title: Comparative metabolic study between two selective estrogen receptor modulators, toremifene and tamoxifen, in human liver microsomes.
abstract: Toremifene (TOR) and Tamoxifen (TAM) are widely used as endocrine therapy for estrogen receptor positive breast cancer. Poor metabolizers of TAM are likely to have worse clinical outcomes than patients who exhibit normal TAM metabolism due to lower plasma level of its active metabolite, 4-hydroxy-N-desmethyl (4OH-NDM) tamoxifen (endoxifen). In this study, we examined the role of individual cytochrome P450 (CYP) isoforms in the metabolism of TOR to N-desmethyl (NDM), 4-hydroxy (4OH) and 4OH-NDM metabolites in comparison with TAM using human liver microsomes (HLMs) with selective chemical inhibitors for each CYP isoform and recombinant CYP proteins. Similar levels of NDM metabolites were formed for both TOR and TAM, and N-demethylation of both compounds was primarily carried out by CYP3A4. We found that the formation of 4OH-NDM-TOR was catalyzed both by CYP2C9 and CYP2D6, whereas the formation of 4OH-TAM and endoxifen was specifically catalyzed by CYP2D6 in HLMs. Our results suggest that the potential contribution of CYP2D6 in the bioactivation pathway of TOR may be lower compared to TAM, and may have a different impact on clinical outcome than CYP2D6 polymorphisms.
authors.affiliation: Pharmaceutical Research Laboratories, Nippon Kayaku Co., Ltd., 31-12 Shimo, Kita-ku, Tokyo 115-8588, Japan. Electronic address: miyuki.watanabe@nipponkayaku.co.jp.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Pharmaceutical Research Laboratories, Nippon Kayaku Co., Ltd., 31-12 Shimo, Kita-ku, Tokyo 115-8588, Japan. Electronic address: noriko.watanabe@nipponkayaku.co.jp.
authors.forename: Noriko
authors.initials: N
authors.lastname: Watanabe
authors.affiliation: Pharmaceutical Research Laboratories, Nippon Kayaku Co., Ltd., 31-12 Shimo, Kita-ku, Tokyo 115-8588, Japan. Electronic address: sakiko.maruyama@nipponkayaku.co.jp.
authors.forename: Sakiko
authors.initials: S
authors.lastname: Maruyama
authors.affiliation: Pharmaceutical Research Laboratories, Nippon Kayaku Co., Ltd., 31-12 Shimo, Kita-ku, Tokyo 115-8588, Japan. Electronic address: takashi.kawashiro@nipponkayaku.co.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kawashiro
mesh_terms: D001711:Biotransformation; D045744:Cell Line, Tumor; D065729:Cytochrome P-450 CYP2C9 / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D020845:Selective Estrogen Receptor Modulators / Q000378:metabolism*; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000378:metabolism*; D017312:Toremifene / Q000378:metabolism*
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; C055492:4-hydroxy-N-desmethyltamoxifen; D017312:Toremifene; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D019389:Cytochrome P-450 CYP2D6
keywords: Bioactivation; CYP2C9; CYP2D6; CYP3A4; Metabolite kinetics; Pharmacogenomics; Polymorphisms; Tamoxifen; Toremifene