Tamoxifen-DNA Adducts Formed by a-Acetoxytamoxifen N-Oxide

DNA adduct formation is assumed to be a major carcinogenic event, leading to the development of endornetnal 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-a-acetoxytamoxifen N-oxides were synthesized as model-activated forms via major tamoxifen metabolites, tamoxifen TV-oxide and alpha-hydroxytamoxifen N-oxide. When a-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-alpha-hydroxytamoxifen N-oxide was 1.5-fold higher than that formed by the cis form. Both trans- and cis-R-acetoxytamoxifen N-oxide reacted with 2ʹ-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-I was identified as a mixture of the epimers of trans-alpha.-(N2-deoxyguanosinyl)tamoxifen N-oxide. fr-2-1 and fr-2-2 were determined to be epimors of cis-alpha.-(N2-deoxyguanosinyl)tamoxifen N-oxide.