Resolution of α-Hydroxytamoxifen; R-Isomer Forms More DNA Adducts in Rat Liver Cells

The genotoxic tamoxifen metabolite α-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 (−)-α-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-(+)-α-hydroxytamoxifen gave at least eight times as many DNA adducts as the S-(−)-isomer.