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:1.6.5.2 (NQO1)
6,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The system involved in the reduction of 2-[4'-di(2''-bromopropyl) aminophenylazolbenzoic acid (CB10-252), an agent designed for treating primary liver cell cancer, has been demonstrated to be localised mainly in the 108 000 X g supernatant fraction of rat liver homogenate. It is also present in other organs particularly in the spleen. DAB-azoreductase as shown previously is present almost entirely in the microsomal fraction and is found in high concentration only in liver. The pH maximum for CB10-252-azoreductase implying the importance of the 2'-carboxyl group in determining substrate specificity. The use of enzyme inhibitors and other additives showed that CB10-252 WAS NOT AXANTHINE OXIDASE OR DIHYDROFOLATE REDUCTASE. Its activity was not affected by carbon monoxide, phenobarbitone (PB), or 3-methylcholanthrene (MC) pretreatment. Enhancement of the activity by ferrous ions and FAD indicated that at least part of the reduction system could involve a flavoprotein with FAD as the prosthetic group. The activity of CB10-252-azoreductase and methylred-azoreductase was reduced by menadione (vitamin K3), cyanide and propylgallate. A diaphorase preparation from pig heart reduced both CB10-252 and methylred with both NADPH- and NADH-generating systems.
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PMID:Some characteristics of two azoreductase systems in rat liver. Relevance to the activity of 2-[4'-di(2"-bromopropyl)-aminophenylazo]benzoic acid (CB10-252), a compound possessing latent cytotoxic activity. 0 Jan 49

The carcinogens, N-acetyl-aminofluorene, 7,12-dimethylbenzanthracene, 3,4-benzpyrene and 3-methylcholanthrene, increase the activity of the soluble enzyme D-T-diaphorase. This action is observed 24 h after the administration of these chemicals to rats. Dicumarol blocks this effect. Dicumarol does not inhibit the increase in activity of the microsomal aryl hydrocarbon hydroxylase system as elicited by 3,4-benz(a)pyrene and 3-methylcholanthrene. The functional significance of these findings and the possible role of cytosolic enzymic changes in chemical toxicity are discussed.
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PMID:Carcinogens and dicumarol: opposite effects on rat liver NAD(P)H dehydrogenation. 8 Nov 30

The transverse distribution of enzyme proteins and phospholipids within microsomal membranes was studied by analyzing membrane composition after treatment with proteases and phospholipases. Upon trypsin treatment of closed microsomal vesicles, NADH- and NADPH-cytochrome c reductases as well as cytochrome b5 were solubilized or inactivated, while cytochrome P-450 was partially inactivated. When microsomes were exposed to a concentration of deoxycholate which makes them permeable to macromolecules but does not disrupt the membrane, the detergent alone was sufficient to release four enzymes: nucleoside diphosphatase, esterase, beta-glucuronidase, and a portion of the DT-diaphorase. Introduction of trypsin into the vesicle lumen inactivated glucose-6-phosphatase completely and cytochrome P-450 partially. The rest of this cytochrome, ATPase, AMPase, UDP-glucuronyltransferase, and the remaining 50% of DT-diaphorase activity were not affected by proteolysis from either side of the membrane. Phospholipase A treatment of intact microsomes in the presence of albumin hydrolyzed all of the phosphatidylethanolamine, phosphatidylserine, and 55% of the phosphatidylcholine. From this observation, it was concluded that these lipids are localized in the outer half of the bilayer of the microsomal membrane; Phosphatidylinositol, 45% of the phosphatidylcholine, and sphingomyelin are tentatively assigned to the inner half of this bilayer. It appears that the various enzyme proteins and phospholipids of the microsomal membrane display an asymmetric distribution in the transverse plane.
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PMID:Enzyme and phospholipid asymmetry in liver microsomal membranes. 19 Feb 41

Addition of beta-lapachone, an o-naphthoquinone endowed with trypanocidal properties to respiring Trypanosoma cruzi epimastigotes induced the release of O2- and H2O2 from the whole cells to the suspending medium. The same beta-lapachone concentration (4 micron) that released H2O2 at maximal rate completely inhibited T. cruzi growth in a liquid medium. The position isomer, alpha-lapachone, did not stimulate O2- and H2O2 release, and did not inhibit epimastigote growth. beta-Lapachone was able to stimulate H2O2 production by the epimastigote homogenate in the presence of NADH as reductant. The same effect was observed with the mitochondrial fraction supplemented with NADH, where beta-lapachone enhanced the generation of O2- and H2O2 4.5- and 2.5-fold respectively. beta-Lapachone also increased O2- and H2O2 production (2.5 and 2-fold respectively) by the microsomal fraction with NADPH as reductant. Cyanide-insensitive NADH and NADPH oxidation by the mitochondrial and microsomal fractions (quinone reductase activity) was stimulated to about the same extent by beta-lapachone. alpha-Lapachone was unable to increase O2- and H2O2 production and quinone reductase activity of the mitochondrial and microsomal fractions.
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PMID:Effect of beta-lapachone on superoxide anion and hydrogen peroxide production in Trypanosoma cruzi. 21 40

