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)

We report DNA interstrand cross-linking caused by the anti-tumour indoloquinone EO9 following reductive activation with purified rat liver DT-diaphorase or xanthine oxidase. Reduction was a necessary event for cross-linking to occur. DNA cross-link formation by EO9 following DT-diaphorase reduction was completely inhibited by addition 10 microM dicoumarol, whereas only a minor effect of dicoumarol on xanthine oxidase-mediated DNA cross-linking by EO9 was observed. DNA cross-linking was pH dependent, with increasing cross-link formation from pH 5.5 to 7.0 for both DT-diaphorase and xanthine oxidase mediated reactions. Also, conversion of EO9 upon reduction was pH dependent. However, in contrast to DNA cross-linking, conversion rates of EO9 decreased at higher pH. EO9 was shown to be more efficient in DNA cross-linking than mitomycin C under identical conditions, using both DT-diaphorase and xanthine oxidase reductive activation at pH 5.5 and 7.0. This study indicates that the anti-tumour activity of EO9 may be at least partly mediated by interstrand DNA cross-link formation, and that various reducing enzymes may be important for activation of EO9 in vitro and in vivo.
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PMID:Indoloquinone EO9: DNA interstrand cross-linking upon reduction by DT-diaphorase or xanthine oxidase. 753 24

Aqueous-ethanolic extracts from Fraxinus excelsior, Populus tremula and Solidago virgaurea inhibit biochemical model reactions representing inflammatory situations to various extents. These model reactions include xanthine oxidase, diaphorase in the presence of the autoxidizable quinone juglone, lipoxygenase and photodynamic reactions driven by riboflavin or rose bengal. The tested extracts are the components of the phytomedicine Phytodolor N (abbreviated as PD) which possesses antipyretic, analgesic, antiinflammatory and antirheumatic activity. Since several reactive oxygen species produced by the mentioned model systems are also involved in inflammatory processes, the beneficial activities of the complete drug may at least in part be due to the reported antioxidative functions of the individual components.
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PMID:Antioxidative properties of alcoholic extracts from Fraxinus excelsior, Populus tremula and Solidago virgaurea. 771 Apr 43

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

Both phenylbutazon and mofebutazon inhibit oxidative fragmentation of the methionine derivative, 2-keto-4-methylthio-butyric acid (KMB) by xanthine oxidase--or diaphorase mediated OH radical production. Differentiation of the two non-steroidal antiinflammatory drugs is possible by means of determining oxygen reduction by xanthine oxidase or diaphorase in the presence of the naphthoquinone, juglone, where only mofebutazon shows an inhibitory effect.
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PMID:Antioxidative properties of phenazone derivatives: differentiation between phenylbutazon and mofebutazon. 821 10

Ethanolic extracts of Propolis are used as antiinflammatory and wound healing drugs since ancient times. In order to facilitate a comparison of different extracts, the standardization on the basis of quantitative determination of prominent components of these extracts has been substituted for simple biochemical "activity" tests. One of these activity tests bases on the inhibition of peroxidase-catalyzed oxidation of indole acetic acid indicating the presence of a defined mixture of monophenolic and diphenolic compounds. Other tests (diaphorase-catalyzed reductions and xanthine oxidase-catalyzed oxidations) demonstrate significant radical scavenging properties. Water-soluble extracts of propolis exhibit higher antioxidative and inhibitory activities as compared to the ethanolic extract.
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PMID:Biochemical activities of propolis extracts. I. Standardization and antioxidative properties of ethanolic and aqueous derivatives. 829 22

