Abstract
Nicotine, a major constituent of tobacco, plays a critical role in smoking addiction. In humans, nicotine is primarily metabolized to cotinine, which is further metabolized to trans-3′-hydroxycotinine. Recently, we have demonstrated that heterologously expressed human CYP2A13 is highly active in the metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a nicotine-derived carcinogen. In the present study, CYP2A13-catalyzed NNK metabolism was found to be inhibited competitively by nicotine and N′-nitrosonornicotine (NNN), suggesting that both nicotine and NNN are also substrates of CYP2A13. We have further demonstrated that human CYP2A13 is indeed an efficient enzyme in catalyzing C-oxidation of nicotine to form cotinine, with the apparent Km and Vmax values of 20.2 μM and 8.7 pmol/min/pmol, respectively. CYP2A13 also catalyzes the 3′-hydroxylation of cotinine to form trans-3′-hydroxycotinine, with the apparent Km and Vmax values of 45.2 μM and 0.7 pmol/min/pmol, respectively. The importance of CYP2A13-catalyzed nicotine and cotinine metabolism in vivo remains to be determined.
Footnotes
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Part of this work was supported by National Institutes of Health Grant R01-ES10048 (J.-Y.H.), R01-CA 092596 (X.D.) and National Institute of Environmental Health Sciences Center Grant ES05022.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.104.002105.
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ABBREVIATIONS: P450, cytochrome P450; NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; NNN, N′-nitrosonornicotine; HPLC, high-performance liquid chromatography.
- Received August 30, 2004.
- Accepted November 3, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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