Inhibition of microsomal oxidative drug metabolism by 1,4-bis (2-[(2-hydroxyethyl)amino]-ethylamino)-9,10-anthracenedione diacetate, a new antineoplastic agent.
The effects of 1,4-bis(2-[(2-hydroxyethyl)amino]-ethylamino)-9,10-anthracenedione diacetate (HAQ) on rabbit liver microsomal oxidative drug metabolism were investigated. HAQ was found to inhibit O-dealkylase and N-demethylase activities in phenobarbital-induced microsomes, and aryl hydrocarbon hydroxylase activity in beta-naphthoflavone-induced microsomes. The inhibition was noncompetitive with respect to substrate concentration, with inhibitory constant (Ki) values of 2.9, 2.6, and 3.0 mM for p-nitroanisole, N,N-dimethylaniline, and benzo[a]pyrene, respectively. In contrast, HAQ failed to inhibit p-nitroanisole metabolism when the reaction was supported with cumene hydroperoxide. HAQ also inhibited basal and substrate-stimulated microsomal NADPH oxidation. The degree of inhibition of NADPH oxidation and product formation were comparable. These data, in conjunction with the results of previous studies, suggest that HAQ inhibits electron transfer by microsomal NADPH-cytochrome P-450 reductase, diminishing electron flow to cytochrome P-450 and thereby inhibiting substrate metabolism. This mechanism differs markedly from that for inhibition of drug metabolism by other quinones, such as menadione, in which accelerated electron flow through P-450 reductase to the quinone diverts reducing equivalents from cytochrome P-450.
D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D055598:Chemical Phenomena; D002621:Chemistry; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D008942:Mitoxantrone / Q000031:analogs & derivatives*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors; D009249:NADP / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase / Q000037:antagonists & inhibitors; D010084:Oxidation-Reduction; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011817:Rabbits
D000880:Anthraquinones; D000970:Antineoplastic Agents; D004364:Pharmaceutical Preparations; D009249:NADP; D008942:Mitoxantrone; D006899:Mixed Function Oxygenases; D009251:NADPH-Ferrihemoprotein Reductase; C020182:ametantrone