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)

HA-1 hamster fibroblasts receiving fresh media every 24 h were continuously passaged in progressively increasing O2 concentrations for 18 mo (designated O2R95). These cells were significantly more resistant than parental HA-1 to clonogenic inactivation mediated by 95% O2 without media replacement. The O2R95 cell line exhibited increases in the activities of catalase (CAT), Mn superoxide dismutase (MnSOD), Cu,Zn superoxide dismutase (Cu,Zn SOD), and glutathione peroxidase (GPx). O2R95 cells demonstrated uniformly distributed increased staining for CAT, MnSOD, Cu,Zn SOD, and GPx proteins, as determined by immunohistochemistry. Cellular resistance to and metabolism of 4-hydroxy-2-nonenal (4HNE), a toxic byproduct of lipid peroxidation implicated in mechanisms of O2 toxicity, was examined in HA-1 and O2R95 cell lines. O2R95 cells were significantly more resistant to 4HNE cytotoxicity, which was accompanied by a significant increase in 4HNE metabolism. O2R95 cells also demonstrated an increase in total glutathione (GSH) and glutathione S-transferase (GST) activity, an enzymatic system believed to be involved with 4HNE metabolism. Furthermore, homogenates from O2R95 cells consumed greater quantities of 4HNE in the presence of NADPH (but not NADH, NAD+, or NADP+), suggesting that an enzyme(s) utilizing NADPH contributes to 4HNE metabolism, resistance to 95% O2 and 4HNE as well as increased total GSH, antioxidant enzyme activities, and NADPH-dependent metabolism of 4HNE, persisted in O2R95 cells for 75 days of growth in 21% O2. These findings are compatible with the hypothesis that aldehydic byproducts of lipid peroxidation contribute to mechanisms of O2 toxicity and the selective pressure exerted by exposure of cells to hyperoxia.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A stable O2-resistant cell line: role of lipid peroxidation byproducts in O2-mediated injury. 161 58

Contribution of various hemoproteins to peroxidase oxidation of benzidine and its derivatives as well as effects of these substances on functional state of hepatocytes are discussed. Benzidine and its derivatives were shown to induce those forms of cytochrome P-450 which were involved in accelerated oxidation of the carcinogenic drugs studied as well as affected the glutathione transferase, NADPH-dependent glutathione reductase activities and the activity of antioxidant system enzymes. Increase in content of cytochrome P-450, glutathione-dependent enzymes and other effects specific for adult hepatocytes, which occurred in presence of aminobiphenyls, were accompanied by decrease in content of receptors to epidermal factor of growth regulating the hepatocytes proliferation.
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PMID:[The role of carcinogenic aminobiphenyls in hepatocyte differentiation]. 181 15

The activities of tissue glutathione (reduced and oxidized) and glutathione-dependent enzymes such as glutathione S-transferase (GSH S-transferase), glutathione reductase (GSSG reductase) and glutathione peroxidase (GSH-Px) were determined for control and uremic rats. Acute renal failure (ARF) was produced by glycerol-water injection. Cytosolic and microsomal GSH S-transferase activity in the kidney was decreased by 38% and 15%, respectively. Hepatic microsomal GSH S-transferase was also decreased by 40% in uremic rats. GSH-Px activity was decreased by 51% in the cytosolic fraction and 33% in the microsomal fraction in the kidney, but was not affected in the liver and whole blood. GSSG reductase activity was also decreased by 48% in the cytosolic fraction in the kidney of uremic rats. In whole blood, however, GSSG reductase activity was increased by 12-fold (0.66 +/- 0.12 mumol NADPH oxidized/min/ml blood in the control; 8.03 +/- 3.29 mumol NADPH oxidized/min/ml blood in uremia). Although the total glutathione concentrations were not significantly affected, the GSSG/GSH ratio, which is an indication of oxidative stress, was significantly increased in the liver and whole blood of uremic rats. In addition to the decreases in hepatic and renal GSH S-transferase activities, which is important in drug disposition, ARF caused decreases in GSSG reductase and GSH-Px activity, which are essential for the protection against lipid peroxidation.
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PMID:Effects of glycerol-induced acute renal failure on tissue glutathione and glutathione-dependent enzymes in the rat. 187 Mar 54

