate that acute methapyrilene hepatotoxicity in vivo is not a consequence of GSH depletion, or oxidative stress, but that enterohepatic recirculation of biliary metabolites may be important. Progressive exposure to non-oxidizing, reactive metabolic intermediates may be responsible for hepatotoxicity.
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PMID:Methapyrilene hepatotoxicity is associated with increased hepatic glutathione, the formation of glucuronide conjugates, and enterohepatic recirculation. 1113 66


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