Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.6.5.2 (NQO1)
 6,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In an attempt to characterize metabolism enzymes of the estrogen-induced kidney tumor in male Syrian hamsters, the activities of enzymes involved in drug and glutathione metabolism were determined in tumor tissue. Kidney tumors were induced in male Syrian hamsters by treatment with estradiol for 8 months. Cytochrome P-450 and cytochrome b5 concentrations in tumors were below detectable levels. However, when cytochrome P-450-mediated oxidation was analyzed by product formation assays, the oxidation of E-diethylstilbestrol to diethylstilbestrol-4',4"-quinone by tumor microsomes was 10-20% of the rate found in control microsomes. In kidney tissue surrounding estrogen-induced tumors, cytochrome P-450 and b5 contents were 50-60% less than those in untreated kidney. Activities of reducing enzymes of drug metabolism (cytochrome P-450, cytochrome b5 and NADH:cytochrome c reductases), glutathione metabolism enzymes (glutathione peroxidase, glutathione transferase, glutathione reductase, and gamma-glutamyl transpeptidase), and free radical scavenging enzymes (superoxide dismutase, catalase, and quinone reductase) in tumor were significantly lower than in untreated kidney tissue. The activities of these enzymes in renal tumor surrounding tissue were between those observed in tumor and control kidney. Glucose-6-phosphate dehydrogenase activity was increased by 50% in surrounding tissue and 430% in tumor compared to values in untreated controls. The decreased enzyme activity levels in hormone-exposed tissue surrounding tumors likely represented an adaptation of this tissue to the neoplastic environment induced by chronic estrogen treatment.
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PMID:Characterization of drug metabolism enzymes in estrogen-induced kidney tumors in male Syrian hamsters. 304 47

The exact contribution of the quinone group to the activity of quinone antitumor agents remains uncertain. Two L5178Y murine lymphoblastic cell lines resistant to the model quinone antitumor agent, hydrolyzed benzoquinone mustard, and one partial-revertant cell line were isolated and characterized. The antitumor activity of hydrolyzed benzoquinone mustard has been shown previously to be due to its ability to induce free radical mediated DNA strand breaks. Resistant cells were obtained by growing a cloned L5178Y parental cell line in media containing increasing concentrations of hydrolyzed benzoquinone mustard. L5178Y/HBM2 cells were selected from L5178Y cells growing in media containing 0.2 mM drug, while L5178Y/HBM10 cells were selected from cells growing in media containing 1.0 mM drug. The L5178Y/HBMR cells were obtained by growing L5178Y/HBM10 cells in media without hydrolyzed benzoquinone mustard. The resistant cell lines, L5178Y/HBM2 and L5178Y/HBM10, were 2.5- and 6-fold less sensitive, respectively, to hydrolyzed benzoquinone mustard compared to parental cells, and this was accompanied by a decrease in the formation of DNA single and double strand breaks by this drug. The partial-revertant cell line, L5178Y/HBMR was 2.9-fold less sensitive to hydrolyzed benzoquinone mustard compared to parental cells. Drug uptake appeared to be lower in the resistant cells compared to parental cells. The resistant cells had a slightly elevated level of superoxide dismutase activity compared to parental cells, but there was no increase in the mRNA for superoxide dismutase nor any amplification of the gene for this enzyme. Intracellular catalase activities of the L5178Y/HBM2 and L5178Y/HBM10 cells were elevated by 1.25- and 2.6-fold, respectively, and the increased enzyme activity in the L5178Y/HBM10 cells appeared to result from a 3.6-fold increase in mRNA for this enzyme. Glutathione peroxidase activity was slightly elevated in L5178Y/HBM2 cells, but was unchanged in the other resistant cells. The L5178Y/HBM2 and L5178Y/HBM10 cells showed increased concentrations of glutathione and elevated levels of glutathione transferase activity. The resistant cell lines also had DT-diaphorase activity that was 3- and 24-fold higher in L5178Y/HBM2 and L5178Y/HBM10 cells, respectively, compared to sensitive cells. However, cytochrome P-450 reductase activity and the ratio of reduced to oxidized pyridine nucleotides was unchanged in the resistant cell lines. The partial-revertant cell line, L5178Y/HBMR, showed approximately the same level of resistance to hydrolyzed benzoquinone mustard as the L5178Y/HBM2 cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Characterization of L5178Y murine lymphoblasts resistant to quinone antitumor agents. 312 38

