Species differences in the metabolic activation of tamoxifen into genotoxic derivatives: risk assessment in women.

Rats and Rhesus monkeys are compared in their response to tamoxifen treatment, with particular reference to tamoxifen-related liver DNA damage and bioactivation of tamoxifen by isolated microsomes in vitro. Monkeys, treated with tamoxifen, accumulate in their livers a metabolite of tamoxifen, N,N-didesmethyl tamoxifen, with powerful inhibitory activity on cytochrome P450-dependent drug metabolism. The accumulation of this metabolite in the monkeys may limit the cytochrome P450-dependent conversion of tamoxifen into reactive derivatives and, in this way, protect against the formation of DNA adducts. This metabolite is also found in the liver and serum of patients taking tamoxifen, but more work is needed to determine whether inhibition of tamoxifen bioactivation also exists in the human patient in vivo and, if so, to what extent and in which organ.