PT  - JOURNAL ARTICLE
AU  - Khojasteh-Bakht, Siamak C.
AU  - Koenigs, Luke L.
AU  - Peter, Raimund M.
AU  - Trager, William F.
AU  - Nelson, Sidney D.
TI  - (<em>R</em>)-(+)-Menthofuran Is a Potent, Mechanism-Based Inactivator of Human Liver Cytochrome P450 2A6
DP  - 1998 Jul 01
TA  - Drug Metabolism and Disposition
PG  - 701--704
VI  - 26
IP  - 7
4099  - http://dmd.aspetjournals.org/content/26/7/701.short
4100  - http://dmd.aspetjournals.org/content/26/7/701.full
SO  - Drug Metab Dispos1998 Jul 01; 26
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