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)

The mechanisms by which 2(3)-tert-butyl-4-hydroxyanisole (BHA) protects against chemical carcinogenesis and toxicity include enhancement of the activities of several detoxification enzymes. In previous studies, 14-day administration of BHA to female CD-1 mice at 0.75% of the diet led to large increases in cytosolic glutathione transferase (EC 2.5.1.18) and reduced nicotinamide adenine dinucleotide (phosphate) dehydrogenase (quinone) (EC 1.6.99.2) [NAD(P)H:quinone reductase; DT-diaphorase] specific activities in several tissues, and elevated hepatic glutathione transferase messenger RNA. In the present study, one day of dietary BHA significantly increased NAD(P)H:quinone reductase and glutathione transferase activities in the liver, kidney, and proximal small intestine, and NAD(P)H:quinone reductase activity in the forestomach and lung. In the proximal small intestine, glutathione transferase specific activities toward 1-chloro-2,4-dinitrobenzene and 1,2-dichloro-4-nitrobenzene rose to 2.6 and 8 times those of control, respectively, and NAD(P)H:quinone reductase specific activity doubled, within 1 day on the BHA diet. Six hr after a single p.o. dose of BHA (620 mg/kg), intestinal glutathione transferase specific activities were 30 to 50% above those of control mice. In liver, the kinetics of increase of glutathione transferase messenger RNA were in accord with increased synthesis as the mechanism of elevation of glutathione transferase activity in response to BHA. Although changes in mixed-function oxygenase activities have been reported to occur more rapidly, the kinetics of the response of glutathione transferase and NAD(P)H:quinone reductase specific activities to BHA indicates that nonoxidative detoxification potential is substantially enhanced within 24 hr or less after initiation of BHA administration.
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PMID:Kinetics of glutathione transferase, glutathione transferase messenger RNA, and reduced nicotinamide adenine dinucleotide (phosphate):quinone reductase induction by 2(3)-tert-butyl-4-hydroxyanisole in mice. 643 66

2(3)-tert-Butyl-4-hydroxyanisole (BHA) is one of several widely used antioxidant food additives that protect against chemical carcinogenesis and toxicity. The present report concerns the enhancement of dicoumarol-inhibited NAD(P)H:quinone reductase [NAD(P)H dehydrogenase (quinone); NAD(P)H:(quinone acceptor) oxidoreductase, EC 1.6.99.2] activity in mouse tissues in response to dietary administration of BHA. Cytosolic quinone reductase specific activity was increased significantly in 10 of 15 tissues examined from BHA-fed mice. The greatest proportionate increase, to 10 times control levels, was observed in liver. BHA also increased the quinone reductase activities of kidney, lung, and the mucosa of the upper small intestine severalfold. The increases of quinone reductase activities in liver and digestive tissues in response to BHA were comparable to the increases previously observed in glutathione S-transferase (EC 2.5.1.18) and epoxide hydratase (EC 3.3.2.3) activities. Quinones are among the toxic products of oxidative metabolism of aromatic hydrocarbons. NAD(P)H:quinone reductase exhibits broad specificity for structurally diverse hydrophobic quinones and may facilitate the microsomal metabolism of quinones to readily excreted conjugates. The protective effects of BHA appear to be due, at least in part, to the ability of this antioxidant to increase the activities in rodent tissues of several enzymes involved in the nonoxidative metabolism of a wide variety of xenobiotics.
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PMID:Increase of NAD(P)H:quinone reductase by dietary antioxidants: possible role in protection against carcinogenesis and toxicity. 693 53

Changes in hepatic drug-metabolizing enzymes after intraperitoneal treatment of rats with 2-acetylaminofluorene have been investigated. This treatment was found to increase microsomal epoxide hydrolase to 762%, cytochrome P-450 to 143%, NADPH-cytochrome c reductase to 160%, cytochrome b5 to 171%, cytoplasmic DT-diaphorase to 229% and soluble glutathione S-transferase activities to 200-250% of control values. These increases were time- and dose-dependent, being maximal after injection of 50 mg 2-acetylaminofluorene/kg body wt. once daily for 5 days. Enzyme markers for the plasma membrane, mitochondria, lysosomes and the soluble cytoplasm were not affected by treatment with 2-acetylaminofluorene. The present study indicates that this induction is different from that obtained with phenobarbital and 3-methylcholanthrene and more closely resembles that seen with trans-stilbene oxide.
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PMID:Characterization of the induction of drug-metabolizing enzymes by 2-acetylaminofluorene. 722 16

