TAMOXIFEN METABOLISM AND ACTIVATION - THE REASON FOR INTERSPECIES DIFFERENCES

Tamoxifen induces liver tumours in rats by a genotoxic mechanism. Acti vation to DNA binding products involves, firstly, cytochrome P450-medi ated hydroxylation at the ex-ethyl position. This occurs in both rats and humans, alpha-Hydroxytamoxifen is then further metabolised to a su lphate ester in rat hepatocytes by hydroxysteroid sulphotransferase (h ST). This activation occurs in bacterial and mammalian cells expressin g rat hST, but not in cells expressing human hST. It is proposed that the activation pathway in rats does not occur to a significant extent in humans and thus may not account for the increase in endometrial can cer among women taking tamoxifen. (C) 1998 Elsevier Science Ltd. AU ri ghts reserved.