Isoform-selective metabolism of mianserin by cytochrome P-450 2D

The involvement of cytochrome P-450 (CYP) 2D isoforms in the metabolism of mianserin and the stereoselectivity of their catalytic activities were inve stigated by using five CYP2D isoforms (CYP2D1, 2D2, 2D3, 2D4, and 2D6). Usi ng RS-mianserin as a substrate, we found that five CYP2D isoforms had simil ar levels of 8-hydroxylation activity. However, N-demethylation activity di ffered among the isoforms; CYP2D3 and 2D4 efficiently demethylated RS-mians erin compared with the other three isoforms. N-Oxidation activity was speci fic to CYP2D1 although its level was relatively low. Another metabolite, as signed as 8-hydroxy-N-des-methylmianserin by liquid chromatography/mass spe ctrometry analysis, was formed by CYP2D4 and 2D6. The metabolism exhibited stereoselectivity. CYP2D1 and 2D4 selectively 8-hydroxylated the R(2)-enant iomer, and CYP2D6 predominately N-demethylated R(-)-enantiomer. N-Oxidation by CYP2D1 was specific to R( 2) enantiomer. In conclusion, CYP2D isoforms are involved in several metabolic pathways of mianserin acting in an isofor m-specific manner. Stereoselectivity of the catalytic activities was clearl y observed in the reactions of CYP2D1, 2D4, and 2D6.