Stereoselective Metabolic Activation of α-Hydroxy-N-desmethyltamoxifen:  The R-Isomer Forms More DNA Adducts in Rat Liver Cells

• Published in: Chemical research in toxicology 2004-05, Vol.17 (5), p.697-701
• Main Authors: Osborne, Martin R, Hewer, Alan, Phillips, David H
• Format: Article
• Language: English
• Subjects: Animals; DNA Adducts - chemistry; DNA Adducts - drug effects; DNA Adducts - metabolism; Hepatocytes - drug effects; Hydrolysis; Liver - metabolism; Rats; Stereoisomerism; Tamoxifen - analogs & derivatives; Tamoxifen - metabolism; Tamoxifen - pharmacology
• ISSN: 0893-228X; 1520-5010
• DOI: 10.1021/tx049957w

The antiestrogenic drug tamoxifen forms DNA adducts in rat liver through two genotoxic metabolites, α-hydroxytamoxifen and α-hydroxy-N-desmethyltamoxifen. These have now each been resolved into R- and S-enantiomers. The work with α-hydroxytamoxifen was published earlier [Osborne, et al. (2001) Chem. Res. Toxicol. 14, 888−893]. Here, we publish results with α-hydroxy-N-desmethyltamoxifen. We prepared the derivative N-ethoxycarbonyl-N-desmethyltamoxifen-α-S-camphanate, separated it into two diastereoisomers, and hydrolyzed them to give (+)- and (−)-α-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-(+)-α-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.