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 mutagenicity of various quinones, a class of compounds widely distributed in nature, is demonstrated in the Salmonella TA104 tester strain. The metabolic pathways by which four quinones, menadione, benzo[a]pyrene 3,6-quinone, 9,10-phenanthrenequinone, and danthron, caused mutagenicity in this test system were investigated in detail as were the detoxification pathways. The two-electron reduction of these quinones by NAD(P)H-quinone oxidoreductase (DT-diaphorase) was not mutagenic, whereas the one-electron reduction, catalyzed by NADPH-cytochrome P-450 reductase, was mutagenic, except for danthron, which was only slightly mutagenic. The mutagenicity of the quinones via this pathway was found to be attributable to the generation of oxygen radicals. The cytochrome P-450 monooxygenase also played a significant role in the detoxification and bioactivation of these quinones. For example, phenanthrenequinone was converted to a nonmutagenic metabolite in a cytochrome P-450-dependent reaction, whereas danthron was converted to a highly mutagenic metabolite. These studies show the complexity of metabolic pathways involved in the mutagenicity of quinones.
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PMID:Mutagenicity of quinones: pathways of metabolic activation and detoxification. 658 3

Sensitization by 1-methyl-3-isobutylxanthine (MIX), a potent inhibitor of cAMP phosphodiesterase, of cellular sensitivity to mitomycin C (MC) was tested using various cell lines. Sensitization was seen with CHO cells and Balb/c 3T3 cells, but a decrease in sensitivity was seen with HeLa, K-balb and other cell lines. To measure the extent of crosslinks produced by MC, we used an alkaline elution assay. The extent of crosslinks was increased by MIX in CHO cells and decreased in K-balb cells. These changes in extent are well reflected by changes in sensitivity to MC in both cell lines. In CHO cells, an intracellular dose of MC was increased by MIX with no change in the rate of uptake or efflux of MC. There was a slight decrease in the dose in HeLa or K-balb cells. Among the enzymes which engage in the reductive activation of MC, we tested DT-diaphorase and NADPH-cytochrome P450 reductase using CHO, HeLa and K-balb cells. MIX had almost no effect on the activity of NADPH-cytochrome P450 in each cell line, whereas it suppressed the activity of DT-diaphorase, significantly in HeLa and K-balb cells, and slightly in CHO cells. All these facts indicate that MIX caused an increase in the extent of crosslinks via an increase in the intracellular dose of MC in CHO cells, and that these increases may lead to the sensitization. On the other hand, the decrease in the sensitivity shown in HeLa and K-balb cells may be due to the suppression of DT-diaphorase activity and/or to a decrease in MC dose.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cell line-dependent changes in sensitivity to mitomycin C by 1-methyl-3-isobutylxanthine is due to an altered intracellular dose of the anticancer drug and/or to changes in DT-diaphorase activity. 753 Oct 52

NADPH-cytochrome P-450 reductase catalyzes one-electron reduction of aminochrome to the corresponding ortho-semiquinone, which was found to be unstable as indicated by the occurrence of NADPH oxidation and oxygen consumption. The addition of superoxide dismutase and catalase, alone or together, to the incubation mixture, during reduction of aminochrome catalyzed by NADPH-cytochrome P-450 reductase, did not prevent the autoxidation of ortho-semiquinone, but instead they increased NADPH oxidation. These results contrast with the almost complete inhibition of autoxidation (NADH oxidation) of ortho-hydroquinone during reduction of aminochrome catalyzed by DT-diaphorase in the presence of both superoxide dismutase and catalase. However, the effect of superoxide dismutase and catalase on oxygen consumption was found to differ from the effect on NADH or NADPH oxidation, since these enzymes, alone or together, inhibited the oxygen consumption during the reduction of aminochrome catalyzed by both NADPH-cytochrome P-450 reductase and DT-diaphorase. These results support the proposed role of NADPH-cytochrome P-450 reductase in neurodegeneration as a consequence of activation of aminochrome to reactive oxygen species. In addition, they also support the protective and antioxidant role of DT-diaphorase, together with superoxide dismutase and catalase, by competing with NADPH-cytochrome P-450 reductase to reduce aminochrome to ortho-hydroquinone and prevent the formation of reactive oxygen species. A possible mechanism is proposed.
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PMID:Superoxide dismutase and catalase enhance autoxidation during one-electron reduction of aminochrome by NADPH-cytochrome P-450 reductase. 755 11

