Identification of tamoxifen-DNA adducts induced by alpha-acetoxy-N-desmethyltamoxifen

Chem Res Toxicol. 2000 Aug;13(8):761-9. doi: 10.1021/tx000074o.

Abstract

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 alpha-(N(2)-deoxyguanosinyl)tamoxifen (dG-N(2)-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 alpha-acetoxy-N-desmethyltamoxifen as a model activated metabolite of N-desmethyltamoxifen. The overall yield of alpha-acetoxy-N-desmethyltamoxifen from alpha-hydroxytamoxifen was approximately 42%. alpha-Acetoxy-N-desmethyltamoxifen was highly reactive to 2'-deoxyguanosine, as was similarly observed for tamoxifen alpha-sulfate. The two reaction products were identified as a mixture of epimers of the trans form or cis form of alpha-(N(2)-deoxyguanosinyl)-N-desmethyltamoxifen (dG-N(2)-N-desmethylTAM) by mass and proton magnetic resonance spectroscopy. In addition, the trans and cis forms of dG 3'-monophosphate-N(2)-N-desmethylTAM were prepared as standard markers for (32)P-postlabeling/HPLC analysis. Using this technique, dG-N(2)-N-desmethylTAM adducts were detected in calf thymus DNA reacted with alpha-acetoxy-N-desmethyltamoxifen.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cattle
  • Chromatography, High Pressure Liquid
  • DNA Adducts / analysis
  • DNA Adducts / metabolism*
  • Estrogen Antagonists / metabolism*
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry
  • Protons
  • Tamoxifen / analogs & derivatives*
  • Tamoxifen / analysis
  • Tamoxifen / metabolism*

Substances

  • DNA Adducts
  • Estrogen Antagonists
  • Protons
  • alpha-(N(2)-deoxyguanosinyl)tamoxifen
  • Tamoxifen