The use of Aroclor 1254 to induce S9 liver fractions is a standard method for conducting short-term genotoxicity assays. An alternative induction procedure, using beta-naphthoflavone (beta-NF), as a safe (non-carcinogenic) substitute for polychlorinated biphenyls, combined with sodium phenobarbital (PB), was found to be equally effective. The aim of this work is to realize a novel schedule of induction for the preparation of metabolizing systems containing a wider spectrum of induced cytochrome P450s. Five inducers of different 'classes' such as PB (class IIB P450s), beta-NF (IA), isosafrol (IA2), ethanol (IIE1) and pregnenolone 16 alpha-carbonitrile (IIIA) were injected daily both separately (to achieve maximal monooxygenase induction) in male and female mice. Induction was monitored using specific P450-linked activities. In the optimal schedule for complete induction, the various monooxygenases were greater (2- to 4-fold) than those achieved by the classical schedule. More than a 14-fold increase of total P450 and 3.3-fold increase of NADPH-cytochrome (P450) c-reductase activity, over those uninduced, account for the above increase. For example, there was a marked increase in the deethylation of ethoxyresorufin (37-fold) compared to the uninduced mice that was considerably higher than classical induction (8-fold over uninduced). On the contrary, phase II reactions i.e. epoxide hydrolase, glutathione S-transferase, glutathione S-epoxide transferase and UDP-glucuronosyl transferase, examined to compare the phase I/phase II ratios in the traditional and proposed procedures, were increased to a lesser extent (2-fold over uninduced). No significant sex differences were seen. Five precarcinogens specifically metabolized by each of the induced P450s elicited a higher mutagenicity response in the presence of superinduced fractions with respect to the classical one, when tested on Salmonella typhimurium (cyclophosphamide, benzo[alpha]pyrene, 2-naphthylamine and dimethylnitrosamine) or Saccharomyces cerevisiae D7 strain (diethylstilbestrol). These novel metabolizing biosystems, with an enhanced spectrum of induced P450s and oxidative/post-oxidative reaction rates, are recommended for detecting unknown xenobiotics in genotoxicity studies.
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PMID:Wide spectrum detection of precarcinogens in short-term bioassays by simultaneous superinduction of multiple forms of cytochrome P450 isoenzymes. 190 89

The effects of pyrethroid insecticides on hepatic microsomal enzymes were studied in rats. Animals were treated orally with cypermethrin (80 mg/kg), deltamethrin (15 mg/kg), and permethrin (100 mg/kg), as a solution in soyabean oil, for 1 to 20 days. The content of cytochromes P-450 and b5, activity of NADPH cytochrome P-450 reductase, glutathione S-transferase, aniline 4-hydroxylase, p-nitroanisole O-demethylase in microsomes, the activity of glutathione S-transferase, and the level of sulfhydryl groups in cytosol were determined. Also the relative liver weight was measured. Only few changes in the investigated parameters were ascertained. These changes have an irregular and transient character. On the whole, the action of pyrethroids on microsomal enzymes results in a slight induction.
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PMID:Effects of pyrethroid insecticides on hepatic microsomal enzymes in rats. 190 8

