NAD(P)H (quinone acceptor) oxidoreductase (DT-diaphorase)-mediated two-electron reduction of anthraquinone-based antitumour agents and generation of hydroxyl radicals.
The anthraquinone-based antitumour agents mitoxantrone, daunorubicin and ametantrone were found to be substrates for NAD(P)H (quinone acceptor) oxidoreductase (DT-diaphorase) [QAO] isolated from rat liver. This was indicated by the stimulation of QAO-dependent NADPH oxidation by these agents. This effect followed Michaelis-Menten kinetics and was dependent on the concentration of QAO, inhibited by the specific QAO inhibitor dicumarol (15 microM) and enhanced by the QAO activators bovine serum albumin (0.01%) and Triton X-100 (0.03%). As indicated by the Vmax/Km ratio, mitoxantrone (26.53) was considerably more active than ametantrone (11.25) or daunorubicin (7.35). Metabolism of these anthraquinones was associated with the formation of superoxide anions, hydrogen peroxide and hydroxyl radicals as indicated by electron spin resonance spin trapping studies with 5,5-dimethyl-1-pyrroline-N-oxide. This is likely to be due to the slow auto-oxidation of the respective dihydroquinones in the presence of molecular oxygen. QAO needs to be considered as a possible route of bioreductive activation of these agents.
Fisher
G R
GR
Department of Pharmacy, Leicester Polytechnic, U.K.
Gutierrez
P L
PL
Oldcorne
M A
MA
Patterson
L H
LH
D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003630:Daunorubicin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006878:Hydroxides / Q000378:metabolism; D017665:Hydroxyl Radical; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008942:Mitoxantrone / Q000031:analogs & derivatives / Q000494:pharmacology; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000302:isolation & purification / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D013329:Structure-Activity Relationship; D013481:Superoxides / Q000378:metabolism
D000880:Anthraquinones; D000970:Antineoplastic Agents; D006878:Hydroxides; D013481:Superoxides; D017665:Hydroxyl Radical; D009249:NADP; D008942:Mitoxantrone; D016660:NAD(P)H Dehydrogenase (Quinone); C020182:ametantrone; D003630:Daunorubicin