chapter  5
19 Pages

Recent Studies on Mechanisms of Bioactivation and Detoxification of 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone (NNK), A Tobacco-Specific Lung Carcinogen

WithStephen S. Hecht

This chapter reviews advances in the biochemistry and molecular biology of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific pulmonary carcinogen believed to be involved in the induction of lung cancer in smokers. Several aspects of NNK bioactivation are addressed, including identification of its metabolites in laboratory animals and humans, cytochrome P450 enzyme involvement in its metabolic activation, DNA and protein adduct formation, biological significance of the major DNA adducts formed, and mutations in oncogenes from tumors induced by NNK. Collectively, the available data indicate that NNK generates a wide spectrum of DNA damage in target tissues of rats and mice. Types of damage include methylation, pyridyloxobutylation, oxidation, and strand breakage. The metabolic activation of NNK, by a-hydroxylation results in methylation and pyridyloxobutylation of DNA. There are competing partial detoxification reactions, including pyridine-N-oxidation and glucuronidation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol. In parallel with DNA adduct formation in the lung, NNK also pyridyloxobutylates hemoglobin.