NAD(P)H dehydrogenase ('DT-diaphorase', EC 1.6.99.2) and vitamin K epoxidase were removed by affinity chromatography from detergent-solubilized microsomal fractions. Thereby the microsomal fractions normally carrying out vitamin K1-dependent carboxylation of the microsomal precursor proteins of the prothrombin complex were inactivated. Purified NAD(P)H dehydrogenase added to this system restored carboxylation in the presence of vitamin K1 (2-methyl-3-phytyl-1,4-naphthoquinone) plus NADH. Vitamin K1 hydroquinone (2-methyl-3-phytyl-1,4-naphthoquinol) had no effect, in contrast with its effect in the intact system, where it can substitute for vitamin K1 plus NADH. The ability of NAD(P)H dehydrogenase to restore carboxylation in a system without vitamin K epoxidase activity shows that there is no obligatory coupling of the vitamin K1-dependent carboxylation with vitamin K1 epoxidation. These results suggest that the form of vitamin K1 that is active in the carboxylation reaction can be produced independently in two reactions: by NAD(P)H dehydrogenase in the reduction of the quinone and by vitamin K epoxidase in the epoxidation of the hydroquinone.
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PMID:No strict coupling of vitamin K1 (2-methyl-3-phytyl-1,4-naphthoquinone)-dependent carboxylation and vitamin K1 epoxidation in detergent-solubilized microsomal fractions from rat liver. 45 61

A simple three-step method was established for the purification of NAD(P)H dehydrogenase (quinone) ('DT-diaphorase', EC 1.6.99.2) from rat liver by affinity chromatography with a recovery of above 50%. The final enzyme preparation was purified about 750-fold and was electrophoretically homogeneous. Gel filtration showed that the enzyme had a mol.wt. of about 55 000, and one molecule of FAD was found per 55 000 mol.wt. Sodium dodecyl sulphate/polyacrylamide-gel electrophoresis gave a mol.wt. of about 27 000. Two N-terminal amino acids, asparagine/aspartic acid and glutamine/glutamic acid, were found in about equal yield, suggesting the presence of two non-identical polypeptide chains in the enzyme. NAD(P)H dehydrogenase was selectively removed by this affinity-chromatographic method from a microsomal carboxylation system. The system, which was solubilized by detergent and is dependent on vitamin K (2-methyl-3-phytyl-1,4-naphthaquinone or analogues with other side chains), lost its activity on the removal of the enzyme. The activity can be completely restored to the system by adding purified cytoplasmic NAD(P)H dehydrogenase or by using the quinol form of vitamin K1 (2-methyl-3-phytyl-1,4-naphthaquinol).
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PMID:NAD(P)H dehydrogenase and its role in the vitamin K (2-methyl-3-phytyl-1,4-naphthaquinone)-dependent carboxylation reaction. 62 56

Intermittent inhalation of 300 ppm of xylene vapour 6 h daily for 2 weeks caused a marked accumulation of the solvent in the perirenal fat. Simultaneous ethanol ingestion reduced the solvent load significantly although the perirenal xylene concentration increased in both test groups between the first and second week of exposure. Xylene inhalation enhanced hepatic and renal ethoxycoumarin 0-deethylase activity about 1.5-fold. The combination of inhaled xylene and peroral ethanol showed a markedly potentiated effect on microsomal ethoxycoumarin 0-deethylase activity especially in the kidneys. The enhanced monooxygenase activity was compatible with the decreased body solvent burden. Therefore, simultaneous ethanol intake might significantly modify the toxicological hazard in xylene exposure. Slightly increased proteolysis was detected in brain of animals in the xylene-ethanol experiment after the second week. Brain RNA content decreased after 2 weeks of exposure in the ethanol consuming animals. Xylene inhalation enhanced cerebral DT-diaphorase activity in both groups after 2 weeks of exposure. Ethanol intake also potentiated the behavioural effects caused by the solvent inhalation.
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PMID:Biochemical and toxicological effects of short-term, intermittent xylene inhalation exposure and combined ethanol intake. 73 90

The stimulation of reduced-NAD(P):menadione oxidoreductase (EC 1.6.99.2) activity in liver cytosol is highly correlated with the stimulation of hepatic microsomal aryl hydrocarbon (benzo[a]pyrene) hydroxylase (EC 1.14.14.2) activity in 3-methylcholanthrene-, beta-naphthoflavone-, phenobarbital-, or pregnenolone-16alpha-carbonitrile-treated inbred C57BL/6N and DBA/2N mice and in eight other inbred strains treated with 3-methylcholanthrene. No oxidoreductase activity is detectable in mouse liver microsomes. Cytochrome c and 2,6-dichlorophenolindophenol are equally good electron acceptors for the oxidoreductase. There is no preferential in vitro inhibition of induced versus control oxidoreductase activities by either alpha-naphthoflavone or metyrapone. In 3-methylcholanthrene-treated F1 and F2 progeny and offspring from backcrosses between the F1 and either C57BL/6N or DBA/2N parent, however, there is not a strict correlation between induced or noninducible aryl hydrocarbon hydroxylase and oxidoreductase activities. 2,3,7,8-Tetrachlorodibenzo-p-dioxin, at doses (80 mug kg-1) sufficiently high to induce the hydroxylase almost as well in DBA/2N as in C57BL/6N mice, induces the oxidoreductase about 3-fold in C57BL/6N and less than 50% in DBA/2N mice. All the data are consistent with an hypothesis that two loci (Ox-1 and Ox-2) regulate oxidoreductase induction by 3-methylcholanthrene, that one of the genes is linked to the Ah locus (with an estimated recombination frequency between 2% and 23%), and that the other gene is not linked to the Ah locus. These experimental data might be useful in the protein activator hypothesis of the Britten-Davidson model for gene regulation.
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PMID:Genetic differences in induction of cytosol reduced-NAD(P):menadione oxidoreductase and microsomal aryl hydrocarbon hydroxylase in the mouse. 83 15

