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Identification of Tamoxifen-DNA Adducts in Monkeys Treated with Tamoxifen¹

Laboratory of Chemical Biology, Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, New York 11794-8651 [S. S., N. S., Y. R. S. L., A. P. G.], and Carcinogen-DNA Interactions Section, National Cancer Institute, NIH, Bethesda, Maryland 20892-4255 [L. J. S., R. L. D., M. C. P.]

The risk of developing endometrial cancer is increased in breast cancer patients treated with tamoxifen (TAM) and in healthy women undergoing TAM chemoprevention. We have detected previously TAM-DNA adducts in the endometrium of women receiving TAM (Shibutani et al., Carcinogenesis, 21: 1461–1467, 2000). To investigate the genotoxic damage induced by TAM in the uterus and other tissues of primates, we gave adult female cynomolgus monkeys six times the human-equivalent dose of TAM (2 mg/kg body weight/day) for 30 days. DNA samples were prepared from the uterus, ovary, liver, kidney, and brain cortex of three TAM-exposed monkeys and one control monkey and were analyzed as coded specimens. To identify the TAM-DNA adducts, we established a new high-performance liquid chromatography gradient system for ³²P-postlabeling/high-performance liquid chromatography analysis, which can resolve the trans- and cis-diastereoisomers of -(N²-deoxyguanosinyl)TAM (dG-N²-TAM), -(N²-deoxyguanosinyl)-N-desmethylTAM, and -(N²-deoxyguanosinyl)tamoxifen N-oxide. Trans-forms of dG-N²-TAM and dG-N²-N-desTAM adducts were detected in the livers of all three TAM-fed monkeys at levels of 2.7 adducts/10⁸ nucleotides and 1.7 adducts/10⁸ nucleotides, respectively. The levels of dG-N²-TAM adducts observed in the uterus of one monkey and in the ovaries of two monkeys were 10-fold lower than those observed in the livers. TAM exposure also induced dG-N²-TAM adduct in the brain cortex of all three monkeys with a value of 1.5 adducts/10⁸ nucleotides. No TAM-DNA adducts were detected in the kidneys or in any tissues obtained from the unexposed monkey. Our results suggest that women receiving TAM may form genotoxic damage in many organs, including the reproductive organs.

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