4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a tobacco-specific nitrosamine carcinogen.¹Reactive metabolites of NNK alkylate DNA, forming pyridyloxobutyl (POB) and pyridylhydroxybutyl (PHB) adducts, and induce DNA methylation. NNK (100 mg/kg, single dose) increases the protein levels of DNA methyltransferase 1 (DNMT1) in mouse bronchial epithelial cells within one day and increases hypermethylation of the tumor suppressor genesChd13,Prdm2, andRunx3in lung tissue within three days.²It induces tumor formation preferentially in the lungviavarious routes of administration in animal models.³NNK induces adenomas and adenocarcinomas, which are present after 16 and 50 weeks, respectively, in mouse lung when administered at a single dose of 10 &#181mol/animal. Lifetime administration of NNK (63.5 mg/animal) to rats results in a 90% incidence of lung tumors.⁴

1.Carlson, E.S., Upadhyaya, P., Villalta, P.W., et al.Analysis and identification of 2’-deoxyadenosine-derived adducts in lung and lover DNA of F-344 rats treated with the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and enantiomers of its metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanolChem. Res. Toxicol.31(5)358-370(2018) 2.Jin, H., Chen, J.X., Wang, H., et al.NNK-induced DNA methyltransferase 1 in lung tumorigenesis in A/J mice and inhibitory effects of (-)-epigallocatechin-3-gallateNutr. Cancer67(1)167-176(2016) 3.Hecht, S.S.Biochemistry, biology, and carcinogenicity of tobacco-specific N-nitrosaminesChem. Res. Toxicol.11(6)559-603(1998) 4.Rivenson, A., Hoffmann, D., Prokopczyk, B., et al.Induction of lung and exocrine pancreas tumors in F344 rats by tobacco-specific and Areca-derived N-nitrosaminesCancer Res.48(23)6912-6917(1988)