Until now, no data are available concerning the biotransformation and toxicity of 2-methylpropene (or isobutene), a gaseous alkene widely used in industry (rubber, fuel additives, plastic polymers, adhesives, antioxidants). In this work, the biotransformation of 2-methylpropene (MP) has been studied, using total liver homogenates of mice, supplemented with a NADPH-generating system. In analogy to other olefins, 2-methylpropene is metabolized to its epoxide 2-methyl-1,2-epoxypropane (MEP), as proved by the identification by gas chromatography coupled with mass spectrometry. The epoxidation is cytochrome P-450 dependent, as shown by experiments in the absence of the NADPH-generating system and in the presence of various concentrations of metyrapone and SKF 525-A, two known inhibitors of the mono-oxygenases. A simple gas chromatographic headspace method has been developed for the quantitative determination of the epoxide formed. The formation of MEP is never linear in function of time and it reaches a maximum after 20 min. Thereafter is decreases continuously to undetectable levels. This observation can be explained by the immediate action of epoxide hydrolase and glutathione S-transferase, converting the epoxide to 2-methyl-1,2-propanediol and to the glutathione conjugate respectively. The involvement of both enzymes has been demonstrated by the addition of 3,3,3-trichloropropene oxide and indomethacin. These inhibitors of, respectively, epoxide hydrolase and glutathione S-transferase increase the epoxide formation in a significant way. The actual concentration of MEP is therefore not only dependent on its formation by cytochrome P-450 dependent mono-oxygenases, but also on its conversion by epoxide hydrolase and glutathione S-transferase, both very active in liver tissue.
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PMID:In vitro biotransformation of 2-methylpropene (isobutene): epoxide formation in mice liver. 195 44

H69AR is a multidrug-resistant small cell lung cancer cell line derived from a drug-sensitive cell line, H69, by selection in doxorubicin. It is cross-resistant to a wide variety of natural product-type antineoplastic agents but does not overexpress P-glycoprotein. In the present study, the levels of GSH and GSH-related enzymes in the H69AR cell line were determined and compared with those found in H69 cells. Unlike other drug-resistant cell lines, GSH levels were diminished 6-fold in H69AR cells (0.67 +/- 0.28 microgram/mg of protein), compared with H69 cells (4.23 +/- 1.17 micrograms/mg of protein) (p less than 0.01). This unusually low level of GSH may explain the pronounced collateral sensitivity of H69AR cells to buthionine sulfoximine (BSO), an inhibitor of the rate-limiting enzyme in GSH biosynthesis (ID50 of 4.4 microM BSO for H69AR cells versus ID50 of 300 microM BSO for H69 cells). BSO did not enhance doxorubicin cytotoxicity in the H69AR cell line, despite further depletion of GSH. GSH-reductase (EC 1.6.4.2) activity was elevated 2-fold in H69AR cells, compared with sensitive H69 cells (75.34 +/- 14.94 versus 38.62 +/- 5.06 nmol of NADPH/min/mg of protein) (p less than 0.05). Both selenium-dependent and -independent GSH-peroxidase (EC 1.11.1.9) activities were unchanged in the resistant H69AR cell line, compared with its parent cell line. gamma-Glutamyl transpeptidase (EC 2.3.2.2) activity was 5-fold elevated in H69AR cells, compared with H69 cells (2.50 +/- 0.44 versus 0.46 +/- 0.21 nmol of p-nitroaniline/min/mg of protein) (p less than 0.01), whereas GSH-S-transferase (EC 2.5.1.18) activity was 10-fold higher (201.98 +/- 43.62 versus 19.77 +/- 1.72 nmol of 1-chloro-2,4-dinitrobenzene/min/mg of protein in H69AR and H69 cells, respectively) (p less than 0.01). The GSH-S-transferases from both cell lines were purified by affinity chromatography and immunoblot analysis identified the GSH-S-transferases as belonging to the anionic pi class. GSH-S-transferases from the mu or alpha classes were not detectable in either cell line. In conclusion, marked differences in GSH levels and the activities of three of four GSH-related enzymes were observed between the multidrug-resistant H69AR cell line and its parent cell line. Further study is required to determine whether these changes are causally related to the development of drug resistance in this model system.
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PMID:Alterations in glutathione and glutathione-related enzymes in a multidrug-resistant small cell lung cancer cell line. 196 21

