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

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.