Reduction of mitomycin C is catalysed by human recombinant NRH:quinone oxidoreductase 2 using reduced nicotinamide adenine dinucleotide as an electron donating co-factor.
NRH:Quinone Oxidoreductase 2 (NQO2) has been described as having no enzymatic activity with nicotinamide adenine dinucleotide (NADH) or NADPH as electron donating cosubstrates. Mitomycin C (MMC) is both a substrate for and a mechanistic inhibitor of the NQO2 homologue NQO1. NRH:quinone oxidoreductase 2 catalysed the reduction of MMC at pH 5.8 with NADH as a co-factor. This reaction results in species that inhibit the NQO2-mediated metabolism of CB1954. In addition, MMC caused an increase in DNA cross-links in a cell line transfected to overexpress NQO2 to an extent comparable to that observed with an isogenic NQO1-expressing cell line. These data indicate that NQO2 may contribute to the metabolism of MMC to cytotoxic species.
Jamieson
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Northern Institute for Cancer Research, University of Newcastle upon Tyne, Paul O'Gorman Building, Medical School, Newcastle upon Tyne NE2 4HH, UK. david.jamieson@newcastle.ac.uk
Tung
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Knox
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Boddy
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D000477:Alkylating Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001388:Aziridines / Q000737:chemistry / Q000378:metabolism; D002384:Catalysis / Q000187:drug effects; D002460:Cell Line; D020552:Comet Assay; D004579:Electron Transport / Q000187:drug effects; D006801:Humans; D016685:Mitomycin / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D009243:NAD / Q000737:chemistry / Q000378:metabolism*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D011794:Quercetin / Q000494:pharmacology; D011808:Quinone Reductases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection
D000477:Alkylating Agents; D001388:Aziridines; D011994:Recombinant Proteins; D009243:NAD; D016685:Mitomycin; C100099:tretazicar; D011794:Quercetin; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C419642:NRH - quinone oxidoreductase2; D011808:Quinone Reductases