RT Journal Article
SR Electronic
T1 Isoform-Selective Metabolism of Mianserin by Cytochrome P-450 2D
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1200
OP 1204
VO 27
IS 10
A1 Toshio Chow
A1 Toyoko Hiroi
A1 Susumu Imaoka
A1 Kan Chiba
A1 Yoshihiko Funae
YR 1999
UL http://dmd.aspetjournals.org/content/27/10/1200.abstract
AB The involvement of cytochrome P-450 (CYP) 2D isoforms in the metabolism of mianserin and the stereoselectivity of their catalytic activities were investigated by using five CYP2D isoforms (CYP2D1, 2D2, 2D3, 2D4, and 2D6). Using RS-mianserin as a substrate, we found that five CYP2D isoforms had similar levels of 8-hydroxylation activity. However, N-demethylation activity differed among the isoforms; CYP2D3 and 2D4 efficiently demethylated RS-mianserin compared with the other three isoforms. N-Oxidation activity was specific to CYP2D1 although its level was relatively low. Another metabolite, assigned as 8-hydroxy-N-desmethylmianserin by liquid chromatography/mass spectrometry analysis, was formed by CYP2D4 and 2D6. The metabolism exhibited stereoselectivity. CYP2D1 and 2D4 selectively 8-hydroxylated the R(−)-enantiomer, and CYP2D6 predominately N-demethylatedR(−)-enantiomer. N-Oxidation by CYP2D1 was specific to R(−)-enantiomer. In conclusion, CYP2D isoforms are involved in several metabolic pathways of mianserin acting in an isoform-specific manner. Stereoselectivity of the catalytic activities was clearly observed in the reactions of CYP2D1, 2D4, and 2D6.