TY - JOUR T1 - THE INVOLVEMENT OF CYP3A4 AND CYP2C9 IN THE METABOLISM OF 17α-ETHINYLESTRADIOL JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1209 LP - 1212 DO - 10.1124/dmd.104.000182 VL - 32 IS - 11 AU - Bonnie Wang AU - Rosa I. Sanchez AU - Ronald B. Franklin AU - David C. Evans AU - Su-Er W. Huskey Y1 - 2004/11/01 UR - http://dmd.aspetjournals.org/content/32/11/1209.abstract N2 - The role of specific cytochrome P450 (P450) isoforms in the metabolism of ethinylestradiol (EE) was evaluated. The recombinant human P450 isozymes CYP1A1, CYP1A2, CYP2C9, CYP2C19, and CYP3A4 were found to be capable of catalyzing the metabolism of EE (1 μM). Without exception, the major metabolite was 2-hydroxy-EE. The highest catalytic efficiency (Vmax/Km) was observed with rCYP1A1, followed by rCYP3A4, rCYP2C9, and rCYP1A2. The P450 isoforms 3A4 and 2C9 were shown to play a significant role in the formation of 2-hydroxy-EE in a pool of human liver microsomes by using isoform-specific monoclonal antibodies, in which the inhibition of formation was ∼54 and 24%, respectively. The involvement of CYP3A4 and CYP2C9 was further confirmed by using selective chemical inhibitors (i.e., ketoconazole and sulfaphenazole). The relative contribution of each P450 isoform to the 2-hydroxylation pathway was obtained from the catalytic efficiency of each isoform normalized by its relative abundance in the same pool of human liver microsomes, as determined by quantitative Western blot analysis. Collectively, these results suggested that multiple P450 isoforms were involved in the oxidative metabolism of EE in human liver microsomes, with CYP3A4 and CYP2C9 as the major contributing enzymes. The American Society for Pharmacology and Experimental Therapeutics ER -