To investigate the resistant mechanisms against MMC in human tumor cells, we isolated an MMC-resistant variant (HT-29/MMC) of HT-29 human colon carcinoma cells. HT-29/MMC cells showed 5-fold resistance to MMC as compared with the parental cell line but did not show cross-resistance to Adriamycin, vincristine, ACNU, bleomycin, or cisplatin. Treatment of the cells with dicoumarol, an inhibitor of DT-diaphorase, reduced the cytotoxicity of MMC in DT-diaphorase proficient HT-29 cells but not in HT-29/MMC cells. HT-29/MMC cells were 5 times more sensitive than HT-29 cells to menadione, which is detoxified by DT-diaphorase, DT-diaphorase was deficient in HT-29/MMC cells as determined by the enzyme activity and immunoblot analysis of the cytoplasmic proteins. Levels of cytochrome P-450 reductase and glutathione S-transferase, however, were comparable in both cell lines. The amount of [3H]-MMC found covalently bound to chromosomal DNA in HT-29/MMC cells was one-fourth that detected in HT-29 cells. Treatment with dicoumarol reduced the DNA-bound MMC in HT-29 cells but not in HT-29/MMC cells. These results indicate that the deficiency in DT-diaphorase, an activating enzyme of MMC, is one of the mechanisms of resistance in HT-29/MMC cells.
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PMID:Isolation and characterization of a mitomycin C-resistant variant of human colon carcinoma HT-29 cells. 750 23

The peroxisome proliferators perfluorooctanoic acid (PFOA; 0.02% w/w), perfluorodecanoic acid (PFDA; 0.02%, w/w), nafenopin (0.125%, w/w), clofibrate (0.5%, w/w), and acetylsalicylic acid (ASA; 1%, w/w) were administered to male C57 BL/6 mice in their diet for two weeks. Parameters for Fe3+ ADP, NADPH or ascorbic acid-initiated lipid peroxidation in vitro were measured. Approximately a twofold increase in susceptibility to lipid peroxidation was obtained for all the peroxisome proliferators tested. Cotreatment of mice with the peroxisome proliferator ASA (1%, w/w) and a catalase inhibitor, 3-amino-1,2,4-triazole (AT; 0.4%, w/w) for 7 days resulted in little inhibition of peroxisome proliferation, an elevated level of H2O2 in vivo, and total inhibition of the increased susceptibility to lipid peroxidation in vitro. No increase in lipid peroxidation in vivo was observed. Certain antioxidant enzymes (DT-diaphorase, superoxide dismutase, glutathione transferase, glutathione peroxidase, and glutathione reductase) and components (ubiquinone and alpha-tocopherol) were also measured. The results showed that there was some induction of these antioxidant enzymes and components by ASA or aminotriazole, except for glutathione peroxidase and superoxide dismutase, which were inhibited. The possible involvement of oxidative stress in the carcinogenicity of peroxisome proliferators is discussed.
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PMID:Hepatic oxidative stress and related defenses during treatment of mice with acetylsalicylic acid and other peroxisome proliferators. 756 57

Southern armyworm, Spodoptera eridania, larvae were provided ad libitum 0.002-0.25% w/w dichlone, 2,3-dichloro-1,4-naphthoquinone (CNQ). Larval mortality occurred in a time-and-dose dependent manner, with an LC17 of 0.01% and an LC50 of 0.26% CNQ at day-5. Extracts of larvae fed control, 0.01, and 0.25% CNQ diets for 5 days were assayed for antioxidant enzymes. While 0.01% CNQ had a mild effect, 0.25% CNQ profoundly increased levels of all antioxidant enzymes that were examined. The increases as compared to control were: 5.3-, 1.9-, 3.2-, 2.6-, 2.8-, and 3.5-fold higher for superoxide dismutase, catalase, glutathione transferase and its peroxidase activity, glutathione reductase and DT-diaphorase, respectively. At 0.01% CNQ, the thiobarbituric acid reactive substances (TBARS) were similar to the control group. However, despite the induction from 0.25% CNQ of all enzymes examined, the lipid peroxidation was not attenuated; the TBARS were 29.7% over the control value. High mortalities and CNQ-induced pathologies reflected in retarded growth, wasting syndrome, and diuresis clearly indicated that the insect sustained severe oxidant-induced injuries before appropriate defenses were fully mobilized. Thus, this quinone causes an oxidative stress in a model insect species analogous to that observed in mammalian species.
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PMID:Dichlone-induced oxidative stress in a model insect species, Spodoptera eridania. 757 83

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

Established cell lines derived from newborn livers of c14CoS/c14CoS and cch/cch mice were examined for differences in menadione toxicity. The 14CoS/14CoS cells exhibit 10-fold higher NAD(P)H:menadione oxidoreductase (NMO1) activity and 3-fold greater concentrations of reduced glutathione (GSH) than the ch/ch cells. In 14CoS/14CoS cells there are also 50% to 3-fold increases in glutathione transferase (GSTA1), UDP glucuronosyltransferase, and the copper, zinc-dependent superoxide dismutase activities. Catalase activity, on the other hand, is six times lower in the 14CoS/14CoS than the ch/ch line. The 14CoS/14CoS cells are two to four times more resistant to menadione killing than ch/ch cells. At concentrations of dicumarol that completely block NMO1 and GSTA1 activities, the 14CoS/14CoS cells show more than twice as much resistance to menadione toxicity than the ch/ch cells. Although superoxide formation is three times higher in untreated 14CoS/14CoS than ch/ch cells, menadione-induced superoxide formation is greater in the dying ch/ch than in the 14CoS/14CoS cells. Cellular resistance to menadione toxicity is correlated with intracellular GSH levels, rather than with the percentage of oxidized glutathione; cytotoxicity is not observed as long as GSH concentrations are sufficiently high (about 5-8 nmol/mg protein). For menadione, the results are consistent with a dominant role of GSH depletion in mediating toxicity and support a protective role for NMO1 activity. This report demonstrates the usefulness of these cell lines as a model system to study mechanisms of oxidative chemically induced toxicity, as well as to understand how intracellular levels of GSH are regulated.
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PMID:Menadione toxicity in two mouse liver established cell lines having striking genetic differences in quinone reductase activity and glutathione concentrations. 769 Sep 96

