Stereoselective metabolic activation of alpha-hydroxy-N-desmethyltamoxifen: the R-isomer forms more DNA adducts in rat liver cells.

Abstract

The antiestrogenic drug tamoxifen forms DNA adducts in rat liver through two genotoxic metabolites, alpha-hydroxytamoxifen and alpha-hydroxy-N-desmethyltamoxifen. These have now each been resolved into R- and S-enantiomers. The work with alpha-hydroxytamoxifen was published earlier [Osborne, et al. (2001) Chem. Res. Toxicol. 14, 888-893]. Here, we publish results with alpha-hydroxy-N-desmethyltamoxifen. We prepared the derivative N-ethoxycarbonyl-N-desmethyltamoxifen-alpha-S-camphanate, separated it into two diastereoisomers, and hydrolyzed them to give (+)- and (-)-alpha-hydroxy-N-desmethyltamoxifen. The configuration of the (-)-isomer was shown to be S- by degradation of the above ester to a derivative of (-)-2-hydroxy-1-phenyl-1-propanone, which has already been shown to have S-configuration. The two enantiomers have the same chemical properties and were equally reactive toward DNA in vitro at pH 6. However, on treatment of rat hepatocytes in culture, R-(+)-alpha-hydroxy-N-desmethyltamoxifen gave 10 times as many DNA adducts as the S-(-)-isomer. This suggests that the R-isomer more readily undergoes sulfate conjugation to generate a reactive carbocation that attacks DNA.