Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.17.1.4 (xanthine dehydrogenase)
 1,236 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Considerable evidence suggests that the release of iron from ferritin is a reductive process. A role in this process has been proposed for two hepatic enzymes, namely xanthine oxidoreductase and an NADH oxidoreductase. The abilities of xanthine and NADH to serve as a source of reducing power for the enzyme-mediated release of ferritin iron (ferrireductase activity) were compared with turkey liver and rat liver homogenates. The maximal velocity (Vmax.) for the reaction with NADH was 50 times greater than with xanthine; however, the substrate concentration required to achieve half-maximal velocity (Km) was 1000 times less with xanthine than with NADH. NADPH could be substituted for NADH with little loss in activity. Dicoumarol did not inhibit the reaction with NADH or NADPH, demonstrating that the ferrireductase activity with those substrates was not the result of the liver enzyme 'DT-diaphorase' [NAD(P)H dehydrogenase (quinone)]. A flavin nucleotide was required for ferrireductase activity with rat and turkey liver cytosol when xanthine, NADH or NADPH was used as the reducing substrate. FMN yielded twice the activity with NADH or NADPH, whereas FAD was twice as effective with xanthine as substrate. Kinetic comparisons, differences in lability and partial chromatographic resolution of the ferrireductase activities with the two types of reducing substrates strongly indicate that the ferrireductase activities with xanthine and NADH are catalysed by separate enzyme systems contained in liver cytosol. Complete inhibition by allopurinol of the ferrireductase activity endogenous to undialysed liver cytosol preparations and the ability of xanthine to restore equivalent activity to dialysed preparations indicate that the source of reducing power for the endogenous activity is xanthine. These studies suggest that xanthine, NADH or NADPH can serve as a source of reducing power for the enzyme-mediated reduction of ferritin iron, with a flavin nucleotide serving as the shuttle of electrons from the enzymes to the ferritin iron.
 ...
PMID:The mobilization of ferritin iron by liver cytosol. A comparison of xanthine and NADH as reducing substrates. 277 99

Reduced nicotinamide adenine dinucleotide (NADH):ferricyanide reductase and DT-diaphorase specific activity in total homogenates of rat liver are markedly decreased as a very early biochemical event of hepatocarcinogenesis induced by the carcinogen 2-acetylaminofluorene (AAF). A 50 to 75% decrease in NADH:ferricyanide reductase was observed after 1 day of AAF (0.025% in the diet) feeding and persisted throughout a 7-week continuum of AAF administration. Carcinogen added directly to cell extracts had no effect. Similar results were obtained with single injections of either AAF or diethylnitrosamine. Xanthine dehydrogenase was also reduced in liver following AAF administration to nearly the same extent as NADH:ferricyanide reductase and DT-diaphorase. Total NADH-cytochrome c reductase and mitochondrial activity as estimated from succinic dehydrogenase were not affected by carcinogen administration relative to basal dietary controls. The reduced nicotinamide adenine dinucleotide phosphate:cytochrome c reductase that functions in drug detoxification was elevated. With livers of animals fed 4-acetamidophenol, a hepatotoxin chemically related to AAF, small decreases were noted in NADH:ferricyanide reductase, but not in xanthine dehydrogenase nor in DT-diaphorase. Initial lowering of these activities in the livers of the carcinogen-treated animals is preceded by or concomitant with a reduction in the levels of extramitochondrial pyridine nucleotides known from other studies to result from DNA damage.
 ...
PMID:Decreased NADH-oxidoreductase activities as an early response in rat liver to the carcinogen 2-acetylaminofluorene. 396 29

Anti-tumor quinone, including mitomycin C (MMC), needs to be activated by bioreduction to exert its cytotoxic activities. The enzymes underlying this bioreductive activation have been the subject of extensive research on Mitomycin C. Cytochrome P450 reductase, cytochrome b5 reductase, xanthine oxidase, xanthine dehydrogenase and DT-diaphorase (DTD) have been shown to be involved in the reduction of MMC. The relationship between bioreductive enzymes and the cytotoxicity of quinone, however, has not been analyzed yet. In this study, we investigated the relationship between the bioreductive enzymes and the cytotoxicity of MMC. We carried out the following experiments and the following results were obtained. I) We isolated an MMC-resistant variant. This cell showed five-fold resistance to MMC as compared with the parental cell line. DTD was deficient in this resistant cell. II) We have examined the bioreductive enzyme activities of DTD and cytochrome P450 reductase and IC50's of MMC in 13 colon and gastric carcinoma cell lines. A positive correlation was not found between the enzyme activities and MMC sensitivities, but the cells with little or no DTD activity showed higher IC50 values compared to the other cell lines. III) To elucidate directly the role of DTD in MMC sensitivity, we introduced NQO1 gene into St-4 cells. NQO1 gene encodes DTD and St-4 cells have no DTD activity. All of the transfectants showed five- to ten-fold higher sensitivity to MMC as compared to the parental St-4 cells. The above data indicate that DTD is a critical determinant of sensitivity to MMC in aerobic conditions.
 ...
PMID:[DT-diaphorase]. 930 61