4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, or NNK, is one of volatile N-nitrosamines that are found in tobacco smoke[1]. N-nitrosamines are able to induce cancer in large number of rather different species and tissues, and humans are no exclusion from the number of species susceptible to carcinogenic impact of N-nitrosamines[2].
NNK content in smoke of a single cigarette is about 201-1440 ng in side smoke and 0, 2 – 29, 3 ng in second-hand smoke[3]. According to S Hecht[4] and Hoffmann[5], content of NNK in side smoke is among the highest, and in secondhand smoke NNK is contained in medium doses comparing with concentrations of other chemicals. NNK contains in its structure a heterocyclic aromatic ring linked to the 1-st carbon atom of 1-butanone[6].
Thus electron atmospheres of pyridine ring and olefinic link of cetonic group can interact easily forming shared electron atmosphere. Methylnitrosamine group linked to 4-th carbon atom also has shared electron cloud of nitrogen and oxygen atoms that compose this functional group. This existence of shared electrons and common electron clouds renders NNK with good reactive capacity and with ability to bind to proteins and DNA.[7]NNK, as many other N-nitrosamines, is tobacco-specific substance. Therefore, metabolites of NNK are specific biomarkers of exposure to tobacco smoke or other nicotine-containing products[8].
Main metabolites that are used as biomarkers of NNK are 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and conjugate of NNAL with glucuronic acid (NNAL-Gluc)[9]. As shown in studies of Hecht SS[10], NNK is responsible for carcinogenesis in all three commonly used rodent models – rats, mice and hamster. Exposure to NNK resulted in formations of lung tumors in all model species[11]. b.
How does NNK work, any in vivo and vitro experiment have doneNNK, as many carcinogens that are contained in tobacco, are not influencing cells and cellular structures directly, but rather need to enter metabolic pathways of an organism and undergo metabolic activation[12]. Upon activation, NNK metabolites covalently bind nucleotides of DNA and amino acids of cellular proteins. Covalent binding of NNK metabolites with DNA results in formation of DNA adducts, which, if not repaired by the cellular reparation system, result in mutations[13] that can possibly trigger process of tumor formation, especially if mutation occurred in tumor suppressing gene or in oncogene sequence[14]. Covalent binding of NNK metabolites with proteins inactivates these proteins and decreases or ceases their specific functions[15]c. What is the cytotoxicity data reported before? Especially using lung epithelial cell line BEAS-2B and lung cancer cell line A549d.
How does NNK cause cancer? Especially lung cancere. How about the P53 gene or protein alteration after NNK exposure in vivo and vitro study. Bibliography1. Hecht SS, ‘ Biochemistry, biology, and carcinogenicity of tobacco-specific N-nitrosamines’, Chemical Resources of Toxicology, vol.. 11, 1998, pp. 559–603. 2.
Hecht, S, ‘ Carcinogen derived biomarkers: applications in studies of human exposure to secondhand tobacco smoke’, Tobacco Control, Vol. 13 Suppl. 1, 2004, pp. i48-i56.
3. Hecht SS, ‘ Tobacco smoke carcinogens and lung cancer’, Journal of the National Cancer Institute, vol. 91, no. 14, 1999, pp. 1194-210.
4. Hoffmann D, Hoffmann I, El Bayoumy K, ‘ The less harmful cigarette: a controversial issue. A tribute to Ernst L. Wynder’, Chemical Resources of Toxicology, vol. 14, 2001, pp. 767–90.[1] S Hecht, ‘ Carcinogen derived biomarkers: applications in studies of human exposure to secondhand tobacco smoke’, Tobacco Control, Vol. 13 Suppl.
1, 2004, p. i48-49[2] ibid.[3] ibid.
, p. i50[4] ibid[5] D Hoffmann, I Hoffmann & K El Bayoumy, ‘ The less harmful cigarette: a controversial issue. A tribute to Ernst L. Wynder’, Chemical Resources of Toxicology, vol. 14, 2001, pp. 767-790[6] Hecht, p. i49[7] ibid, p.
i50[8] ibid, p. i53[9] ibid.[10] S Hecht, ‘ Biochemistry, biology, and carcinogenicity of tobacco-specific N-nitrosamines’, Chemical Resources of Toxicology, vol..
11, 1998, pp. 559–603.[11] ibid.[12] S Hecht, ‘ Tobacco smoke carcinogens and lung cancer’, Journal of the National Cancer Institute, vol. 91, no. 14, 1999, p. 1194.
[13] ibid.[14] S Hecht, ‘ Carcinogen derived biomarkers ‘, p. 50[15] ibid, p. i53.