Incubation of rat liver cytosolic or microsomal fractions with chromium(VI) led to a dramatic decrease in chromium(VI) mutagenicity, as determined by the Ames Salmonella assay using the TA100 tester strain. The cytosol-dependent decrease in chromium(VI) mutagenicity was found to be counteracted in the presence of dicumarol, an inhibitor of the cytosolic enzyme NAD(P)H:quinone oxidoreductase (DT-diaphorase). In order to determine whether DT-diaphorase is a significant factor in enzymatic reduction of chromium(VI) in rat liver tissue, cytosolic and microsomal fractions were analyzed for NAD(P)H-dependent chromium (VI) reductase activity leading to chromium(V) formation by using electron paramagnetic resonance (EPR) spectroscopy. Reaction of chromium(VI) with NADH or NADPH in the presence of either cytosolic or microsomal fractions led to the formation of stable chromium(V)--NAD(P)H complexes. When glucose 6-phosphate (G6P) was present in the reaction as part of a NADPH-generating system, stable chromium(V)--G6P complexes were formed in addition to the chromium(V)--NAD(P)H complexes. The chromium(V) complexes had g values of 1.980-1.982 and superhyperfine splitting constants of 0.8-0.9 characteristic of bis(diol)oxochromium(V) complexes. Inhibition of 90% of the cytosolic DT-diaphorase activity by dicumarol led to only partial (20-22%) inhibition of chromium(V) formation. Visible and EPR spectroscopic studies showed that purified DT-diaphorase had no detectable chromium(VI) reductase activity and did not catalyze formation of chromium(V). Inhibition of 69% of microsomal aryl hydrocarbon hydroxylase activity by ketoconazole led to partial (10%) inhibition of chromium(V) formation. These results indicate that intracellular NAD(P)H-dependent enzymatic reduction of chromium(VI) in rat liver cannot be attributed to the activity of any one enzyme in the cytosolic or microsomal fractions. DT-diaphorase appears to play an indirect role in decreasing chromium(VI)-induced mutagenicity in Salmonella, possibly through interaction with other redox active cellular components. The involvement of diols such as sugars and pyridine nucleotides in stabilizing intracellularly generated chromium(V) is discussed.
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PMID:Reduction of chromium(VI) to chromium(V) by rat liver cytosolic and microsomal fractions: is DT-diaphorase involved? 137 26

Male mice were exposed via their diet to perfluoro fatty acids of various chain-lengths (2-10 carbon atoms) at different doses (0.02 and 0.1% weight) and for different periods of time (2-10 days). Thereafter, we monitored effects on liver and body weights and a number of hepatic parameters, including mitochondrial protein content, microsomal contents of cytochromes P450 and b5, NADPH-cytochrome P450 reductase activity [measured as NADPH-cytochrome c reductase (EC 1.6.2.3)], microsomal and cytosolic epoxide hydrolase (EC 3.3.2.3) activities, cytosolic DT-diaphorase (EC 1.6.99.2), glutathione transferase (EC 2.5.1.18), glutathione peroxidase (EC 1.11.1.9) and superoxide dismutase (EC 1.15.1.1) activities, and levels of thiobarbituric acid-reactive material (as an indicator of lipid peroxidation) in the mitochondrial subfraction. The most dramatic changes observed were a 5-9-fold increase in mitochondrial protein, a 3-6-fold increase in the microsomal content of cytochrome P450, a 3-10-fold increase in cytosolic DT-diaphorase activity, an approximately 2-fold increase in cytosolic epoxide hydrolase activity and as much as a 60% decrease in the level of thiobarbituric acid-reactive compounds in the mitochondrial fraction. Smaller increases in microsomal epoxide hydrolase activity and decreases in cytosolic glutathione peroxidase activity were also observed. Of the perfluoro fatty acids tested, perfluorooctanoic acid caused the largest changes in the parameters examined here. Dietary exposure of mice to a 0.02% dose of this substance for 10 days results in a maximal or near-maximal effect in most cases.
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PMID:Effects of perfluoro fatty acids on xenobiotic-metabolizing enzymes, enzymes which detoxify reactive forms of oxygen and lipid peroxidation in mouse liver. 141 40


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