Induction of lacI mutations in Big Blue rats treated with tamoxifen and α-hydroxytamoxifen

Abstract

The antiestrogen tamoxifen is carcinogenic in the liver and uterus of rats. Liver tumors appear to result from sequential hydroxylation and esterification of the α-carbon of tamoxifen followed by DNA adduct formation. The mechanism for the induction of uterine tumors is not known. Big Blue rats were treated by intraperitoneal injection with 21 daily doses of 54 μmol/kg tamoxifen or its proximate carcinogenic metabolite α-hydroxytamoxifen. One month after the last treatment, the mutant frequency in the lacI transgene was determined in the liver and uterus. For comparison, the mutant frequency in the hypoxanthine phosphoribosyl transferase ( Hprt) gene of spleen lymphocytes was also measured. In the liver, tamoxifen (32±18 mutants/10 6 plaques; mean±SD) and α-hydroxytamoxifen (770±270 mutants/10 6 plaques) caused a significant increase in the mutant frequency of the lacI gene compared to solvent treated controls (10±10 mutants/10 6 plaques). 32P-Postlabeling analyses of liver DNA indicated three DNA adducts, one each from tamoxifen, N-desmethyltamoxifen, and N, N-didesmethyltamoxifen. Neither tamoxifen nor α-hydroxytamoxifen caused an increase in the mutant frequency in the lacI gene of the uterus or in the Hprt gene of spleen lymphocytes. These results suggest that induction of endometrial tumors in rats is not due to the genotoxicity of tamoxifen.