NADPH diaphorase activity was found in membrane of DMSO-induced differentiated human promyelocytic leukemia HL-60 cells. This membrane-bound diaphorase activity increased dramatically during differentiation of HL-60 cells. A dye reductase was extracted from membrane of DMSO-induced differentiated HL-60 cells with n-octyl glucoside and sodium cholate in the presence of several protease inhibitors such as PMSF, DIFP, TLCK, antipain, chymostatin, leupeptin, pepstatin A and trypsin inhibitor. The NADPH diaphorase was highly purified by two-stage sequential column chromatographies. The purified enzyme, showing both SOD-insensitive cytochrome c and NBT reductase activities, migrated with an apparent molecular mass of 77 kDa on SDS-PAGE. When the purification of this diaphorase was carried out in the presence of only three protease inhibitors, PMSF, DIFP and TLCK, a partially proteolyzed form of the diaphorase with a molecular mass of 68 kDa was prepared. The proteolyzed diaphorase exhibited only an NADPH-dependent cytochrome c reductase. The NADPH diaphorase gave a positive cross-reaction to polyclonal antibodies raised against microsomal NADPH-cytochrome P450 reductase from rabbit liver.
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PMID:Purification of an NADPH-dependent diaphorase from membrane of DMSO-induced differentiated human promyelocytic leukemia HL-60 cells. 769 24

The one- and two-electron enzymic reduction of the bioreductive alkylating agents 2-methylmethoxynaphthoquinone (quinone I) and 2-chloromethylnaphthoquinone (quinone II) was studied with purified NADPH-cytochrome P-450 reductase and DT-diaphorase respectively, and characterized in terms of kinetic constants, oxyradical production, thiol oxidation and DNA-strand-break formation. The catalytic-centre activity values indicated that DT-diaphorase catalysed the reduction of quinone I far more efficiently than NADPH-cytochrome P-450 reductase, although the Km values of the two enzymes for this quinone were similar (1.2-3.0 microM). The one-electron-transfer flavoenzyme also catalysed the reduction of quinone II, but the behaviour of DT-diaphorase towards this quinone did not permit calculation of kinetic constants. A salient feature of the redox transitions caused by the one- and two-electron catalysis of these quinones was the different contributions of disproportionation and autoxidation reactions respectively. In the former case, about 26% of NADPH consumed was accounted for in terms of autoxidation (as H2O2 formation), whereas in the latter, the autoxidation component accounted for most (98%) of the NADPH consumed. This difference was abrogated by superoxide dismutase, which enhanced autoxidation during NADPH-cytochrome P-450 catalysis to a maximal value. E.s.r. analysis indicated the formation of superoxide radicals, the signal of which was suppressed by superoxide dismutase and unaffected by catalase. The one- and two-electron reduction of these quinones in the presence of GSH was accompanied by formation of thiyl radicals. Although superoxide dismutase suppressed the thiol radical e.s.r. signal in both instances, the enzyme enhanced GSSG accumulation during NADPH-cytochrome P-450 catalysis of quinone I, whereas it inhibited GSSG formation during reduction of the quinone by DT-diaphorase. One- and two-electron reduction of quinone I led to calf thymus DNA-strand-break formation, a process that (a) was substantially decreased in experiments performed with dialysed DNA and in the presence of desferal and (b) was partially sensitive to superoxide dismutase and/or catalase. These findings are rationalized in terms of the occurrence of metal ions ligated to DNA, protecting against the toxic effects of superoxide radicals generated during enzymic reduction of quinones.
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PMID:One- and two-electron reduction of 2-methyl-1,4-naphthoquinone bioreductive alkylating agents: kinetic studies, free-radical production, thiol oxidation and DNA-strand-break formation. 803 73

