A comparative study of tamoxifen metabolism in female rat, mouse and human liver microsomes

The metabolisms of tamoxifen in female rat, mouse and humanliver microsomal preparations were compared. Rat, mouse andhuman liver microsomes were incubated with tamoxifen in thepresence of NADPH and MgCl₂ and the metabolites formed wereanalysed by on-line HPLC electrospray ionization MS. The majormetabolites formed by rat liver microsomes were 4-hydroxytamoxifen,4'-hydroxytamoxifen, N-desmethyltamoxifen and tamoxifen N-oxide.In addition, two epoxide metabolites, 3,4-epoxytamoxifen and3',4'-epoxytamoxifen, and their hydrolysed derivatives, 3,4-dihydrodihydroxytamoxifenand 3',4'-dihydrodihydroxytamoxifen, have been identified. Thepattern of the main metabolites obtained with human liver microsomesresembles qualitatively that of rat liver microsomes. The majordifferences between rat and human liver microsomes were thatthe amount of hydroxylated metabolites were much lower in humanand only traces of 3,4-epoxytamoxifen and the correspondingdihydrodihydroxy derivative were detected. No 3',4'-epoxytamoxifendetected in human liver microsomes. The four major metaboliteswere also formed in much larger amounts and with faster ratesof formation by mouse liver microsomes, though tamoxifen N-oxideclearly predominated in this species. Polar metabolites, 3,4-dihydroxytamoxifenand 4-hydroxytamoxifen N-oxide, which were undetectable in ratand human, were formed in significant amounts in mouse microsomes.As in human microsomes, there was only one epoxide metabolite,3,4-epoxytamoxifen, produced by mouse liver microsomes at levelslower than that found in rat. The faster rate of metabolismand the production of polar metabolites may indicate the abilityof mouse to detoxify tamoxifen by rapid elimination comparedwith rat and human. The production of a larger amount of potentiallyreactive epoxide metabolites in rat may be responsible for theliver carcinogenesis in this species.