TY - JOUR T1 - Structure-Activity Relationship and Elucidation of the Determinant Factor(s) Responsible for the Mechanism-Based Inactivation of Cytochrome P450 2B6 by Substituted Phenyl Diaziridines JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 2102 LP - 2110 DO - 10.1124/dmd.106.011452 VL - 34 IS - 12 AU - Yoshimasa Kobayashi AU - Chitra Sridar AU - Ute M. Kent AU - Satish G. Puppali AU - John M. Rimoldi AU - Haoming Zhang AU - Lucy Waskell AU - Paul F. Hollenberg Y1 - 2006/12/01 UR - http://dmd.aspetjournals.org/content/34/12/2102.abstract N2 - It has been demonstrated previously that several 3-trifluoromethyl-3-(4-alkoxyphenyl)diaziridines inhibit the 7-ethoxy-4-(trifluoroethyl)coumarin (7-EFC) O-deethylation activity of P450 2B6 in a mechanism-based manner. In contrast, 3-trifluoromethyl-3-(4-methylthio)phenyl)diaziridine did not have any effect on the activity of P450 2B6. It is interesting that both the alkoxy and the thiophenyl compounds were metabolized by P450 2B6. In this report, the structure-activity relationships for the mechanism-based inactivation of cytochrome P450 2B6 by a series of aryl diaziridines were investigated. Three diaziridines that did not contain a 4-alkoxy-substituent on their phenyl ring, namely, 3-trifluoromethyl-3-(3-methoxyphenyl)diaziridine, 3-trifluoromethyl-3-phenyl diaziridine, and 3-trifluoromethyl-3-(4-chlorophenyl)diaziridine had no effect on the P450 2B6 7-EFC activity. Another analog that did not contain a diaziridine substructure, 3-trifluoromethyl-3-(4-methoxyphenyl)ethanone, also had no effect on the activity of P450 2B6. Glutathione ethyl ester adducts of the phenyldiaziridine reactive intermediates were isolated from reaction mixtures of the inactivated samples and analyzed by liquid chromatography-tandem mass spectrometry. The structures of the conjugates suggested that the electrophilic reactive intermediate in each case was a quinone methide (quinomethane), 4-ethylidene-cyclohexa-2,5-dienone, generated from the 4-alkoxyphenyldiaziridines by removal of both of the diaziridine and the 4-alkyl groups. In conclusion, the determinant factor for the mechanism-based inactivator activity of the aryl diaziridines seems to be the formation of the reactive quinomethane intermediate, which is generated from the 4-alkoxyphenyl diaziridines by a cytochrome P450-catalyzed metabolic reaction. The American Society for Pharmacology and Experimental Therapeutics ER -