This study was performed in order to study the response of epoxide hydrolases in different subcellular compartments of mouse liver to treatment with various compounds. Male C57BL/6 mice were treated with 31 different compounds--including traditional inducers of xenobiotic-metabolizing systems, liver carcinogens, stilbene derivatives, endogenous compounds and various other drugs and xenobiotics. The effects on liver somatic index; protein contents in 'mitochondria', microsomes and cytosol prepared from the liver; epoxide hydrolase activity towards trans- or cis-stilbene oxide in these three fractions; microsomal cytochrome P-450 content; cytosolic and 'mitochondrial' glutathione transferase activity and cytosolic DT-diaphorase activity were then determined. Cytosolic epoxide hydrolase activity was induced by chlorinated paraffins, di(2-ethylhexyl)phthalate and clofibrate and depressed by alpha-naphthylisothiocyanate, 3-methylcholanthrene, benzil and quercitin. Radial immunodiffusion revealed similar changes in the amount of enzyme protein present, except for two cases, where the increase in amount was larger; and the enzyme seems to be inhibited by benzil. Microsomal epoxide hydrolase activity was induced by these same compounds and several others as well, including dibenzoylmethane, butylated hydroxyanisole and polychlorinated biphenyls. 'Mitochondrial' epoxide hydrolase activity towards trans-stilbene oxide was not affected by those compounds which induced the cytosolic enzyme, but increased about two-fold after treatment with 2-acetylaminofluorene, DL-ethionine, aflatoxin B1 and phenobarbital. There does not seem to be any co-regulation of different forms of epoxide hydrolase in mouse liver. In general small effects were observed on liver weight and protein contents in the different subcellular fractions. Polychlorinated biphenyls were the most potent of the 8 compounds which induced cytochrome P-450, while butylated hydroxyanisole induced cytosolic glutathione transferase activity to the highest extent. 'Mitochondrial' glutathione transferase activity was most induced by certain of the stilbene derivatives. The most potent inducers of DT-diaphorase activity were 3-methylcholanthrene, polychlorinated biphenyls and dinitrotoluene.
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PMID:Hepatic levels of cytosolic, microsomal and 'mitochondrial' epoxide hydrolases and other drug-metabolizing enzymes after treatment of mice with various xenobiotics and endogenous compounds. 362 71

Various aspects of the cardiotoxicity of the anthracycline derivative and antineoplastic drug daunorubicin were investigated using isolated and cultured cells from neonatal rat hearts as a model system. Treatment of the cells with concentrations of daunorubicin of the same order of magnitude as those used in chemotherapy was accompanied by marked toxic effects, e.g. a decreased or abolished contraction, and release of lactate dehydrogenase, pyruvate and oxidized glutathione to the medium. A decreased frequency of contraction appeared to be the most sensitive probe of daunorubicin toxicity, followed by release of pyruvate and oxidized glutathione/lactate dehydrogenase. Daunorubicin and/or its metabolites also bound to cellular protein and DNA. Exposure to daunorubicin was shown to be accompanied by a rapid induction of primarily DT-diaphorase and a slower induction of glutathione transferase. The latter observations are interpreted to indicate a protective role of quinone- and peroxide-metabolizing enzymes, respectively, and support the hypothesis that daunorubicin toxicity involves generation of free radical derivatives, which initiate lipid peroxidation. This conclusion is further substantiated by the demonstration that addition of daunorubicin leads to an increased oxygen consumption.
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PMID:Toxic effects of daunorubicin on isolated and cultured heart cells from neonatal rats. 398 1

