Biochemical and pharmacological effects of toremifene metabolites.
Toremifene, a new antiestrogenic antitumor compound, has several biologically active metabolites. The hormonal effects of the main metabolites resemble those of unchanged toremifene. The main metabolite in humans, N-demethyltoremifene, is bound to estrogen receptors (ER), inhibits the growth of MCF-7 cells, and exerts an antiestrogenic effect similar to that of toremifene. However, its antitumor effect in vivo against dimethylbenz(a)anthracene (DMBA)-induced rat mammary cancers is weaker than that of toremifene. Didemethyltoremifene has antiestrogenic actions in mouse and rat uterus at high doses. 4-Hydroxytoremifene is bound to ER with higher affinity and inhibits MCF-7 growth at concentrations lower than those of toremifene. It has a weaker intrinsic estrogenic effect than does toremifene. The efficacy of 4-hydroxytoremifene against DMBA-induced cancers is weak except at very high doses. Oxidations of N-demethylated metabolites to (deamino)hydroxylated compounds and carboxylic acids are the detoxification routes of toremifene. (deaminohydroxy)Toremifene has only weak hormonal actions at high doses and carboxylated metabolites have no estrogenic/antiestrogenic effects. The antitumor effect of toremifene in vivo is mainly due to unchanged toremifene, but hormonal effects (which may have a role in antitumor actions) are partly attributable to metabolites N-demethyltoremifene, didemethyltoremifene, (deaminohydroxy)toremifene, 4-hydroxy-N-demethyltoremifene, and 4-hydroxytoremifene, which have pharmacological properties similar to those of toremifene.
Kangas
L
L
Farmos Group Ltd., Research Center, Turku, Finland.
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D051379:Mice; D051381:Rats; D011960:Receptors, Estrogen / Q000187:drug effects* / Q000378:metabolism; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D017312:Toremifene; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D011960:Receptors, Estrogen; D013629:Tamoxifen; D015127:9,10-Dimethyl-1,2-benzanthracene; D017312:Toremifene; C062262:4-hydroxytoremifene