Resolution of alpha-hydroxytamoxifen; R-isomer forms more DNA adducts in rat liver cells

Chem Res Toxicol. 2001 Jul;14(7):888-93. doi: 10.1021/tx010027b.

Abstract

The genotoxic tamoxifen metabolite alpha-hydroxytamoxifen has been resolved into R- and S-enantiomers. This was achieved by preparing its ester with S-camphanic acid, chromatographic separation into two diastereoisomers, and hydrolysis to give (+)- and (-)-alpha-hydroxytamoxifen. The configuration of the (-)-isomer was shown to be S- by degradation of an ester to a derivative of (-)-2-hydroxy-1-phenyl-1-propanone, which has already been shown to have S-configuration. Metabolism of tamoxifen by rat liver microsomes gave equal amounts of the two enantiomers. They have the same chemical properties but, on treatment of rat hepatocytes in culture, R-(+)-alpha-hydroxytamoxifen gave at least eight times as many DNA adducts as the S-(-)-isomer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Camphanes / chemistry
  • DNA Adducts / biosynthesis
  • DNA Adducts / drug effects*
  • Estrogen Antagonists / chemistry*
  • Hepatocytes / drug effects
  • Isomerism
  • Liver / drug effects*
  • Microsomes, Liver / drug effects
  • Models, Molecular
  • Rats
  • Stereoisomerism
  • Tamoxifen / analogs & derivatives*
  • Tamoxifen / chemistry*
  • Tamoxifen / metabolism
  • Tamoxifen / pharmacology

Substances

  • Camphanes
  • DNA Adducts
  • Estrogen Antagonists
  • alpha-hydroxytamoxifen
  • Tamoxifen