TY - JOUR T1 - (<em>R</em>)-(+)-Menthofuran Is a Potent, Mechanism-Based Inactivator of Human Liver Cytochrome P450 2A6 JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 701 LP - 704 VL - 26 IS - 7 AU - Siamak C. Khojasteh-Bakht AU - Luke L. Koenigs AU - Raimund M. Peter AU - William F. Trager AU - Sidney D. Nelson Y1 - 1998/07/01 UR - http://dmd.aspetjournals.org/content/26/7/701.abstract N2 - (R)-(+)-Menthofuran is a potent, mechanism-based inactivator of human liver cytochrome P450 (CYP or P450) 2A6. Menthofuran caused a time- and concentration-dependent loss of CYP2A6 activity. The inactivation of CYP2A6 was characterized by aKi of 2.5 μM and akinact of 0.22 min−1 for human liver microsomes and aKi of 0.84 μM and akinact of 0.25 min−1 for purified expressed CYP2A6. Addition of various nucleophiles, a chelator of iron, or scavengers of reactive oxygen species or extensive dialysis failed to protect CYP2A6 from inactivation. An antibody to metallothionein conjugates of a suspected reactive metabolite of menthofuran was used to detect reactive menthofuran metabolite adducts with CYP2A6. These adducts were formed only in the presence of NADPH-P450 reductase and NADPH. Glutathione, methoxylamine, and semicarbazide did not prevent adduction of reactive menthofuran metabolites to CYP2A6, however. The menthofuran metabolite formation/CYP2A6 inactivation partition ratio was determined to be 3.5 ± 0.6 nmol/nmol of P450. Menthofuran was unable to inactivate CYP1A2, CYP2D6, CYP2E1, or CYP3A4 in a time- and concentration-dependent manner. The American Society for Pharmacology and Experimental Therapeutics ER -