NNK

Nicotine-derived nitrosamine ketone (NNK)
Names
IUPAC name
4-[Methyl(nitroso)amino]-1-(3-pyridinyl)-1-butanone
Other names
N-Nitrosonornicotine ketone; 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone
Identifiers
64091-91-4 N
3D model (Jmol) Interactive image
ChEBI CHEBI:32692 N
ChEMBL ChEMBL2311069 N
ChemSpider 43038 N
ECHA InfoCard 100.164.147
KEGG C16453 N
UNII 7S395EDO61 N
Properties
C10H13N3O2
Molar mass 207.23 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

Nicotine-derived nitrosamine ketone (NNK), also known as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, is one of the key tobacco-specific nitrosamines which play an important role in carcinogenesis.[1]

Synthesis

NNK is a compound that is naturally synthesized in tobacco leaves that are exposed to light: the pyrrolidine ring in the nicotine opens and turns the nicotine into NNK. Most of the NNK found in tobacco smoke originates from nicotine burning.[2]

It can also be formed synthetically by taking the following steps:

The potent carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is present in tobacco and tobacco smoke. [Carbonyl14C]NNK (6) was synthesized in 27% overall yield. [Carboxyl-14C] nicotinic acid was esterified with benzyl alcohol and the ester was alkylated by 3-lithio-N-methylpyrrolidin-2-one. The resulting keto-lactam was hydrolyzed and decarboxylated by treatment with boiling hydrochloric acid. Nitrosation at pH 4.0 gave [carbonyl-14C]NNK. Carbonyl reduction of [carbonyl-14C]NNK with either sodium borohydride or cultured rat liver slices gave [carbinol-14C] 4-(methylnitrosamino)-1-(3-pyridyl) butan-1-ol.[3]

E-cigarettes

NNK was found in 89% of Korean e-cigarette liquids tested in concentrations from 0.22 to 9.84 µg/L.[4] If 1 ml is equivalent to 20 cigarettes,[5] and there is a 100% conversion of NNK from the liquid to the smoke, and none of the nicotine in an e-cigarette is converted to NNK due to the lower vaporization temperature,[6] then the highest level of NNK in the Korean liquids tested is about 30 times less NNK exposure than cigarettes with a small amount of NNK (0.004 µg/cigarette)[7] and 4000 times less than that of cigarettes with a large amount (1 µg/cigarette).[8]

Biology

Metabolism

NNK is initially a procarcinogen that needs activation to exert its effects. The activation of NNK is done by enzymes of the cytochrome pigment (CYP) multigene family. These enzymes catalyze hydroxylation reactions. Beside the CYP family NNK can also be activated by metabolic genes, like myeloperoxidase (MPO) and epoxide hydrolase (EPHX1). NNK can be activated by two different routes, the oxidative path and the reductive path. In the oxidative metabolism NNK undergoes an α-hydroxylation catalyzed by cytochrome P450. This reaction can be done by two pathways namely by α-methylhydoxylation or by α-methylenehydroxylation. Both pathways produce the carcinogenic metabolized isoform of NNK, NNAL.

In the reductive metabolism NNK undergoes either a carbonyl reduction or a pyridine N-oxidation, both producing NNAL.

NNAL can be detoxified by glucuronidation producing an non-carcinogenic compounds known as NNAL-Glucs. The glucuronidation can take place on the oxygen next to the ring (NNAL-O-Gluc), or it takes place on the nitrogen inside the ring(NNAL-N-Gluc). The NNAL-Glucs are then excreted by the kidneys into the urine.[9]

Signaling pathways

Once NNK is activated, NNK initiates a cascade of signaling pathways (for example ERK1/2, NFκB, PI3K/Akt, MAPK, FasL, K-ras), resulting in uncontrolled cellular proliferation and tumorigenesis.[1]

NNK activates µ en m-calpain kinase which induce lung metastasis via the ERK1/2 pathway. This pathway upregulate cellular myelocytomatosis (c-Myc) and B cell leukemia/lymphoma 2 (Bcl2) in which the two oncoprotein are involved in cellular proliferation, transformation and apoptosis. Also does NNK promotes cell survival via phosphorylation with cooperation of c-Myc and Bcl2 causing cellular migration, invasion and uncontrolled proliferation.[10]

The ERK1/2 pathway also phosphorylate NFκB causing a upregulation of cyclin D1, a G1 phase regulator protein. When NNK is present it directly involves cellular survival dependent on NFκB. Further studies are needed to better understand NNK cellular pathyways of NFκB.[11][12]

The phosphoinositide 3-kinase (PI3K/Akt) pathway is also an important contributor to NNK-induced cellular transformations and metastasis. This process ensures the proliferation and survival of tumorigenic cells.[13] The ERK1/2 and Akt pathways show consequential changes in levels of protein expression as a result of NNK-activation in the cells, but further research is needed to fully understand the mechanism of NNK-activated pathways.

Pathology

Toxicity

NNK is known as a mutagen, which means it causes polymorphisms in the human genome. Studies showed that NNK induced gene polymorphisms in cells that involve in cell growth, proliferation and differentiation. There are multiple NNK dependent routes that involve cell proliferation. One example is the cell route that coordinates the downregulation of retinoic acid receptor beta (RAR-β). Studies showed that with a 100 mg/kg dose of NNK, several point mutations were formed in the RAR-β gene, inducing tumorigenesis in the lungs.

