Toremifene metabolism in rat, mouse and human liver microsomes: identification of alpha-hydroxytoremifene by LC-MS.
The in vitro metabolism of toremifene has been studied in liver microsomal preparations from rat, mouse and human sources using high-performance liquid chromatography-electrospray ionisation mass spectrometry (HPLC-ESIMS). The metabolites detected were N-desmethyltoremifene (m/z 392), 4-hydroxytoremifene (m/z 422), 4'-hydroxytoremifene (m/z 422) and toremifene N-oxide m/z 422). In addition, a new polar metabolite with a protonated molecule at m/z 422 has been detected in all three species. The compound was identified by tandem MS-MS as alpha-hydroxytoremifene, an analogue of alpha-hydroxytamoxifen. The results showed that alpha-hydroxylation is a common feature of tamoxifen and toremifene metabolism and that alpha-hydroxytamoxifen is unlikely to be the reactive metabolite responsible for the hepatocarcinogenesis in rat, as widely believed.
Jones
Russell M
RM
MRC Bioanalytical Science Group, School of Biological and Chemical Sciences, Birkbeck, University of London, Malet Street, UK.
Lim
C K
CK
D000818:Animals; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism*; D051381:Rats; D020845:Selective Estrogen Receptor Modulators / Q000378:metabolism*; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods*; D017312:Toremifene / Q000031:analogs & derivatives / Q000378:metabolism*
D020845:Selective Estrogen Receptor Modulators; D017312:Toremifene