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-alpha-acetoxytamoxifen N-oxides were synthesized as model-activated forms via major tamoxifen metabolites, tamoxifen N-oxide and alpha-hydroxytamoxifen N-oxide. When alpha-acetoxytamoxifen N-oxide was reacted with human DNA, at least three DNA adducts were detected by (32)P-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-alpha-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-alpha-(N(2)-deoxyguanosinyl)tamoxifen N-oxide. fr-2-1 and fr-2-2 were determined to be epimers of cis-alpha-(N(2)-deoxyguanosinyl)tamoxifen N-oxide.
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http://dx.doi.org/10.1021/tx990132+ | DOI Listing |
J Am Chem Soc
January 2025
Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States.
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Clinical Center for Tumor Therapy, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China. Electronic address:
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Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, MA, USA.
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January 2025
National Key Laboratory, School of Food Science and Technology, Jiangnan University, 1800 Lihu Road, Wuxi 214122, China.
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January 2025
Department of Chemical Engineering, Key Laboratory of Advanced Materials (MOE), Tsinghua University, Beijing 100084, China.
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