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.
Osborne
M R
MR
Section of Molecular Carcinogenesis, Haddow Laboratories, Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK. martino@icr.ac.uk
Hewer
A
A
Phillips
D H
DH
D000818:Animals; D001892:Camphanes / Q000737:chemistry; D018736:DNA Adducts / Q000096:biosynthesis / Q000187:drug effects*; D004965:Estrogen Antagonists / Q000737:chemistry*; D022781:Hepatocytes / Q000187:drug effects; D007536:Isomerism; D008099:Liver / Q000187:drug effects*; D008862:Microsomes, Liver / Q000187:drug effects; D008958:Models, Molecular; D051381:Rats; D013237:Stereoisomerism; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology
D001892:Camphanes; D018736:DNA Adducts; D004965:Estrogen Antagonists; C110902:alpha-hydroxytamoxifen; D013629:Tamoxifen