Journal Article

Biotransformation of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in freshly isolated human lung cells

Graeme B.J. Smith, Andre Castonguay, Patty J. Donnelly, Ken R. Reid, Dimitri Petsikas and Thomas E. Massey

in Carcinogenesis

Volume 20, issue 9, pages 1809-1818
Published in print September 1999 | ISSN: 0143-3334
Published online September 1999 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/20.9.1809
Biotransformation of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in freshly isolated human lung cells

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Metabolism of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was characterized in human lung cells isolated from peripheral lung specimens obtained from 12 subjects during clinically indicated lobectomy. NNK biotransformation was assessed in preparations of isolated unseparated cells (cell digest), as well as in preparations enriched in alveolar type II cells, and alveolar macrophages. Metabolite formation was expressed as a percentage of the total recovered radioactivity from [5-3H]NNK and its metabolites per 106 cells per 24 h. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) was the major metabolite formed in all lung cell preparations examined, and its formation ranged from 0.50 to 13%/106 cells/24 h. Formation of α-carbon hydroxylation end-point metabolites (bioactivation) and pyridine N-oxidation metabolites (detoxification), ranged from non-detectable to 0.60% and from non-detectable to 1.5%/106 cells/24 h, respectively, reflecting a large degree of intercellular and inter-individual variability in NNK metabolism. Formation of the α-hydroxylation end-point metabolite 4-hydroxy-1-(3-pyridyl)-1-butanol (diol) was consistently higher in alveolar type II cells than in cell digest or alveolar macrophages (0.0146 ± 0.0152, 0.0027 ± 0.0037 and 0.0047 ± 0.0063%/106 cells/24 h, respectively; n = 12; P < 0.05). SKF-525A was used to examine cytochrome P450 contributions to the biotransformation of NNK. SKF-525A inhibited keto reduction of NNK to NNAL by 85, 86 and 74% in cell digest, type II cells, and macrophages, respectively (means of 11 subjects, P < 0.05). Type II cell incubates treated with SKF-525A formed significantly lower amounts of total α-hydroxylation metabolites compared with type II cells without SKF-525A (0.0776 ± 0.0841 versus 0.1694 ± 0.2148%/106 cells/24 h, respectively; n = 11; P < 0.05). The results of this first study examining NNK biotransformation in freshly isolated human lung cells indicate that NNK metabolism is subject to a large degree of inter-individual and intercellular variability, and suggest a role for P450s in human lung cell NNK metabolism. Both alveolar type II cells and alveolar macrophages may be potential target cells for NNK toxicity based on their α-carbon hydroxylation capabilities. In addition, carbonyl reduction of NNK to NNAL is SKF-525A sensitive in human lung cells.

Keywords: 11β-HSD, 11β-hydroxysteroid dehydrogenase; ANOVA, analysis of variance; d.p.m., disintegrations per minute; diol, 4-hydroxy-1-(3-pyridyl)-1-butanol; HPLC, high-performance liquid chromatography; LOX, lipoxygenase; NNAL, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol; NNAL-N-oxide, 4-(methylnitrosamino)-1-(3-pyridyl N-oxide)-1-butanol; NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; NNK-N-oxide, 4-(methylnitrosamino)-1-(3-pyridyl N-oxide)-1-butanone; PHS, prostaglandin H synthase.

Journal Article.  6772 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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