The characterization of the enzymatic step(s) involved in the reduction of 3'-azido-3'-deoxythymidine (zidovudine)(ZDV) to 3'-amino-3'-deoxythymidine (AMT) was pursued. AMT formation by human liver microsomes was NADPH dependent, enhanced under anaerobic conditions, and increased by flavin adenine dinucleotide (FAD) and FMN. Carbon monoxide inhibited AMT formation by up to 80%. The effect of theophylline (CYP1A substrate), tolbutamide (CYP2C substrate), chlorzoxazone, thiobenzamide, p-nitrophenol, mercaptoethanol, isoniazid (CYP2E substrates), cortisol (CYP3A substrate), ketoconazole, itraconazole, fluconazole, cimetidine, micronazole (CYP inhibitors), methimazole (flavin-containing mono-oxygenase inhibitor), chloramphenicol (undergoes nitroreduction), allopurinol (xanthine oxidase inhibitor) and dicoumarol (DT-diaphorase inhibitor) on AMT formation were studied to see if the reduction reaction was mediated by a particular isozyme. The greatest inhibition was observed with ketoconazole (concentration producing 50% inhibition = 78.0 microM). At this concentration ketoconazole acted as a non-selective inhibitor of several CYP isozymes. Overall, these data suggested that ZDV reduction was probably mediated by both cytochrome P450 isozymes and NADPH-cytochrome P450 reductase. Formation of AMT, as measured by intrinsic clearance (Clint), was significantly increased in microsomes from rats pre-treated with phenobarbitone, dexamethasone and clofibrate (inducers of CYP2B, CYP3A and CYP4A, respectively). Pre-treatment of rats with beta-naphthoflavone and ethanol (CYP1A and CYP2E1 inducers, respectively) had no effect on AMT formation.
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PMID:The metabolism of zidovudine by human liver microsomes in vitro: formation of 3'-amino-3'-deoxythymidine. 805 24

NADPH-cytochrome1 P450 reductase and DT-diaphorase catalyze and one- and two-electron reduction of adrenochrome to its o-semiquinone and o-hydroquinone, respectively. Under aerobic conditions both adrenochrome o-semiquinone and o-hydroquinone proved to be unstable, undergoing autoxidation with concomitant oxygen consumption and continuous NADPH and NADH oxidation. Molecular oxygen was found to play a predominant role in autoxidation of o-semiquinone during reduction of adrenochrome catalyzed by NADPH-cytochrome P450 reductase. In addition, molecular oxygen, in the presence of manganese, was found to be responsible for the majority of autoxidation of o-semiquinone. However, the role of superoxide radicals in the autoxidation of leucoadrenochrome during the reduction of adrenochrome by DT-diaphorase was found to be predominant. Catalase different significantly with respect to NADPH and NADH oxidation during reduction of adrenochrome catalyzed by NADPH-cytochrome P450 reductase and DT-diaphorase. Catalase increased NADPH oxidation slightly, while NADH oxidation was inhibited during reduction of adrenochrome by NADPH cytochrome P450 reductase and DT-diaphorase, respectively. The presence of manganese in the incubation mixture was found to increase the prooxidant role of catalase on autoxidation during one-electron reduction of aminochrome catalyzed by NADPH cytochrome P450 reductase. A marked difference in the inhibitory effect of superoxide dismutase on oxygen consumption during adrenochrome reduction catalyzed by NADPH-cytochrome P450 reductase and DT-diaphorase was also observed. A possible mechanism for reduction of adrenochrome by NADPH-cytochrome P450 reductase and DT-diaphorase and a role for superoxide dismutase and catalase are proposed.
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PMID:Effects of superoxide dismutase and catalase during reduction of adrenochrome by DT-diaphorase and NADPH-cytochrome P450 reductase. 859 36

