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

The genotoxic tamoxifen metabolite alpha -hydroxytamoxifen has been resolve d 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 deriv ative of (-)-2-hydroxy-1-phenyl-1-propanone, which has already been shown t o have S-configuration. Metabolism of tamoxifen by rat liver microsomes gav e equal amounts of the two enantiomers. They have the same chemical propert ies but, on treatment of rat hepatocytes in culture, R-(+)-alpha -hydroxyta moxifen gave at least eight times as many DNA adducts as the S-(-)-isomer.