Role of NAD(P)H:(quinone acceptor) oxidoreductase (DT-diaphorase) in activation of mitomycin C under hypoxia.
The role of the two-electron reducing enzyme DT-diaphorase in the activation of mitomycin C under hypoxic conditions was investigated. Mitomycin C activity was compared in L5178Y murine lymphoblasts, which have low levels of DT-diaphorase activity, and L5178Y/HBM10 cells, which have elevated levels of enzyme activity. The cytotoxic and DNA cross-linking activities of mitomycin C were greater in L5178Y/HBM10 cells than in L5178Y cells. In L5178Y/HBM10 cells, dicoumarol, an inhibitor of DT-diaphorase, decreased cell kill and DNA cross-linking by mitomycin C in air but had no significant effect on these activities under hypoxia. By comparison, in L5178Y cells, dicoumarol had no effect on drug activity under either aerobic or hypoxic conditions. A model for the activation of mitomycin C by both one-electron and two-electron reduction is proposed. Our findings suggest that two-electron reduction by DT-diaphorase has only a limited role in the activation of mitomycin C under hypoxic conditions, although this enzyme appears to be an important contributor to drug activation under aerobic conditions.
Begleiter
A
A
Department of Internal Medicine, University of Manitoba, Winnipeg, Canada.
Robotham
E
E
Leith
M K
MK
D000818:Animals; D001711:Biotransformation; D015687:Cell Hypoxia; D002470:Cell Survival / Q000187:drug effects; D003432:Cross-Linking Reagents; D004247:DNA / Q000187:drug effects; D004249:DNA Damage; D001728:Dicumarol / Q000494:pharmacology; D051379:Mice; D016685:Mitomycin / Q000493:pharmacokinetics*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D003432:Cross-Linking Reagents; D016685:Mitomycin; D001728:Dicumarol; D004247:DNA; D016660:NAD(P)H Dehydrogenase (Quinone)