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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.

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