DNA adduct formation and mutant induction in Sprague-Dawley rats treated with tamoxifen and its derivatives

The non-steroidal anti-estrogen tamoxifen is used as an adjunct chemotherap eutic agent for the treatment of all stages of breast cancer and more recen tly as a chemoprotective agent in women with elevated risk of developing br east cancer. While beneficial for the treatment of breast cancer, tamoxifen increases the risk of endometrial cancer. In addition, it has been shown t o induce liver and endometrial tumors in rats. Tamoxifen is genotoxic in ra t liver, as indicated by the formation of DNA adducts, through a metabolic pathway involving the alpha -hydroxylation of tamoxifen and N-desmethyltamo xifen. Since the contribution of these cc-hydroxy metabolites of tamoxifen to the induction of endometrial tumors is presently unknown, we compared th e extent of DNA adduct formation in liver and selected non-hepatic tissues of female Sprague-Dawley rats treated by gavage with tamoxifen, alpha -hydr oxytamoxifen, N-desmethyltamoxifen, alpha -hydroxy-N-desmethyltamoxifen and N,N-didesmethyltamoxifen, or intraperitoneal injection with tamoxifen, alp ha -hydroxytamoxifen, 3-hydroxytamoxifen and 4-hydroxytamoxifen. In additio n, spleen lymphocytes from rats treated by gavage with tamoxifen or alpha - hydroxytamoxifen were assayed for the induction of mutants in the hypoxanth ine phosphoribosyl transferase (Hprt) gene. The relative levels of binding in rats treated by gavage were alpha -hydroxytamoxifen > tamoxifen approxim ate to N-desmethyltamoxifen approximate to alpha -hydroxy-N-desmethyltamoxi fen > N,N-didesmethyltamoxifen. In rats dosed intraperitoneally, the relati ve order of binding was alpha -hydroxytamoxifen > tamoxifen > 3-hydroxytamo xifen approximate to 4-hydroxytamoxifen. None of the compounds resulted in an increase in DNA adducts in uterus, spleen, thymus or bone marrow DNA fro m rats treated by gavage or in uterus DNA from rats injected intraperitonea lly. Neither tamoxifen nor alpha -hydroxy-tamoxifen increased the Hprt muta nt frequency in spleen T-lymphocytes. These results confirm previous observ ations that tamoxifen is activated to a genotoxic agent in rat liver throug h alpha -hydroxylation, and also suggest that endometrial tumors in rats do not arise from the formation of tamoxifen-DNA adducts.