Bacterial systems have long been of use in toxicology. In addition to providing general models of enzymes and paradigms for biochemistry and molecular biology, they have been adapted to practical genotoxicity assays. More recently, bacteria also have been used in the production of mammalian enzymes of relevance to toxicology. Escherichia coli has been used to express cytochrome P450, NADPH-cytochrome P450 reductase, flavin-containing monooxygenase, glutathione S-transferase, quinone reductase, sulfotransferase, N-acetyltransferase, UDP-glucuronosyl transferase, and epoxide hydrolase enzymes from humans and experimental animals. The expressed enzymes have been utilized in a variety of settings, including coupling with bacterial genotoxicity assays. Another approach has involved expression of mammalian enzymes directly in bacteria for use in genotoxicity systems. Particularly with Salmonella typhimurium. Applications include both the reversion mutagenesis assay and a system using a chimera with an SOS-response indicator and a reporter.
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PMID:New applications of bacterial systems to problems in toxicology. 889 30

Since the toxicity of diesel exhaust particles (DEP) after intratracheal injection, was suppressed by pretreatment with superoxide dismutase (SOD) modified with polyethylene glycol (Sagai et al. Free Rad. Biol. Med. 14: 37-47; 1993), the possibility that superoxide could be enzymatically and continuously generated from diesel exhaust particles (DEP), was examined. Nicotinamide-adenine dinucleotide phosphate, reduced (NADPH) oxidation was stimulated during interaction of a methanol extract of DEP with the Triton N-101 treated microsomal preparation of mouse lung whereas the cytosolic fraction was less active, suggesting that DEP contains substrates for NADPH-cytochrome P450 reductase (EC 1.6.2.4, P450 reductase) rather than DT-diaphorase. When purified P450 reductase was used as the enzyme source, the turnover value was enhanced approximately 260-fold. Quinones appeared to be served as substrate for P450 reductase because reaction was inhibited by addition of glutathione (GSH) to form those GSH adduct or pretreatment with NaBH4 to reduce those to the hydroxy compounds although a possibility of nitroarenes as the alternative substrates cannot be excluded. A methanol extract of DEP (37.5 micrograms) caused a significant formation of superoxide (3240 nmol/min/mg protein) in the presence of P450 reductase. Electron spin resonance (ESR) experiments revealed that hydroxyl radical was formed as well. The reactive species generated by DEP in the presence of P450 reductase caused DNA scission which was reduced in the presence of superoxide dismutase (SOD), catalase, or hydroxyl radical scavenging agents. Taken together, these results indicate that DEP components, probably quinoid or nitroaromatic structures, that appear to promote DNA damage through the redox cycling based generation of superoxide.
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PMID:Generation of reactive oxygen species during interaction of diesel exhaust particle components with NADPH-cytochrome P450 reductase and involvement of the bioactivation in the DNA damage. 898 Oct 40

Daunomycin-induced cardiotoxicity has been regarded to be the result of oxygen-mediated lipid peroxidation of cell membranes. The aim of the present work was to evaluate the extent of lipid peroxidation in rat heart after administration of this anticancer drug and, further, to examine possible activation of some endogenous antioxidant defense systems. Myocardial tissue from both control and drug-treated rats was tested for lipid peroxidation using a selective third-order derivative method that is based on the analysis of the free malondialdehyde produced. Determination of reduced/oxidized glutathione levels and measurement of the activity of DT-diaphorase, glutathione-S-transferase, glutathione reductase, glucose-6-phosphate dehydrogenase and NADPH-cytochrome P-450 reductase were also carried out using literature methods. Significant increase of malondialdehyde content, and DT-diaphorase and glutathione-S-transferase activities were found in myocardial tissue from daunomycin-treated rats. On the other hand, reduced and oxidized glutathione levels were significantly decreased while the activity of glutathione reductase, glucose-6-phosphate dehydrogenase and NADPH-cytochrome P-450 reductase remained unchanged after daunomycin administration. The results of the present study give further evidence that daunomycin can induce lipid peroxidation in heart. However, additional experimentation is needed in order to delineate the molecular details of this process as well as of the mechanisms evolved to limit it.
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PMID:Lipid peroxidation of rat myocardial tissue following daunomycin administration. 962 May 40


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