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 Smith, G. B. J. Articles by Massey, T. E. Search for Related Content PubMed PubMed Citation Articles by Smith, G. B. J. Articles by Massey, T. E.

BIOTRANSFORMATION OF 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANONE (NNK) IN PERIPHERAL HUMAN LUNG MICROSOMES

Departments of Pharmacology and Toxicology (G.B.J.S., L.L.B., T.E.M.), Surgery (K.R.R., D.P.), and Medicine (T.E.M.), and School of Environmental Studies (T.E.M.), Queen's University, Kingston, Ontario, Canada; and Department of Pharmacology and Toxicology (J.R.B.), University of Western Ontario, London, Ontario, Canada

The contributions of different enzymes to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) biotransformation were assessed in human lung microsomes prepared from peripheral lung specimens obtained from seven subjects. Metabolite formation was expressed as a percentage of total recovered radioactivity from [5-³H]NNK and its metabolites per milligram of protein per minute. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol was the major metabolite formed in the presence of an NADPH-generating system, with production ranging from 0.5186 to 1.268%/mg of protein/min, and total NNK bioactivation (represented by the sum of the four -carbon hydroxylation endpoint metabolites) ranged from 0.002100 to 0.005685% -hydroxylation/mg of protein/min. Overall, production of bioactivation metabolites was greater than that of detoxication (i.e., N-oxidation) products. Based on total bioactivation, subjects could be classified as high or low NNK bioactivators. In the presence of an NADPH-generating system, microsomal formation of the endpoint metabolite 1-(3-pyridyl)-1-butanone-4-carboxylic acid (keto acid) was consistently higher than that of all other -carbon hydroxylation endpoint metabolites. Contributions of cytochrome P450 (P450) enzymes to NNK oxidation were demonstrated by NADPH dependence, inhibition by carbon monoxide, and inhibition by the nonselective P450 inhibitors proadifen hydrochloride (SKF-525A) and 1-aminobenzotriazole (ABT), particularly in lung microsomes from high bioactivators. At 5.0 mM, ABT inhibited total NNK bioactivation by 54 to 100%, demonstrating the importance of ABT-sensitive enzyme(s) in human pulmonary NNK bioactivation. Contributions of CYP2A6 and/or CYP2A13, as well as CYP2B6, to NNK bioactivation were also suggested by selective chemical and antibody inhibition in lung microsomes from some subjects. It is likely that multiple P450 enzymes contribute to human pulmonary microsomal NNK bioactivation, and that these contributions vary between individuals.

This article has been cited by other articles:

				X. Zhang, J. D'Agostino, H. Wu, Q.-Y. Zhang, L. von Weymarn, S. E. Murphy, and X. Ding CYP2A13: Variable Expression and Role in Human Lung Microsomal Metabolic Activation of the Tobacco-Specific Carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone J. Pharmacol. Exp. Ther., November 1, 2007; 323(2): 570 - 578. [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]

				A. M. Lee and R. F. Tyndale Drugs and genotypes: how pharmacogenetic information could improve smoking cessation treatment. J Psychopharmacol, July 1, 2006; 20(4 Suppl): 7 - 14. [Abstract] [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]