TY - JOUR T1 - Enantioselective, Mechanism-Based Inactivation of Guinea Pig Hepatic Cytochrome P450 by<em>N</em>-(α-Methylbenzyl)-1-Aminobenzotriazole JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 681 LP - 688 VL - 26 IS - 7 AU - Christopher J. Sinal AU - Maurice Hirst AU - Christopher D. Webb AU - John R. Bend Y1 - 1998/07/01 UR - http://dmd.aspetjournals.org/content/26/7/681.abstract N2 - N-Aralkylated derivatives of 1-aminobenzotriazole are well-established, mechanism-based inhibitors of cytochrome P450 (CYP or P450). In this study, the kinetics of inactivation of CYP2B-dependent 7-pentoxyresorufin O-depentylation (PROD) and CYP1A-dependent 7-ethoxyresorufin O-deethylation (EROD) activities by enantiomers ofN-(α-methylbenzyl)-1-aminobenzotriazole (αMB) were compared. The racemic mixture (±)-αMB, as well as the enantiomers (−)-αMB and (+)-αMB, produced a time-, concentration-, and NADPH-dependent loss of PROD and EROD activity in hepatic microsomes from phenobarbital-treated guinea pigs. The rates of PROD inactivation by (−)-αMB were significantly faster than for (+)-αMB. Consistent with this, the derived maximal kinact was also significantly greater for (−)-αMB than for (+)-αMB (0.49vs. 0.35 min−1). In contrast, the concentrations required for the half-maximal rate of inactivation (Ki ) were equivalent for (−)-αMB and (+)-αMB, whereas the degree of competitive inhibition of PROD activity was greater for (+)-αMB. No significant differences were found among (−)-αMB, (+)-αMB, and (±)-αMB with respect to mechanism-based inactivation (kinact = 0.18, 0.16, and 0.17 min−1, respectively) or competitive inhibition of EROD activity. No differences were found for the maximal extent of PROD or EROD inhibition or the loss of spectral P450 after an extended 30-min incubation with the inhibitors. We conclude that mechanism-based inactivation of guinea pig CYP2B, but not CYP1A, isozymes by αMB occurs in a stereoselective manner, most likely as a result of a difference in the balance between metabolic activation and deactivation for the αMB enantiomers. The American Society for Pharmacology and Experimental Therapeutics ER -