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First published on September 27, 2005; DOI: 10.1124/jpet.105.091306

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Received for publication June 22, 2005.
Revised September 19, 2005.
Accepted for publication September 26, 2005.

Inactivation of CYP2A6 and CYP2A13 during nicotine metabolism

Linda B. von Weymarn 1, Kathryn M. Brown 2, Sharon Murphy 2*

1 University of MinnesotaUniversity of Minnesota Cancer Center 2 University of Minnesota Cancer Center

* Address correspondence to: E-mail: murph062{at}umn.edu

Abstract

Nicotine is the major addictive agent in tobacco. The primary catalyst of nicotine metabolism in humans is CYP2A6. However, the closely related enzyme CYP2A13 is a somewhat better catalyst. CYP2A13 is an extrahepatic enzyme that is an excellent catalyst of the metabolic activation of the tobacco specific carcinogen 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone (NNK). We report here that both CYP2A6 and CYP2A13 were inactivated during nicotine metabolism. Inactivation of both enzymes was dependent on NADPH and increased with time and concentration. Alternate substrates for CYP2A6 and CYP2A13 protected these enzymes from inactivation. Inactivation of CYP2A13 was irreversible upon extensive dialysis and appears to be mechanism-based. The KI of CYP2A13 inactivation by nicotine was 17 µM, the rate of inactivation, kinact, was 0.1 min-1 and the t1/2 was 7 min. However, the loss in enzyme activity occurs after nicotine metabolism was complete, suggesting that a secondary or possible tertiary metabolite of nicotine may be responsible for the inactivation. [5-3H]-Nicotine metabolism by CYP2A13 was monitored by radioflow HPLC during the course of enzyme inactivation; the major product was the {Delta}5'(1')iminium ion. However, cotinine was a significant metabolite even at short reaction times. The metabolism of the nicotine {Delta}5'(1')iminium ion to cotinine did not require the addition of aldehyde oxidase. CYP2A13-catalyzed this reaction as well as the further metabolism of cotinine to 5'-hydroxycotinine, trans-3'-hydroxycotinine, and N-(hydroxy-methyl)-norcotinine as enzyme inactivation occurred. Studies are on-going to identify the metabolite responsible for nicotine-mediated inactivation of CYP2A13.


Key words: P450, P450 2A13, P450 2A6, mechanism-based inactivation, nicotine, nicotine metabolism


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Home page
 Drug Metab. Dispos.Home page
P. J. Brown, L. L. Bedard, K. R. Reid, D. Petsikas, and T. E. Massey
Analysis of CYP2A Contributions to Metabolism of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone in Human Peripheral Lung Microsomes
Drug Metab. Dispos., November 1, 2007; 35(11): 2086 - 2094.
[Abstract] [Full Text] [PDF]


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