The effect of tetrachloroethylene on Phase I and II drug-metabolizing enzymes in rat liver was examined. Rats were treated orally with tetrachloroethylene daily for five days, at doses of 125, 250, 500, 1,000 and 2,000 mg/kg. The higher doses (> 500 mg/kg) of tetrachloroethylene induced the hepatic microsomal 7-pentoxyresorufin O-depentylase and 7-benzyloxyresorufin O-debenzylase activities associated with the CYP2B subfamily. 7-ethoxyresorufin O-deethylase activity was also induced about 2-fold compared with that of control rats at 500, 1,000, and 2,000 mg/kg dose levels of tetrachloroethylene. However, 7-ethoxycoumarin O-deethylase and 7-methoxyresorufin O-demethylase activities were increased significantly at only the 1,000 mg/kg dose level of tetrachloroethylene (1.4- and 1.5-fold). Although other cytochrome P450-mediated monooxygenase activities such as nitrosodimethylamine N-demethylase, aminopyrine N-demethylase and erythromycin N-demethylase were also induced by tetrachloroethylene, the relative induction to control activity was lower than those of 7-pentoxyresorufin O-depentylase and 7-benzyloxyresorufin O-debenzylase. Western immunoblotting showed that the levels of CYP2B1 and CYP2B2 proteins in liver microsomes were increased at doses of 1,000 and 2,000 mg/kg of tetrachloroethylene. In addition to cytochrome P450-mediated monooxygenases, there was significant induction of the Phase II drug-metabolizing enzymes, DT-diaphorase, glutathione S-transferase activities towards 1-chloro-2,4-dinitrobenzene and 1,2-dichloro-4-nitrobenzene, and UDP-glucuronyltransferase activities towards 4-nitrophenol and 7-hydroxycoumarin. The results indicate that tetrachloroethylene induces both Phase I (CYP2B-mediated monooxygenase) and Phase II drug-metabolizing enzymes (DT-diaphorase, glutathione S-transferase and UDP-glucuronyltransferase) in the rat liver.
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PMID:Induction of rat liver drug-metabolizing enzymes by tetrachloroethylene. 772 43

The effects of 1,2,3,4-tetrachlorodibenzo-p-dioxin (1,2,3,4-TCDD) on drug-metabolizing enzymes were studied in male and female rats. 1,2,3,4-TCDD (25, 50, 100 and 200 mumol/kg) was administered by i.p. injection once. Among the cytochrome P-450 (P450)-mediated monooxygenase activities tested, 7-ethoxyresorufin O-deethylase (EROD) activities in both male and female rats, which are associated with CYP1A1, were remarkably induced by all doses of 1,2,3,4-TCDD. The relative induction to each control activity were from 3.0- to 24.5-fold and from 2.2- to 16.5-fold, respectively. Also, 1,2,3,4-TCDD increased other CYP1A-mediated monooxygenase activities such as 7-ethoxycoumarin O-deethylase (ECOD) and 7-methoxyresorufin O-demethylase (MROD) in male and female rats dose-dependently (1.4- to 4.3-fold). Western immunoblotting showed that the levels of CYP1A1 and CYP1A2 proteins in liver microsomes were increased by 1,2,3,4-TCDD. Although the activities of other P450-mediated monooxygenases, namely 7-pentoxyresorufin O-depentylase (PROD), 7-benzyloxyresorufin O-debenzylase (BROD), aminopyrine N-demethylase (APND) and nitrosodimethylamine N-demethylase (NDAND) in both male and female rats were induced at high doses (> or = 50 mumol/kg) of 1,2,3,4-TCDD, the relative level was low compared with those of the CYP1A-mediated monooxygenase such as EROD, ECOD or MROD. In addition to P450-mediated monooxygenase, there was significant induction in the activities of the Phase II drug-metabolizing enzymes, UDP-glucuronyltransferase (UGT) activities towards 4-nitrophenol (4-NP) and 7-hydroxycoumarin (7-HC) and glutathione S-transferase (GST) towards 1-chloro-2,4-dinitrobenzene (CDNB), 1,2-dichloro-4-nitrobenzene (DCNB) and DT-diaphorase. These results indicate that 1,2,3,4-TCDD induces both Phase I (CYP1A-mediated monooxygenase) and Phase II drug-metabolizing enzymes (UGT, GST, DT-diaphorase) in the male and female rat liver, and that the alterations of drug-metabolizing enzyme are characteristic of PCDD toxicity.
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PMID:The effect of 1,2,3,4-tetrachlorodibenzo-p-dioxin on drug-metabolizing enzymes in the rat liver. 786 51


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