Other genes affected by NNK include sulfotransferase 1A1 (SULT1A1), transforming growth factor beta (TGF-β), and angiotensin II (AT2).

NNK plays a very important role in gene silencing, modification, and functional disruption which induce carcinogenesis.[1]

Inhibition

Chemical compounds derived from cruciferous vegetables and EGCG inhibit lung tumorigenesis by NNK in animal models.[14] Whether these effects have any relevance to human health is unknown and is a subject of ongoing research.

See also

References

  1. 1 2 3 Akopyan, Gohar; Bonavida, Benjamin (2006). "Understanding tobacco smoke carcinogen NNK and lung tumorigenesis". International Journal of Oncology. 29 (4): 745–52. doi:10.3892/ijo.29.4.745. PMID 16964372.
  2. ↑ Adams, John D.; Lee, Suk Jong; Vinchkoski, Norma; Castonguay, Andre; Hoffmann, Dietrich (1983). "On the formation of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone during smoking". Cancer Letters. 17 (3): 339–46. doi:10.1016/0304-3835(83)90173-8. PMID 6831390.
  3. ↑ Castonguay, Andre; Hecht, Stephen S. (1985). "Synthesis of carbon-14 labeled 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone". Journal of Labelled Compounds and Radiopharmaceuticals. 22 (1): 23–8. doi:10.1002/jlcr.2580220104.
  4. ↑ Kim, Hyun-Ji; Shin, Ho-Sang (2013). "Determination of tobacco-specific nitrosamines in replacement liquids of electronic cigarettes by liquid chromatography–tandem mass spectrometry". Journal of Chromatography A. 1291: 48–55. doi:10.1016/j.chroma.2013.03.035. PMID 23602640.
  5. ↑ http://www.electroniccigaretteconsumerreviews.com/how-much-nicotine-is-in-one-cigarette/[]
  6. ↑ Farsalinos, Konstantinos; Gillman, Gene; Poulas, Konstantinos; Voudris, Vassilis (2015). "Tobacco-Specific Nitrosamines in Electronic Cigarettes: Comparison between Liquid and Aerosol Levels". International Journal of Environmental Research and Public Health. 12 (8): 9046–53. doi:10.3390/ijerph120809046. PMC 4555263Freely accessible. PMID 26264016.
  7. ↑ Kumar, R.; Siddiqi, M.; Tricker, A.R.; Preussmann, R. (1991). "Tobacco-specific N-nitrosamines in tobacco and mainstream smoke of Indian cigarettes". Food and Chemical Toxicology. 29 (6): 405–7. doi:10.1016/0278-6915(91)90081-H. PMID 1874469.
  8. ↑ Hecht, S. S.; Chen, C. B.; Ornaf, R. M.; Hoffmann, D.; Tso, T. C. (1978). "Chemical studies on tobacco smoke LVI. Tobacco specific nitrosamines: origins, carcinogenicity and metabolism". IARC Scientific Publications (19): 395–413. PMID 680735.
  9. ↑ Wiener, D.; Doerge, D. R.; Fang, J. L.; Upadhyaya, P.; Lazarus, P (2004). "Characterization of N-glucuronidation of the lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) in human liver: importance of UDP-glucuronosyltransferase 1A4". Drug Metabolism and Disposition. 32 (1): 72–9. doi:10.1124/dmd.32.1.72. PMID 14709623.
  10. ↑ Jin, Z.; Gao, F.; Flagg, T.; Deng, X. (2004). "Tobacco-specific Nitrosamine 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone Promotes Functional Cooperation of Bcl2 and c-Myc through Phosphorylation in Regulating Cell Survival and Proliferation". Journal of Biological Chemistry. 279 (38): 40209–19. doi:10.1074/jbc.M404056200. PMID 15210690.
  11. ↑ Ho, Y; Chen, C; Wang, Y; Pestell, R; Albanese, C; Chen, R; Chang, M; Jeng, J; Lin, S; Liang, Y (2005). "Tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces cell proliferation in normal human bronchial epithelial cells through NFκB activation and cyclin D1 up-regulation". Toxicology and Applied Pharmacology. 205 (2): 133–48. doi:10.1016/j.taap.2004.09.019. PMID 15893541.
  12. ↑ Tsurutani, J.; Castillo, S. S.; Brognard, J.; Granville, C. A.; Zhang, C; Gills, J. J.; Sayyah, J.; Dennis, P. A. (2005). "Tobacco components stimulate Akt-dependent proliferation and NFkappaB-dependent survival in lung cancer cells". Carcinogenesis. 26 (7): 1182–95. doi:10.1093/carcin/bgi072. PMID 15790591.
  13. ↑ West, K. A.; Linnoila, I. R.; Belinsky, S. A.; Harris, C. C.; Dennis, P. A. (2004). "Tobacco carcinogen-induced cellular transformation increases activation of the phosphatidylinositol 3'-kinase/Akt pathway in vitro and in vivo". Cancer Research. 64 (2): 446–51. doi:10.1158/0008-5472.CAN-03-3241. PMID 14744754.
  14. ↑ Chung, F.-L.; Morse, M. A.; Eklind, K. I.; Xu, Y. (1993). "Inhibition of the Tobacco-Specific Nitrosamine-Induced Lung Tumorigenesis by Compounds Derived from Cruciferous Vegetables and Green Tea". Annals of the New York Academy of Sciences. 686: 186–201; discussion 201–2. doi:10.1111/j.1749-6632.1993.tb39174.x. PMID 8512247.
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