Effect of N,N-didesmethyltamoxifen upon DNA adduct formation by tamoxifen and α-hydroxytamoxifen

Tamoxifen undergoes sequential metabolism to N-desmethyltamoxifen and N,N-didesmethyltamoxifen. Whereas N-desmethyltamoxifen is a major metabolite in humans, nonhuman primates, and rats, appreciable concentrations of N,N-didesmethyltamoxifen are formed in humans and nonhuman primates but not in rats. This difference in the extent of N,N-didesmethyltamoxifen formation may be important because it has been proposed that N,N-didesmethyltamoxifen inhibits the cytochrome P450 (CYP)-catalyzed α-hydroxylation of tamoxifen and resultant tamoxifen–DNA adduct formation. To test this hypothesis directly, we compared the extent of tamoxifen–DNA adduct formation in rats co-administered 27 μmol N,N-didesmethyltamoxifen per kg body weight and either 27 μmol tamoxifen per kg body weight or 27 μmol α-hydroxytamoxifen per kg body weight daily for 7 days. Female Sprague–Dawley rats treated with N,N-didesmethyltamoxifen had a 44% decrease (p > 0.05) in CYP 3A2 content (the CYP isoform responsible for tamoxifen α-hydroxylation), an 18% decrease (p = 0.010) in CYP 3A activity, and higher blood levels of tamoxifen and N-desmethyltamoxifen compared to rats treated with solvent. Total tamoxifen–DNA adduct levels were 4.1-fold higher (p < 0.001) in rats given α-hydroxytamoxifen as compared to tamoxifen. N,N-Didesmethyltamoxifen treatment caused a 1.2-fold increase in total tamoxifen–DNA adduct levels with both tamoxifen and α-hydroxytamoxifen, a difference that was not significant. These results indicate that, with this experimental model, N,N-didesmethyltamoxifen does not impair the metabolism of tamoxifen to a reactive electrophile.