COMPARATIVE METABOLISM OF THE TOBACCO-SPECIFIC NITROSAMINES 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANONE AND 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANOL BY RAT CYTOCHROME P450 2A3 AND HUMAN CYTOCHROME P450 2A13

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Abstract
The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and its carbonyl-reduction product, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), are potent lung carcinogens in rats and are presumed human lung carcinogens. NNK and NNAL are bioactivated to DNA-binding intermediates via hydroxylation of the carbon atoms adjacent to the nitroso moiety (i.e., α-hydroxylation) by cytochrome P450s (P450s). Therefore, it is important to delineate which P450s are efficient catalysts of this metabolic transformation. In this study, the kinetic parameters for NNK and NNAL metabolism were determined for two extrahepatic P450s that are expressed in the lung: rat P450 2A3 and human P450 2A13. P450s 2A3 and 2A13 exhibited Vmax values for NNK 4-hydroxylation of 10.8 ± 0.4 and 13.8 ± 0.8 pmol min-1 pmol P450-1, respectively; the corresponding Km values were 4.6 ± 0.5 and 3.6 ± 0.7 μM. The respective Vmax values for P450 2A3- and 2A13-mediated N-methyl hydroxylation of NNK were 8.2 ± 0.3 and 4.6 ± 0.2 pmol min-1 pmol P450-1. These data indicate that P450s 2A3 and 2A13 are both efficient catalysts of the metabolic activation of NNK and are, along with mouse P450 2A5, the best catalysts of this reaction currently known. Both enzymes also catalyzed the α-hydroxylation and N-oxidation of NNAL, and its oxidation to NNK. In general, Vmax/Km values for NNAL metabolism were 1 to 2 orders of magnitude lower than those for NNK metabolism, and P450 2A3 was a slightly better catalyst of NNAL metabolism than was P450 2A13. Given the exquisite sensitivity of the rat lung to NNK-induced carcinogenesis, the efficient bioactivation of NNK by rat P450 2A3, and the similar catalytic efficiency of P450s 2A3 and 2A13, P450 2A13 may be an important contributor to NNK bioactivation in the human lung.

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