title: Mitomycin C is not metabolized by but is an inhibitor of human kidney NAD(P)H: (quinone-acceptor)oxidoreductase.
abstract: It has been suggested that quinone reductase [NAD(P)H: (quinone-acceptor)oxidoreductase], also known as DT-diaphorase, protects hypoxic cells against mitomycin C cytotoxicity by metabolizing mitomycin C to less toxic metabolites. This hypothesis is based on an increase in mitomycin C's cytotoxicity in the presence of the potent quinone reductase inhibitor dicumarol. It has been suggested that under aerobic conditions the metabolism of mitomycin C by quinone reductase leads to the formation of cytotoxic metabolites. In the present study, mitomycin C was found not to be a substrate for partially purified quinone reductase from human kidney. Mitomycin C did not cause the oxidation of NADPH by quinone reductase and there was no utilization of mitomycin C and no appearance of its metabolites. Quinone reductase did not catalyze the formation of alkylating metabolites from mitomycin C, determined by the lack of formation of 4-(p-nitrobenzyl)pyridine conjugates. However, mitomycin C was a weak competitive inhibitor of quinone reductase with dichloroindophenol as the substrate, with Ki = 0.32 mM. Therefore, the alteration of mitomycin C's cytotoxicity by dicumarol in tumor cell lines appears to involve a mechanism other than the direct inhibition of mitomycin C reduction by quinone reductase.
mesh_terms: D015086:2,6-Dichloroindophenol / Q000494:pharmacology; D000478:Alkylation; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D007668:Kidney / Q000201:enzymology*; D016685:Mitomycin; D008937:Mitomycins / Q000378:metabolism* / Q000494:pharmacology; D016660:NAD(P)H Dehydrogenase (Quinone); D011808:Quinone Reductases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D008937:Mitomycins; D016685:Mitomycin; D015086:2,6-Dichloroindophenol; D016660:NAD(P)H Dehydrogenase (Quinone); D011808:Quinone Reductases