“…Tamoxifen is metabolized variously via primary N-demethylation, 4-hydroxylation, α-hydroxylation and N-oxidation ( Figure 1) by hepatic microsomes and cell lines (19)(20)(21)(22)(23), and additionally via secondary O-glucuronidation in hepatocytes (24) and in vivo (25)(26)(27)(28)(29), Ndemethylation being the principal biotransformation in humans and human liver microsomes (20,23,28). Both aromatic hydroxylation and α-hydroxylation have been consistently implicated in the formation of reactive tamoxifen metabolites in vitro and in experimental animals, and they appear to represent the initial steps of distinct bioactivation pathways in vivo (16,30). Although α-hydroxytamoxifen reacts directly, if slowly, with isolated DNA (31), both it and the chemically unreactive 4-hydroxytamoxifen are regarded as precursors of DNA-binding derivatives that have yet to be identified as metabolites, namely α-esters such as the highly reactive α-sulphate tamoxifen (31,32) and 4-hydroxytamoxifen quinone methide (33), respectively.…”