288617-57-2Relevant academic research and scientific papers
Identification of tamoxifen-DNA adducts induced by α-acetoxy-N-desmethyltamoxifen
Kitagawa,Ravindernath,Suzuki,Rieger,Terashima,Umemoto,Shibutani
, p. 761 - 769 (2000)
Treatment with tamoxifen increased the risk of endometrial cancers in breast cancer patients and women participating in the chemoprevention study. In our laboratory, tamoxifen-DNA adducts, including α-(N2-deoxyguanosinyl)tamoxifen (dG-N2-TAM), were detected in the endometrium of women taking tamoxifen [Shibutani, S., et al. (1999) Chem. Res. Toxicol. 12, 646-653]. On the basis of recent animal studies, deoxyguanosinyl-N-desmethyltamoxifen (dG-N-desmethylTAM) adducts are also suspected to be formed in the liver. In the study presented here, we synthesized α-acetoxy-N-desmethyltamoxifen as a model activated metabolite of N-desmethyltamoxifen. The overall yield of α-acetoxy-N-desmethyltamoxifen from α-hydroxy-tamoxifen was approximately 42%. α-Acetoxy-N-desmethyltamoxifen was highly reactive to 2'-deoxyguanosine, as was similarly observed for tamoxifen α-sulfate. The two reaction products were identified as a mixture of epimers of the trans form or cis form of α-(N2-deoxyguanosinyl)-N-desmethyltamoxifen (dG-N2-N-desmethylTAM) by mass and proton magnetic resonance spectroscopy. In addition, the trans and cis forms of dG 3'-monophosphate-N2-N-desmethylTAM were prepared as standard markers for 32P-postlabeling/HPLC analysis. Using this technique, dG-N2-N-desmethylTAM adducts were detected in calf thymus DNA reacted with α-acetoxy-N-desmethyltamoxifen.
