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 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

This study describes characteristics of a human bladder cancer cell line J82/MMC that is 6-fold more resistant to mitomycin C (MMC) than the parental cells. The J82/MMC subline was isolated by repeated continuous exposures of the J82/WT cells to increasing concentrations of MMC. The J82/MMC cell line showed (1) collateral sensitivity to taxol, 5-FU and topoisomerase II inhibitors; and (2) cross-resistance to cisplatin, melphalan and MMC analogues BMY 25282 and BMY 25067. Levels of two key MMC activation enzymes, NADPH cytochrome P450 reductase and DT-diaphorase, were significantly lower in J82/MMC cells compared with J82/WT, suggesting that lower sensitivity of J82/MMC cells to MMC may result from deficient drug activation. Further support is indicated by: 1) reduction in the differential in toxicity between the 2 cell lines by BMY 25282; and 2) a higher effect of DT-diaphorase inhibitor dicumarol on the wild-type cells compared with J82/MMC. Although glutathione (GSH) levels did not differ in these cells, a small but significant increase in GSH transferase (GST) activity was noticed in J82/MMC cells. GST inhibitor ethacrynic acid significantly enhanced MMC cytotoxicity in the J82/MMC cell line. A small but significant increase in the level of anti-oxidative enzyme catalase, but not GSH peroxidase, was also observed in J82/MMC cell line compared with J82/WT. Thus, the possibility that relatively lower sensitivity of J82/MMC cells to MMC may result from reduced oxygen radical generation cannot be ruled out. MMC-induced DNA interstrand cross-linking was markedly lower in the J82/MMC cell line compared with J82/WT. Our results suggest that the MMC resistance in the J82/MMC cell line may be multifactorial.
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PMID:Characterization of a human bladder cancer cell line selected for resistance to mitomycin C. 807 54

Dopa was oxidized by Mn(3+)-pyrophosphate complex to the corresponding o-quinone, accompanied by the cyclization of the amino chain to form cyclized dopa ortho-quinone (cDoQ) with absorption maxima at wavelengths of 305 and 475 nm. The cyclization was found to proceed in a single step from DoQ to cDoQ without formation of cDoQH2 and oxygen consumption. DT-diaphorase catalyzes the reduction of cDoQ to the corresponding hydroquinone (cDoQH2), which was found to be unstable in the presence of oxygen. The autoxidation of the cDoQH2 was followed by recording the constant oxidation of NADH and oxygen consumption and reduction of cDoQ at a wavelength of 475 nm. It was found that three different oxidizing agents were involved in autoxidation of cDoQH2. The addition of DETAPAC resulted in a strong inhibition of NADH oxidation (65% inhibition) during the reduction of cDoQ by DT-diaphorase, suggesting that manganese was responsible for 65% of the autoxidation of cDoQH2. The addition of SOD to the incubation mixture resulted in the inhibition of NADH oxidation (79%) during the reduction of cDoQ by DT-diaphorase. In the presence of DETAPAC, the addition of SOD inhibited NADH oxidation during cDoQH2 autoxidation 75%, suggesting that superoxide radicals are responsible for 75% of the oxygen-dependent autoxidation. The remaining NADH oxidation, which was not inhibited by DETAPAC and SOD, was accompanied by a constant oxygen consumption, suggesting that this autoxidation of cDoQH2 proceeds by reducing oxygen to superoxide radical. The effect of SOD and catalase in the presence of DETAPAC was also studied. A nearly complete inhibition (90%) of oxygen consumption during the reduction of cDoQ by DT-diaphorase was observed when SOD alone or SOD and catalase were added to the incubation mixture containing DETAPAC. We conclude that SOD and catalase constitute a protective cellular system against formation of reactive oxygen species during reduction of cDoQ by DT-diaphorase.
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PMID:Superoxide dismutase and catalase prevent the formation of reactive oxygen species during reduction of cyclized dopa ortho-quinone by DT-diaphorase. 808 30

The present study was undertaken to characterize effects of selenium (Se) deficiency on 16 enzymes recovered in either one or more of the subcellular fractions of rat liver (as a basis for future studies on the mechanisms underlying the observed changes). Male rats were fed a Torula-yeast based diet with 0.23 mg Se/kg or the same diet with 0.009 mg Se/kg, from weaning and for 10 weeks. Statistically significant effects of Se deficiency were the following: Se-dependent glutathione peroxidase decreased to 0.14% of the Se-adequate controls, while cytosolic glutathione transferase increased 3-fold in Se deficiency when CDNB was the substrate, but decreased significantly when trans-stilbene oxide (diagnostic for subunit 4) was used as the substrate. Cytosolic DT-diaphorase increased about 7-fold in Se deficiency. Further, DT-diaphorase in the microsomal fraction was also significantly increased in Se deficiency, as were the microsomal and mitochondrial epoxide hydrolases and microsomal glutathione transferase. Furthermore, increased activity of the peroxisomal marker enzyme catalase (P < 0.05) was noted in Se-deficient rats. It is our working hypothesis that changes in enzyme activities in Se deficiency are mainly due to changed levels of endogenously generated metabolites or altered functions of endocrine tissues.
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PMID:Effects of selenium deficiency on xenobiotic-metabolizing and other enzymes in rat liver. 832 56

