© 1994 Oxford University Press
research-article |
A comparative study of tamoxifen metabolism in female rat, mouse and human liver microsomes
MRC Toxicology Unit, Hodgkin Building, University of Leicester PO Box 138, Leicester LE1 9HN, UK
The metabolisms of tamoxifen in female rat, mouse and human liver microsomal preparations were compared. Rat, mouse and human liver microsomes were incubated with tamoxifen in the presence of NADPH and MgCl2 and the metabolites formed were analysed by on-line HPLC electrospray ionization MS. The major metabolites formed by rat liver microsomes were 4-hydroxytamoxifen, 4'-hydroxytamoxifen, N-desmethyltamoxifen and tamoxifen N-oxide. In addition, two epoxide metabolites, 3,4-epoxytamoxifen and 3',4'-epoxytamoxifen, and their hydrolysed derivatives, 3,4-dihydrodihydroxytamoxifen and 3',4'-dihydrodihydroxytamoxifen, have been identified. The pattern of the main metabolites obtained with human liver microsomes resembles qualitatively that of rat liver microsomes. The major differences between rat and human liver microsomes were that the amount of hydroxylated metabolites were much lower in human and only traces of 3,4-epoxytamoxifen and the corresponding dihydrodihydroxy derivative were detected. No 3',4'-epoxytamoxifen detected in human liver microsomes. The four major metabolites were also formed in much larger amounts and with faster rates of formation by mouse liver microsomes, though tamoxifen N-oxide clearly predominated in this species. Polar metabolites, 3,4-dihydroxytamoxifen and 4-hydroxytamoxifen N-oxide, which were undetectable in rat and 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 levels lower than that found in rat. The faster rate of metabolism and the production of polar metabolites may indicate the ability of mouse to detoxify tamoxifen by rapid elimination compared with rat and human. The production of a larger amount of potentially reactive epoxide metabolites in rat may be responsible for the liver carcinogenesis in this species.