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CYP2A6 and CYP2A13-catalyzed metabolism of the nicotine {Delta}5'(1')iminium ion.

J Pharmacol Exp Ther. 2012 Aug 6;

Authors: von Weymarn L, Retzlaff C, Murphy S


Nicotine, the major addictive agent in tobacco is primarily metabolized by CYP2A6-catalyzed -oxidation. The product of this reaction, 5'-hydroxynicotine is in equilibrium with the nicotine Δ5'(1')iminium ion and is further metabolized to cotinine. We previously reported that both CYP2A6 and the closely related extrahepatic enzyme CYP2A13 were inactivated during nicotine metabolism, however inactivation occurred after nicotine metabolism was complete. This led to the hypothesis that oxidation of a nicotine metabolite, possibly the nicotine Δ5'(1')iminium ion was responsible for generating the inactivating species. In the studies presented here we confirm that the nicotine Δ5'(1')iminium ion is an inactivator of both CYP2A6 and CYP2A13, and that inactivation is dependent on time, concentration and the presence of NADPH. Inactivation was not reversible and was accompanied by a parallel loss in spectrally active proteins, as measured by reduced CO spectrum. These data are consistent with the characterization of the nicotine Δ5'(1')iminium ion as a mechanism based inactivator of both CYP2A13 and CYP2A6. We also confirm that both CYP2A6 and CYP2A13 catalyze the metabolism of the nicotine Δ5'(1')iminium ion to cotinine, and provide evidence that both enzymes catalyze the sequential metabolism of the nicotine Δ5'(1')iminium ion. That is, a fraction of the cotinine formed may not be released from the enzyme prior to further oxidation to 3'-hydroxyxcotinine.

PMID: 22869927 [PubMed - as supplied by publisher]