Human blood mononuclear cells exposed to visible light increase their antioxidant enzyme (superoxide dismutase, catalase, and glutathione peroxidase) and DT-diaphorase activities. The activities of CuZn-superoxide dismutase (3.70 +/- 0.25 U/mg protein), catalase (4.60 +/- 0.39 U/mg protein), and DT-diaphorase (1.40 +/- 0.11 mumol DCPIP/min.mg protein) increased 1.5-fold when mononuclear cells were exposed at 38 W/m2 for 4 h. Se-containing glutathione peroxidase activity (6.76 +/- 0.21 mU/mg protein) increased 1.3 times after 3 h of exposure to 38 W/m2. Conversely, Mn-superoxide dismutase (2.20 +/- 0.20 U/mg protein), succinate dehydrogenase (0.86 +/- 0.04 mumol DCPIP/min.mg protein), and cytochrome oxidase (0.54 +/- 0.04 min-1 (k')/mg protein) activities remained constant during this period of exposure. The treatment of cells with cycloheximide prevented the response triggered by light exposure. These results introduce new insight to the adaptive response of human cells to light stress suggesting that: (a) the response observed might be ascribed to synthesis of stress proteins rather than to activation of a preexisting pool, and (b) that DT-diaphorase and CuZn-superoxide dismutase may operate biologically in a concerted fashion resulting in antioxidant activity.
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PMID:Induction of antioxidant enzymes and DT-diaphorase in human blood mononuclear cells by light stress. 837 61

Perfluorooctane sulfonic acid is almost as potent as perfluorooctanoic acid in causing increases in peroxisomal fatty acid beta-oxidation, peroxisomal catalase activity, omega-hydroxylation of lauric acid, cytosolic epoxide hydrolase activity and cytosolic DT-diaphorase activity. Octane sulfonic acid was ineffective at doses used for perfluorooctane sulfonic acid and perfluorooctanoic acid. The results support the theory of co-regulation of these parameters and peroxisome proliferation. The fact that perfluorooctane sulfonic acid causes peroxisome proliferation challenges the hypothesis that the first step in this process is formation of a thioester between the proliferator (the carboxylic group) and coenzyme A.
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PMID:Perfluorooctane sulfonic acid is a potent inducer of peroxisomal fatty acid beta-oxidation and other activities known to be affected by peroxisome proliferators in mouse liver. 838 58

It was found that the activities of prooxidant enzymes (NAD(P)H oxidases and NAD(P)H:cytochrome c reductases) in bovine leukemia virus-transformed calf and lamb embryo kidney fibroblasts (lines Mi-18 and FLK) were by 1.25-18 times higher when compared to corresponding nontransformed calf cells. The activity of DT-diaphorase was also increased by about one order of magnitude in transformed cells. The activities of antioxidant enzymes were almost unchanged (superoxide dismutase), decreased by 13% or 53% (catalase) or increased by 25% or 90% (glutathione reductase) in Mi-18 or FLK cells, respectively. These changes of enzyme activity increased the toxicity of simple redox-cycling quinones (duroquinone, naphthazarin) towards transformed cells, but did not affect the toxicity of daunorubicin. The latter was most probably related to the inhibition of plasma membrane NADH dehydrogenase.
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PMID:The changes of prooxidant and antioxidant enzyme activities in bovine leukemia virus-transformed cells. Their influence on quinone cytotoxicity. 839 4

The expression of intrinsic resistance to cisplatin in two lung cancer cell lines, one derived from a small cell carcinoma (SW1271) and the other from an adenocarcinoma (A549), relative to a drug-sensitive small cell line SW900, was characterized by: (i) expression of cross-resistance to mitomycin C and cadmium chloride, but increased sensitivity to adriamycin and etoposide; (ii) significantly decreased cisplatin uptake; (iii) elevated levels of glutathione which could be reduced by buthionine L-sulfoximine resulting in significant sensitization of the cells to cisplatin; (iv) a lack of consistent modification of metallothionein content and expression of levels of glutathione S-transferase, glutathione reductase and glutathione peroxidase or of activities of DT-diaphorase or catalase; (v) significantly reduced total DNA-platination levels immediately following a 1 h cisplatin treatment with 10 micrograms/ml (33.3 microM); (vi) increased removal of Pt-GG and Pt-AG adducts by the A549 cells, consistent with increased repair capacity, but a lack of removal of these major adducts by the SW1271 cells indicative of tolerance of this drug-induced DNA damage. These data therefore provide evidence of differential formation, repair and tolerance of DNA damage following exposure of three human lung carcinoma cell lines to cisplatin.
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PMID:Evidence of differential cisplatin-DNA adduct formation, removal and tolerance of DNA damage in three human lung carcinoma cell lines. 840 Mar 52