We have investigated the metabolism and covalent binding of 1,1-dichloroethylene (1,1-DCE) in isolated unseparated lung cells and in enriched fractions of Clara and alveolar type II cells from mice. Lung cells from control mice separated by centrifugal elutriation were viable and metabolically active as assessed by measurements of 7-ethoxycoumarin deethylase, NADPH cytochrome c reductase, and glutathione S-transferase activities, which were highest in fractions enriched in Clara cells. Mice were treated with [14C]1,1-DCE (125 mg/kg; 20 microCi/kg) in vivo and, 1 hr later, lung cells were isolated and binding of [14C]1,1-DCE determined. Covalent binding was highest in the Clara cell fraction (480 +/- 205 pmol/10(6) cells; 41% Clara cell purity) when compared to the levels present in the fractions containing type II cells (126 +/- 63 pmol/10(6) cells; 51% type II cell purity) and mixed cells from whole lung (29 +/- 13 pmol/10(6) cells). Ultrastructurally, alveolar type II cells from lungs of control and 1,1-DCE-treated mice exhibited normal morphology with well-preserved lamellar bodies. Whereas Clara cells isolated from lungs of control mice appeared structurally unimpaired, those from the lungs of 1,1-DCE-treated mice displayed severe damage and disruption of cellular organelles. The results of these experiments demonstrate the highest binding of [14C]1,1-DCE-metabolite(s) in Clara cells, whereas significantly lower binding was found in both alveolar type II and unseparated lung cells. The substantial binding of [14C]1,1-DCE in Clara cells correlated positively with the high monooxygenase capacity and the preferential damage sustained by this cell population.
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PMID:Morphologic changes and covalent binding of 1,1-dichloroethylene in Clara and alveolar type II cells isolated from lungs of mice following in vivo administration. 197 79

These investigations sought to determine the role of physiological concentrations of natural glucocorticoids in modulating chemical toxicity, and to ascertain if effects on toxicity may be due to alterations of chemical metabolizing enzymes by glucocorticoids. The hepatotoxic response to carbon tetrachloride (CCl4) in adrenalectomized or naive Long Evans rats treated with corticosterone was assessed. Alterations of hepatic cytochrome P-450 concentration, mono-oxygenase activities, NADPH-cytochrome (P-450)c reductase activity, and glutathione S-transferase activity were examined. Adrenalectomy and to a lesser extent sham surgery were protective, but corticosterone administration increased CCl4 hepatotoxicity. Corticosterone administration to adrenalectomized or sham-operated rats reduced the protective effect of these treatments. Correlating with the in vivo response, mono-oxygenase activities decreased after adrenalectomy and sham surgery, but increased with glucocorticoid administration. These studies suggest that basal, stress-associated, and pharmacological concentrations of a natural glucocorticoid can modify chemical toxicity and alter hepatic enzymes important to chemical metabolism.
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PMID:Modulation of carbon tetrachloride hepatotoxicity and xenobiotic-metabolizing enzymes by corticosterone pretreatment, adrenalectomy and sham surgery. 199 98

Chlorothalonil (2,4,5,6-tetrachloroisophthalonitrile) is a broad spectrum fungicide that is a potent acute toxicant to fish. Therefore, the metabolism of chlorothalonil was investigated in liver and gill cytosolic and microsomal fractions from channel catfish (Ictalurus punctatus) using HPLC. All fractions catalyzed the metabolism of chlorothalonil to polar metabolites. Chlorothalonil metabolism by cytosolic fractions was reduced markedly when glutathione (GSH) was omitted from the reaction mixtures. The lack of microsomal metabolism in the presence of either NADPH or an NADPH-regenerating system indicated direct glutathione S-transferase (GST)-catalyzed conjugation with GSH without prior oxidation by cytochrome P450. Cytosolic and microsomal GSTs from both tissues were also active toward 1-chloro-2,4-dinitrobenzene (CDNB), a commonly employed reference substrate. In summary, channel catfish detoxified chlorothalonil in vitro by GST-catalyzed GSH conjugation in the liver and gill. The present report is the first to confirm microsomal GST activity toward CDNB in gill and toward chlorothalonil in liver, and also of gill cytosolic GST activity towards chlorothalonil, in an aquatic species.
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PMID:Glutathione S-transferase-mediated chlorothalonil metabolism in liver and gill subcellular fractions of channel catfish. 206 87


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