265321-58-2Relevant academic research and scientific papers
Characterization of the major DNA adduct formed by α-hydroxy-N- desmethyltamoxifen in vitro and in vivo
Gamboa Da Costa, Goncalo,Hamilton, L. Patrice,Beland, Frederick A.,Marques, M. Matilde
, p. 200 - 207 (2000)
Tamoxifen is hepatocarcinogenic in rats and has been associated with an increased risk of endometrial cancer in women. Recent reports suggest that it may be genotoxic in humans. N-Desmethyltamoxifen is a major tamoxifen metabolite that has been proposed to be responsible for one of the major adducts detected in liver DNA of rats treated with tamoxifen. The metabolic activation of N-desmethyltamoxifen to DNA binding products may involve oxidation to α-hydroxy-N-desmethyltamoxifen followed by esterification. In the study presented here, we report the synthesis of α-hydroxy-N- desmethyltamoxifen and the characterization of the major adduct obtained from α-sulfoxy-N-desmethyltamoxifen in vitro as (E)-α-(deoxyguanosin-N2-yl)-N- desmethyltamoxifen. In addition, we use 32P-postlabeling in combination with HPLC to compare the adducts formed in the livers of female Sprague- Dawley rats treated by gavage with tamoxifen or equimolar doses of α- hydroxy-N-desmethyltamoxifen. We conclude that one of the major adducts formed in vivo and previously suggested to derive from N-desmethyltamoxifen is chromatographically identical to α-(deoxyguanosin-N2-yl)-N- desmethyltamoxifen.