We have utilized cDNA probes and in vitro translation analysis to quantitate the levels of rat liver glutathione transferase (glutathione S-aralkyltransferase; RX:glutathione R-transferase, EC 2.5.1.18) and DT-diaphorase [NAD-(P)H:quinone-acceptor oxidoreductase, EC 1.6.99.2] mRNAs in persistent hepatocyte nodules induced by chemical carcinogens. Our results indicate that within the nodules, glutathione transferase mRNAs specific for the Ya/Yc and Yb subunits are increased 3-fold and 5-fold, respectively, over the levels observed in normal liver or in the liver tissue surrounding the nodules. Similarly, the level of DT-diaphorase mRNA is increased 5- to 7-fold within the nodules as compared to surrounding liver tissue or normal liver. When animals were administered 3-methylcholanthrene, a typical inducer of these mRNAs in normal animals, a further increase in the glutathione transferase Yb mRNA(s) and DT-diaphorase mRNA was observed in the nodules; however, the Ya/Yc mRNA levels remained unaffected. Our data indicate that during chemically induced neoplastic transformation, the mRNA levels for the Yb subunit of glutathione transferase and DT-diaphorase are increased in the nodules but still retain the capacity to be regulated by 3-methylcholanthrene. Although the glutathione transferase Ya/Yc mRNAs are also increased in the nodules, they lost their ability to be regulated by 3-methylcholanthrene. These latter data suggest that within the nodules there is a specific defect in the regulatory mechanism(s) that leads to an induction of the Ya/Yc mRNAs in normal tissue by xenobiotics.
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PMID:Regulation of glutathione transferase and DT-diaphorase mRNAs in persistent hepatocyte nodules during chemical hepatocarcinogenesis. 643 44

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

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

In this study, Morris hepatoma 7800C1 cells (from rat) were exposed to 500 microM perfluorooctanoic acid (PFOA) in the culture medium for 7 days. This treatment resulted in inductions of catalase, lauroyl-CoA oxidase (which catalyzes the first step in peroxisomal beta-oxidation) and of cytochrome P-450IVA (specialized for omega- and omega-1 hydroxylation of fatty acids). Northern blot analysis revealed that the level of mRNA for peroxisomal fatty acyl-CoA oxidase was enhanced in cells treated with PFOA. Inductions of the enzymes mentioned above are generally connected with peroxisome proliferation in vivo. This work also includes a comparison between the activities of catalase, lauroyl-CoA oxidase, DT-diaphorase and glutathione transferase in rat liver homogenate and 7800C1 cells in order to investigate to what extent this cell line differs from the situation in vivo. The findings suggest that the cells selectively lost most of their peroxisomes during transformation into a cell line and subsequent propagation. The control activities of catalase and lauroyl-CoA oxidase (marker enzymes for peroxisomes) were only about 2% of the corresponding enzyme activities in rat liver. In addition, a morphological study revealed that the frequency of peroxisomes in 7800C1 cells is very low. The control activity of glutathione transferase in 7800C1 cells was 11% of the corresponding activity in rat liver homogenate, whereas the level of DT-diaphorase was virtually the same in 7800C1 cells as in rat liver. Electron microscopic investigation of the control cultures revealed all signs of viable cells, with well-developed cell organelles. Treatment of 7800C1 cells with 500 microM PFOA has little effect on cellular morphology.
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PMID:Effects of perfluorooctanoic acid--a potent peroxisome proliferator in rat--on Morris hepatoma 7800C1 cells, a rat cell line. 801 82

Male C57 BL/6 mice were exposed to 1.0% (w/w) acetylsalicylic acid (ASA) in their diet for 10 days and effects related to peroxisome proliferation were subsequently examined. A 2.2-fold increase in mitochondrial protein content was obtained. The activities of the peroxisomal enzymes, lauroyl-CoA oxidase, palmitoyl-CoA oxidation and catalase, were enhanced 4.5-, 4.0- and 2.1-fold, respectively. There was a dramatic increase (9.1-fold) in microsomal cytochrome P450 IVA-catalysed activity, a 1.6-fold induction of total microsomal P450 content and a 2-fold induction of microsomal cytochrome P450 reductase activity (measured as NADPH-cytochrome c reductase). Catalase activity in the cytosol was induced 5.2-fold and DT-diaphorase activity was increased 3.5- and 3.2-fold in the cytosol and mitochondria, respectively. There was a significant increase in the susceptibility of microsomes to lipid peroxidation. Smaller increases in superoxide dismutase, glutathione transferase and glutathione peroxidase activities were also observed. The possible relevance of these effects to the pharmacology of ASA is discussed.
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PMID:Effects of acetylsalicylic acid on parameters related to peroxisome proliferation in mouse liver. 803 14


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