The small intestine can metabolize a variety of substances and can play a role in the presystemic clearance of ingested compounds. Relatively little is known about the ability of small intestine to catalyze the presystemic reductive metabolism of xenobiotics. 1,3-Dinitrobenzene (1,3-DNB), which is known to undergo reductive biotransformation in an intact, oxygenated isolated perfused intestinal preparation, was used as a model substrate for reductive enzymes of the small intestine of the rat. Subcellular fractions from duodenal, jejunal, and ileal regions of rat small intestinal mucosa were used to characterize the enzyme source(s) of those reductive reactions of 1,3-DNB that are relevant in the oxygenated intestinal tissue. 1,3-DNB was reduced to 3-nitroaniline (3-NA) by cytosol from duodenum and jejunum. The rate of reduction was 2 times faster when incubations contained duodenal rather than jejunal cytosol. Jejunal cytosol-catalyzed reduction of 1,3-DNB was supported by hypoxanthine, NADPH, or NADH. Duodenal microsomes catalyzed the reduction of 1,3-DNB to 3-NA in the presence of supplemental NADPH or NADH; however, the reaction was very slow. Jejunal microsomes, ileal microsomes, and ileal cytosol failed to catalyze the reduction of 1,3-DNB. Studies with chemical inhibitors suggested possible roles for DT diaphorase, glutathione reductase, or xanthine oxidase in the jejunal cytosol-catalyzed reaction. Purified, commercially available xanthine oxidase (from buttermilk) catalyzed the reduction of 1,3-DNB to 3-NA when supplemented with NADH or hypoxanthine.
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PMID:Metabolism of [14C]1,3-dinitrobenzene by rat small intestinal mucosa in vitro. 856 89

Mitomycin C (MMC), an alkylating anti-tumor agent, was activated by non-enzymatic and enzymatic mechanisms leading to DNA binding and adduct formation. However, it was enzymatically, not non-enzymatically, activated MMC which induced inter-strand DNA cross-linking, a major determinant of cell death. The enzymatic activation of MMC was catalyzed by microsomal NADPH:cytochrome P450 reductase (P450 reductase) and cytosolic enzyme activities. Human P450 reductase, transiently expressed from its cDNA in the COSI cells, metabolically activated MMC to generate 9 specific MMC-DNA adducts and induced inter-strand DNA cross-linking. Co-chromatography of the MMC-DNA adducts generated by P450 reductase and sodium borohydride in separate experiments indicated that MMC was metabolized by P450 reductase to produce 2,7-diaminomitosenes that exhibited binding to deoxyguanosine. Several experiments indicated that cytosolic enzymes which catalyzed reductive activation of MMC and DNA cross-linking included NAD(P)H:quinone oxidoreductaseI (NQOI or DT diaphorase) when present in extremely high concentrations and a unique cytosolic activity. The unique cytosolic activity was present in several mammalian cells and mouse colon and liver but absent in mouse kidney. The unique activity had properties of a diaphorase but was distinct from NQOI because of a lack of correlation between NQOI (2,6-dichlorophenolindophenol reduction) activity and the amount of MMC-reductive activation leading to DNA cross-linking. This activity was also distinct from xanthine oxidoreductase and NADH-cytochrome b5 reductase, 2 other enzymes that catalyze metabolic activation of MMC, because the unique activity was not inhibited by allopurinol (an inhibitor of xanthine oxidoreductase) and its activity was the same with NADH and NADPH (cytochrome b5 reductase is specific to NADH).
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PMID:Non-enzymatic and enzymatic activation of mitomycin C: identification of a unique cytosolic activity. 856 27

In the present study, we investigated the effects of high levels of dietary fish oil on the growth of MX-1 human mammary carcinoma and its response to mitomycin C (MC) treatment in athymic mice. We found that high levels of dietary fish oil (20% menhaden oil + 5% corn oil, w/w) compared to a control diet (5% corn oil, w/w) not only lowered the tumor growth rate, but also increased the tumor response to MC treatment. We also found that high levels of dietary fish oil significantly increased the activities of tumor xanthine oxidase and DT-diaphorase, which are proposed to be involved in the bioreductive activation of MC. Since menhaden oil is highly unsaturated, its intake caused a significant increase in the degree of fatty acid unsaturation in tumor membrane phospholipids. This alteration in tumor membrane phospholipids made the tumor more susceptible to oxidative stress, as indicated by the increased levels of both endogenous lipid peroxidation and protein oxidation after feeding the host animals the menhaden oil diet. In addition, the tumor antioxidant enzyme activities, catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPOx), and glutathione S-transferase peroxidase (GSTPx), were all significantly enhanced by feeding a diet high in fish oil. MC treatment caused further increases in tumor lipid peroxidation and protein oxidation, as well as in the activities of CAT, SOD, GPOx, and GSTPx, suggesting that MC causes oxidative stress in this tumor model which is exacerbated by feeding a diet high in menhaden oil. Thus, feeding a diet rich in menhaden oil decreased the growth of human mammary carcinoma MX-1, increased its responsiveness to MC, and increased its susceptibility to endogenous and MC-induced oxidative stress, and increased the tumor activities of two enzymes proposed to be involved in the bioactivation of MC, that is, DT-diaphorase and xanthine oxidase. These findings support a role of these two enzymes in the bioactivating of MC and indicate that the type of dietary fat may be important in tumor response to therapy.
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PMID:Dietary menhaden oil enhances mitomycin C antitumor activity toward human mammary carcinoma MX-1. 856 32

