title: Inhibition and inactivation of cytochrome P450 2A6 and cytochrome P450 2A13 by menthofuran, β-nicotyrine and menthol.
abstract: Nicotine is the primary addictive agent in tobacco products and is metabolized in humans by CYP2A6. Decreased CYP2A6 activity has been associated with decreased smoking. The extrahepatic enzyme, CYP2A13 (94% identical to CYP2A6) also catalyzes the metabolism of nicotine, but is most noted for its role in the metabolic activation of the tobacco specific lung carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). In this study, the inhibition and potential inactivation of CYP2A6 and CYP2A13 by two tobacco constituents, 1-methyl-4-(3-pyridinyl) pyrrole (β-nicotyrine) and (-)-menthol were characterized and compared to the potent mechanism based inactivator of CYP2A6, menthofuran. The effect of these compounds on CYP2A6 and CYP2A13 activity was significantly different. (-)-Menthol was a more efficient inhibitor of CYP2A13 than of CYP2A6 (KI, 8.2 μM and 110 μM, respectively). β-Nicotyrine was a potent inhibitor of CYP2A13 (KI, 0.17 μM). Neither menthol nor β-nicotyrine was an inactivator of CYP2A13. Whereas, β-nicotyrine was a mechanism based inactivator of CYP2A6 (KI(inact), 106 μM, kinact was 0.61 min(-1)). Similarly, menthofuran, a potent mechanism based inactivator of CYP2A6 did not inactivate CYP2A13. Menthofuran was an inhibitor of CYPA13 (KI, 1.24 μM). The inactivation of CYP2A6 by either β-nicotyrine or menthofuran was not due to modification of the heme and was likely due to modification of the apo-protein. These studies suggest that β-nicotyrine, but not menthol may influence nicotine and NNK metabolism in smokers.
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Valerie M
authors.initials: VM
authors.lastname: Kramlinger
authors.forename: Linda B
authors.initials: LB
authors.lastname: von Weymarn
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Murphy
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D065637:Cytochrome P-450 CYP2A6; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006418:Heme / Q000737:chemistry / Q000378:metabolism; D008610:Menthol / Q000494:pharmacology*; D039821:Monoterpenes / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D014026:Nicotiana
chemical_list: D004791:Enzyme Inhibitors; D039821:Monoterpenes; D011725:Pyridines; D008610:Menthol; D006418:Heme; C008615:alpha-nicotyrine; C054487:menthofuran; D001189:Aryl Hydrocarbon Hydroxylases; C414206:CYP2A13 protein, human; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6