QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jalas, J. R. Articles by Murphy, S. E. Search for Related Content PubMed PubMed Citation Articles by Jalas, J. R. Articles by Murphy, S. E.

SHORT COMMUNICATION

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

Department of Chemistry (J.R.J.) and Cancer Center (J.R.J., S.E.M.), University of Minnesota, Minneapolis, Minnesota; and Wadsworth Center, New York State Department of Health and School of Public Health, State University of New York at Albany Albany New York (X.D.)

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., -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 V_max values for NNK 4-hydroxylation of 10.8 ± 0.4 and 13.8 ± 0.8 pmol min^-1 pmol P450^-1, respectively; the corresponding K_m values were 4.6 ± 0.5 and 3.6 ± 0.7 µM. The respective V_max 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 -hydroxylation and N-oxidation of NNAL, and its oxidation to NNK. In general, V_max/K_m 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.

This article has been cited by other articles:

				K. E. Schlicht, J. Z. Berg, and S. E. Murphy Effect of CYP2A13 Active Site Mutation N297A on Metabolism of Coumarin and Tobacco-Specific Nitrosamines Drug Metab. Dispos., March 1, 2009; 37(3): 665 - 671. [Abstract] [Full Text] [PDF]

				J. D'Agostino, X. Zhang, H. Wu, G. Ling, S. Wang, Q.-Y. Zhang, F. Liu, and X. Ding Characterization of CYP2A13*2, a Variant Cytochrome P450 Allele Previously Found to Be Associated with Decreased Incidences of Lung Adenocarcinoma in Smokers Drug Metab. Dispos., November 1, 2008; 36(11): 2316 - 2323. [Abstract] [Full Text] [PDF]

				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]

				B. D. Smith, J. L. Sanders, P. R. Porubsky, G. H. Lushington, C. D. Stout, and E. E. Scott Structure of the Human Lung Cytochrome P450 2A13 J. Biol. Chem., June 8, 2007; 282(23): 17306 - 17313. [Abstract] [Full Text] [PDF]

				L. B. von Weymarn, J. A. Chun, and P. F. Hollenberg Effects of benzyl and phenethyl isothiocyanate on P450s 2A6 and 2A13: potential for chemoprevention in smokers Carcinogenesis, April 1, 2006; 27(4): 782 - 790. [Abstract] [Full Text] [PDF]

				L. B. von Weymarn, Q.-Y. Zhang, X. Ding, and P. F. Hollenberg Effects of 8-methoxypsoralen on cytochrome P450 2A13 Carcinogenesis, March 1, 2005; 26(3): 621 - 629. [Abstract] [Full Text] [PDF]

				X.-Y. He, J. Shen, X. Ding, A. Y. H. Lu, and J.-Y. Hong IDENTIFICATION OF CRITICAL AMINO ACID RESIDUES OF HUMAN CYP2A13 FOR THE METABOLIC ACTIVATION OF 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANONE, A TOBACCO-SPECIFIC CARCINOGEN Drug Metab. Dispos., December 1, 2004; 32(12): 1516 - 1521. [Abstract] [Full Text] [PDF]

				X. Zhang, M. Caggana, T. L. Cutler, and X. Ding Development of a Real-Time Polymerase Chain Reaction-Based Method for the Measurement of Relative Allelic Expression and Identification of CYP2A13 Alleles with Decreased Expression in Human Lung J. Pharmacol. Exp. Ther., October 1, 2004; 311(1): 373 - 381. [Abstract] [Full Text] [PDF]

				U. Breyer-Pfaff, H.-J. Martin, M. Ernst, and E. Maser ENANTIOSELECTIVITY OF CARBONYL REDUCTION OF 4-METHYLNITROSAMINO-1-(3-PYRIDYL)-1-BUTANONE BY TISSUE FRACTIONS FROM HUMAN AND RAT AND BY ENZYMES ISOLATED FROM HUMAN LIVER Drug Metab. Dispos., September 1, 2004; 32(9): 915 - 922. [Abstract] [Full Text] [PDF]

				B. Boland, C. Y. Lin, D. Morin, L. Miller, C. Plopper, and A. Buckpitt Site-Specific Metabolism of Naphthalene and 1-Nitronaphthalene in Dissected Airways of Rhesus Macaques J. Pharmacol. Exp. Ther., August 1, 2004; 310(2): 546 - 554. [Abstract] [Full Text] [PDF]