RT Journal Article SR Electronic T1 (R)-(+)-Menthofuran Is a Potent, Mechanism-Based Inactivator of Human Liver Cytochrome P450 2A6 JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 701 OP 704 VO 26 IS 7 A1 Siamak C. Khojasteh-Bakht A1 Luke L. Koenigs A1 Raimund M. Peter A1 William F. Trager A1 Sidney D. Nelson YR 1998 UL http://dmd.aspetjournals.org/content/26/7/701.abstract AB (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