Characterization of the major DNA adduct formed by alpha-hydroxy-N-desmethyltamoxifen in vitro and in vivo

Tamoxifen is hepatocarcinogenic in rats and has been associated with an inc reased risk of endometrial cancer in women. Recent reports suggest that it may be genotoxic in humans. N-Desmethyltamoxifen is a major tamoxifen metab olite that has been proposed to be responsible for one of the major adducts detected in liver DNA of rats treated with tamoxifen. The metabolic activa tion of N-desmethyltamoxifen to DNA binding products may involve oxidation to alpha-hydroxy-N-desmethyltamoxifen followed by esterification. in the st udy presented here, we report the synthesis of alpha-hydroxy-N-desmethyltam oxifen and the characterization of the major adduct obtained from alpha-sul foxy-N-desmethyltamoxifen in vitro as (E)-alpha-(deoxyguanosin-N-2)-N-desme thyltamoxifen. In addition, we use P-32-postlabeling in combination with HP LC to compare the adducts formed in the livers of female Sprague-Dawley rat s treated by gavage with tamoxifen or equimolar doses of alpha-hydroxy-N-de smethyltamoxifen. We conclude that one of the major adducts formed in vivo and previously suggested to derive from N-desmethyloxifen is chromatographi cally identical to alpha-(deoxyguanosin-N-2-yl)-N-desmethyloxifen.