The pathways participating in the metabolism of the nitrofuran antimicrobial drug N-[5-nitro-2-furfurylidene]-3-amino-2-oxazolidinone (furazolidone) in intact cells were investigated in the human intestinal cell line Caco-2. One-electron reduction of furazolidone led to the formation of a free radical intermediate that could be monitored in dense cell suspensions by noninvasive electron spin resonance spectroscopy. The effects of enzyme inhibitors on the kinetics of radical production and decay were used to estimate the relative contribution of different enzymes to the reductive activation of the drug. Although many enzymes are known to reduce nitrofurans in vitro (e.g., xanthine oxidase, aldehyde oxidase, DT-diaphorase, mitochondrial redox chain components), their contributions were insignificant in living Caco-2 cells. The first reducing equivalent required for the formation of the nitroanion derivative of furazolidone appeared to be provided essentially by the microsomal cytochrome P450 reductase. This was confirmed through studies of the NADPH-dependent radical formation by microsomes. Differentiated Caco-2 cells, an established enterocyte model, showed only modestly increased radical formation and the same enzyme-specificity pattern as undifferentiated cells. Consistently, only a small increase in P450 reductase activity was found in differentiated cells, in contrast to the 10-fold increase seen in typical differentiation marker enzymes. With the electron spin resonance method that we describe, it is possible to distinguish between sites of bioactivation of redox active drugs in intact cells.
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PMID:N-[5-nitro-2-furfurylidene]-3-amino-2-oxazolidinone activation by the human intestinal cell line Caco-2 monitored through noninvasive electron spin resonance spectroscopy. 864 95

The absolute configuration at the C-1 position of a 1,10-bisacetoxymitosene (WV15) appears to be important for enzymatic reduction, DNA interstrand cross-linking and in vitro antitumour activity of this compound. DNA cross-linking by the (-)-(S)-enantiomer of WV15 upon reduction with sodium dithionite (Na2S2O4) was more efficient than cross-linking by the (+)-(R)-enantiomer. Also, following enzymatic two-electron reduction by DT-diaphorase or one-electron reduction by xanthine oxidase, (-)-(S)-WV15 was more efficient in DNA cross-linking than (+)-(R)-WV15. However, the difference in cross-linking efficiency was less than upon chemical reduction, and in the case of enzymatic reduction that higher amount of DNA cross-links formed by (-)-(S)-WV15 can be explained by more efficient enzymatic activation of this enantiomer as compared to (+)-(R)-WV15. The enantiomeric preference upon chemical reduction can be explained by a second chemical reduction of DNA-bound WV15, which presumably does not occur upon enzymatic reduction. (-)-(S)-WV15 appeared to be more active than its (+)-(R) counterpart in A204 and L1210 tumour cell lines, with (+)-(R)/(-)-(S) toxicity ratios as high as 200 and 68, respectively. In Chinese hamster V79 cell lines, toxicity of the enantiomers was measured under oxic and hypoxic conditions. The oxic/hypoxic toxicity ratios of (+)-(R)-and (-)-(S)-WV15 in the Chinese hamster V79 cell line were 5.5 and 2.4, respectively. These different oxic/hypoxic toxicity ratios may indicate that different reducing enzymes are involved in the activation of the enantiomers. Generally, in biological systems, different activities of (+)-(R)- and (-)-(S)-WV15 appear not to be caused by different intrinsic cross-linking capacities of the enantiomers, but by more efficient enzymatic activation of (-)-(S)-WV15, as compared to (+)-(R)-WV15. The (-)-(S)-enantiomer of WV15 appears to be more active both in in vitro tumour models and in DNA cross-linking assays, and therefore the absolute configuration of mitosenes is indicated to be important for the antitumour activity of these compounds.
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PMID:Chirality of a 1,10-bisacetoxymitosene compound. Impact on reductive activation, DNA interstrand cross-linking and antitumour activity. 876 32


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