Metabolism of the antimammary cancer antiestrogenic agent tamoxifen. II. Flavin-containing monooxygenase-mediated N-oxidation.Drug Metab Dispos. 1993 Jul-Aug; 21(4):657-61.DM
Earlier studies demonstrated that the major metabolites of tamoxifen generated by mammalian liver microsomes are the corresponding N-oxide, N-desmethyl, and 4-hydroxy derivatives. This study examines the enzymatic activity catalyzing the formation of tamoxifen N-oxide by mammalian liver microsomes. Incubations of tamoxifen with liver microsomes from the various species, supplemented with NADPH, yielded the N-oxide, N-desmethyl, and 4-hydroxy derivatives. Inhibition of N-oxide accumulation by mild heat and low concentrations of methimazole in rat liver microsomes indicated that this reaction is catalyzed by the flavin-containing monooxygenase (FMO). Antibodies to NADPH-P-450 reductase inhibited N-demethylation and 4-hydroxylation, but not N-oxidation, supporting the aforementioned conclusion. Purified mouse liver microsomal FMO converted tamoxifen solely into the N-oxide, providing direct evidence for FMO involvement. Human liver microsomes formed the same tamoxifen metabolites, albeit at a much lower rate. Inhibitors of FMO diminished the accumulation of N-oxide by human liver microsomes, indicating involvement of FMO. Tamoxifen-N-oxide was found to be readily reduced to tamoxifen by rat or human liver microsomes, in the presence of NADPH; the extent of reduction was dramatically increased when incubations were supplemented with methimazole. The facile reduction of tamoxifen N-oxide back to tamoxifen suggests that the N-oxide may serve as a storage form for tamoxifen in vivo.