NAD(P)H:quinone reductase, or DT-diaphorase, has been studied primarily in the liver where it appears to function as an antioxidant-like enzyme in the 2-electron reduction of some quinones to less toxic hydroquinones. This property together with new molecular biology evidence that oxidants such as H2O2 can induce gene transcription of DT-diaphorase provide especially intriguing reasons to examine the possibility that lung DT-diaphorase could have an important antioxidant enzyme role versus pulmonary O2 toxicity during exposure to hyperoxia. We found that similar to the 'classical' lung antioxidant enzymes (superoxide dismutase, catalase and glutathione peroxidase) DT-diaphorase activity increased significantly in the late gestational fetal lung; also its activity was altered in the same way as the antioxidant enzymes by prenatal hormonal treatment. Another similarity is that DT-diaphorase activity was induced in the neonatal animal lung during hyperoxia, but not in the adult animal lung. However, using various drug treatments which markedly increased lung DT-diaphorase activity (e.g., 3-methylcholanthrene, butylated hydroxyanisole, methimazole) we found no improved hyperoxic survival in the treated adult rats. Also, dicumarol treatment, which markedly depressed DT-diaphorase activity, did not diminish the hyperoxic survival rate in an O2-tolerant adult rat model. Thus, we conclude that unlike the classical antioxidant enzymes, increased pulmonary DT-diaphorase activity is probably neither necessary nor sufficient to protect against pulmonary O2 toxicity during hyperoxia.
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PMID:Does lung NAD(P)H:quinone reductase (DT-diaphorase) play an antioxidant enzyme role in protection from hyperoxia? 846 17

This article summarizes available data on the chemopreventive efficacies of tea polyphenols, curcumin and ellagic acid in various model systems. Emphasis is placed upon the anticarcinogenic activity of these polyphenols and their proposed mechanism(s) of action. Tea is grown in about 30 countries and, next to water, is the most widely consumed beverage in the world. Tea is manufactured as either green, black, or oolong; black tea represents approximately 80% of tea products. Epidemiological studies, though inconclusive, suggest a protective effect of tea consumption on human cancer. Experimental studies of the antimutagenic and anticarcinogenic effects of tea have been conducted principally with green tea polyphenols (GTPs). GTPs exhibit antimutagenic activity in vitro, and they inhibit carcinogen-induced skin, lung, forestomach, esophagus, duodenum and colon tumors in rodents. In addition, GTPs inhibit TPA-induced skin tumor promotion in mice. Although several GTPs possess anticarcinogenic activity, the most active is (-)-epigallocatechin-3-gallate (EGCG), the major constituent in the GTP fraction. Several mechanisms appear to be responsible for the tumor-inhibitory properties of GTPs, including enhancement of antioxidant (glutathione peroxidase, catalase and quinone reductase) and phase II (glutathione-S-transferase) enzyme activities; inhibition of chemically induced lipid peroxidation; inhibition of irradiation- and TPA-induced epidermal ornithine decarboxylase (ODC) and cyclooxygenase activities; inhibition of protein kinase C and cellular proliferation; antiinflammatory activity; and enhancement of gap junction intercellular communication. Curcumin is the yellow coloring agent in the spice tumeric. It exhibits antimutagenic activity in the Ames Salmonella test and has anticarcinogenic activity, inhibiting chemically induced preneoplastic lesions in the breast and colon and neoplastic lesions in the skin, forestomach, duodenum and colon of rodents. In addition, curcumin inhibits TPA-induced skin tumor promotion in mice. The mechanisms for the anticarcinogenic effects of curcumin are similar to those of the GTPs. Curcumin enhances glutathione content and glutathione-S-transferase activity in liver; and it inhibits lipid peroxidation and arachidonic acid metabolism in mouse skin, protein kinase C activity in TPA-treated NIH 3T3 cells, chemically induced ODC and tyrosine protein kinase activities in rat colon, and 8-hydroxyguanosine formation in mouse fibroblasts. Ellagic acid is a polyphenol found abundantly in various fruits, nuts and vegetables. Ellagic acid is active in antimutagenesis assays, and has been shown to inhibit chemically induced cancer in the lung, liver, skin and esophagus of rodents, and TPA-induced tumor promotion in mouse skin.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Polyphenols as cancer chemopreventive agents. 853 95


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