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Received for publication March 2, 2005.
Revised April 21, 2005.
Accepted for publication April 21, 2005.
In smokers, the primary pathway of nicotine metabolism is P450 2A6-catalyzed 5'-oxidation. The nicotine 
5'(1')iminium ion product of this reaction is further metabolized to cotinine by aldehyde oxidase. Previous investigators have reported kinetic parameters for cotinine formation using human liver cytosol as a source of aldehyde oxidase. Using [5-3H]nicotine and radioflow HPLC analysis we determined kinetic parameters for nicotine 5'-oxidation by P450 2A6 and the closely related human extrahepatic P450 2A13 as well as the rodent P450s 2A3, 2A4 and 2A5. The formation of both cotinine and nicotine 5'(1')iminium ion was monitored. The Km and Vmax values for P450 2A6 were 144 ± 15 µM and 1.30 ± 0.05 pmol/min/pmol, respectively. Previously reported Km values for cotinine formation by P450 2A6 in the presence of cytosol were much lower, ranging from 11 to 45 µM. P450 2A13 was a somewhat better catalyst of nicotine 5'(1')iminium formation, with 2 fold lower Km and 2-fold higher Vmax values than P450 2A6. The rat P450 2A3 and the mouse P450 2A5, which are 85 and 84% identical to P450 2A6, were much more efficient catalysts of nicotine 5'-oxidation. P450 2A4 was not an efficient catalyst of nicotine metabolism. While 5'-oxidation was the major pathway of nicotine metabolism for all five P450 2A enzymes, these enzymes also catalyzed methyl oxidation. Nornicotine, the product of this reaction was detected as 5 to 15% of the total nicotine metabolites. Nornicotine is the amine precursor to the esophageal carcinogen, N'-nitrosonornicotine. Therefore, methyl oxidation of nicotine by P450 2A6 or P450 2A13 followed by nitrosation of nornicotine are possible endogenous pathways of NNN formation.
Key words:
CYP2A, cytochrome P450 catalyzed oxidations
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