Tamoxifen−DNA Adducts Formed by α-Acetoxytamoxifen N-Oxide

DNA adduct formation is assumed to be a major carcinogenic event, leading to the development of endometrial cancer in breast cancer patients taking tamoxifen and healthy women enrolled in a tamoxifen chemopreventive trial. To determine whether DNA adducts were formed by tamoxifen, trans- and cis-α-acetoxytamoxifen N-oxides were synthesized as model-activated forms via major tamoxifen metabolites, tamoxifen N-oxide and α-hydroxytamoxifen N-oxide. When α-acetoxytamoxifen N-oxide was reacted with human DNA, at least three DNA adducts were detected by 32P-postlabeling coupled with HPLC. The total amount of DNA adducts formed by trans-α-hydroxytamoxifen N-oxide was 1.5-fold higher than that formed by the cis form. Both trans- and cis-α-acetoxytamoxifen N-oxide reacted with 2‘-deoxyguanosine, resulting in the formation of three adducts (fr-1, fr-2-1, and fr-2-2). These products were studied using mass spectroscopy and proton magnetic resonance spectroscopy. fr-1 was identified as a mixture of the epimers of trans-α-(N 2-deoxyguanosinyl)tamoxifen N-oxide. fr-2-1 and fr-2-2 were determined to be epimers of cis-α-(N 2-deoxyguanosinyl)tamoxifen N-oxide.