It has been proposed that the tobacco-specific N-nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) may be involved in the causation of human lung cancer (Hecht and Hoffmann, 1988), but direct evidence for the involvement of NNK in human lung cancer is lacking (Hecht and Tricker, 1999). In the A/J mouse lung tumor model, a single intraperitoneal (i.p.) injection of 10 μmole [2.07 mg] NNK/mouse results in 7–12 lung tumors per mouse after 16 weeks (Hecht et al., 1989). The initial events in NNK-induced A/J mouse lung tumorigenesis are believed to be metabolism of NNK to biological reactive intermediates (BRI) with the potential to react (via methylation of DNA) to produce O6-methylguanine (O6MeG), GC→AT transitional mispairing, and subsequent activation of the K-ras proto-oncogene (Ronai et al., 1993). α-Hydroxylation of the methylene carbon atoms adjacent to the N-nitroso group in NNK and NNAL yields unstable BM which spontaneously decompose to methanediazohydroxide with the potential to react with DNA to produce 7-methylguanine (7-MeG), O4-methylthymidine (O4MeT) and O6MeG adducts. α-Hydroxylation of the NNK methyl group yields a BM with the potential to pyridyloxobutylate DNA, while α-methyl hydroxylation of NNAL is not known to result in DNA adduct formation. Other metabolic transformations represent detoxification pathways for NNK and NNAL.
- Environmental Tobacco Smoke
- Human Lung Cancer
- Mouse Lung
- Cigarette Smoke Exposure
- Lung Tumorigenesis
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Brown, B.G., Chang, C.-J.G., Ayres, P.H., Lee, C.K. and Doolittle, D.J., 1999, The effect of cotinine or cigarette smoke co-administration on the formation of O6-methylguanine adducts in the lung and liver of A/J mice treated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Toxicol. Sci 47:33.
Finch, G.L., Nikula, K.J., Belinsky, S.A., Barr, E.B., Stoner, G.D. and Lechner, J.F., 1996, Failure of cigarette smoke to induce or promote lung cancer in the A/J mouse. Cancer Lett 99:161.
Guerin, M.R., Jenkins, R.A. and Tomkins, B.A., 1992 The Chemistry of Environmental Tobacco Smoke: Composition and Measurement Lewis, Boca Raton, FL.
Hecht, S.S., and Hoffmann, D., 1988, Tobacco-specific nitrosamines, an important group of carcinogens in tobacco and tobacco smoke. Carcinogenesis 9:875.
Hecht, S.S. and Tricker, A.R., 1999, Nitrosamines derived from nicotine and other tobacco alkaloids. In Gorrod, J.W. and Jacob, III, P. (eds.) Analytical Determination of Nicotine and Related Compounds and their Metabolites Elsevier, Amsterdam, pp. 421–488.
Hecht, S.S., Morse, M.A., Amin, S., Stoner, G.D., Jordan, K.G., Choi, C.I. and Chung, F.-L., 1989, Rapid single-dose model for lung tumor induction in A/J mice by 4-(methylnitrosamino)-1-(3-pyridyl)-1butanone and the effect of diet. Carcinogenesis 10:1901.
Richter, E. and Tricker, A.R., 1994, Nicotine inhibits the metabolic activation of the tobacco-specific nitrosamine 4-(methylnitrosamino)-I-(3-pyridyl)-1-butanone in rats. Carcinogenesis 15:1061.
Richter, E., Friesenegger, S., Engl, J. and Tricker, A.R., 2000, Use of precision-cut tissue slices in organ culture to study metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and 4(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) by hamster lung, liver and kidney. Toxicology 114:83.
Ronai, Z.A., Gradia, S., Peterson, L.A. and Hecht, S.S., 1993, G to A transitions and G-T transversions in codon 12 of the Ki-ras oncogene isolated from mouse lung tumors induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and related DNA methylating and pyridyloxobutylating agents. Carcinogenesis 14:2419.
Witschi, H.P., Oreffo, V.I.C. and Pinkerton, K.E., 1995, Six-month exposure of strain A/J mice to cigarette sidestream smoke: Cell kinetics and lung tumor data. Fundam. Appl. Toxicol 26:32.
Witschi, H., Espiritu, I., Peake, J.L., Wu, K., Maronpot, R.R. and Pinkerton, K.E., 1997a, The carcino-genicity of environmental tobacco smoke. Carcinogenesis 18:575.
Witschi, H., Espiritu, I., Maronpot, R.R., Pinkerton, K.E. and Jones, A.D., 1997b, The carcinogenic potential of the gas phase of environmental tobacco smoke. Carcinogenesis 18:2035.
Witschi, H., Uyeminami, D., Moran, D., and Espiritu, I., 2000, Chemoprevention of tobacco-smoke lung carcinogenesis in mice after cessation of smoke exposure. Carcinogenesis 21:977.
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Tricker, A.R., Brown, B.G., Doolittle, D.J., Richter, E. (2001). Metabolism of 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone (Nnk) in A/J Mouse Lung And Effect of Cigarette Smoke Exposure on in Vivo Metabolism to Biological Reactive Intermediates. In: Dansette, P.M., et al. Biological Reactive Intermediates VI. Advances in Experimental Medicine and Biology, vol 500. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-0667-6_67
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