CYP2A6- and CYP2A13-catalyzed metabolism of the nicotine Delta5'(1')iminium ion.

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von Weymarn LB, Retzlaff C, Murphy SE

CYP2A6- and CYP2A13-catalyzed metabolism of the nicotine Delta5'(1')iminium ion.

J Pharmacol Exp Ther. 2012 Nov;343(2):307-15. doi: 10.1124/jpet.112.195255. Epub 2012 Aug 6.

PubMed ID

22869927 [ View in PubMed

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Abstract

Nicotine, the major addictive agent in tobacco, is metabolized primarily by CYP2A6-catalyzed oxidation. The product of this reaction, 5'-hydroxynicotine, is in equilibrium with the nicotine Delta5'(1')iminium ion and is further metabolized to cotinine. We reported previously that both CYP2A6 and the closely related extrahepatic enzyme CYP2A13 were inactivated during nicotine metabolism; however, inactivation occurred after metabolism was complete. This led to the hypothesis that oxidation of a nicotine metabolite, possibly the nicotine Delta5'(1')iminium ion, was responsible for generating the inactivating species. In the studies presented here, we confirm that the nicotine Delta5'(1')iminium ion is an inactivator of both CYP2A6 and CYP2A13, and inactivation depends on time, concentration, and the presence of NADPH. Inactivation was not reversible and was accompanied by a parallel loss in spectrally active protein, as measured by reduced CO spectra. These data are consistent with the characterization of the nicotine Delta5'(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 Delta5'(1')iminium ion to cotinine and provide evidence that both enzymes catalyze the sequential metabolism of the nicotine Delta5'(1')iminium ion. That is, a fraction of the cotinine formed may not be released from the enzyme before further oxidation to 3'-hydroxycotinine.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Nicotine	Cytochrome P450 2A6	Protein	Humans	Unknown	Substrate Inhibitor	Details