NNK

Last updated
Nicotine-derived nitrosone (NNK)
NNK chemical structure.svg
Names
Preferred IUPAC name
Methyl[4-oxo-4-(pyridin-3-yl)butyl]nitrous amide
Other names
N-Nitrosonornicotine ketone; 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone
Identifiers
3D model (JSmol)
3548355
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.164.147 OOjs UI icon edit-ltr-progressive.svg
KEGG
PubChem CID
UNII
UN number 2811
  • InChI=1S/C10H13N3O2/c1-13(12-15)7-3-5-10(14)9-4-2-6-11-8-9/h2,4,6,8H,3,5,7H2,1H3
    Key: FLAQQSHRLBFIEZ-UHFFFAOYSA-N
  • CN(CCCC(=O)c1cccnc1)N=O
Properties
C10H13N3O2
Molar mass 207.233 g·mol−1
Hazards
GHS labelling:
GHS-pictogram-skull.svg GHS-pictogram-exclam.svg GHS-pictogram-silhouette.svg
Danger
H301, H302, H317, H351
P201, P202, P261, P264, P270, P272, P280, P281, P301+P310, P301+P312, P302+P352, P308+P313, P321, P330, P333+P313, P363, P405, P501
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Nicotine-derived nitrosamine ketone (NNK) is one of the key tobacco-specific nitrosamines derived from nicotine. It plays an important role in carcinogenesis. [1] The conversion of nicotine to NNK entails opening of the pyrrolidine ring.

Contents

Synthesis and occurrence

NNK can be produced by standard methods of organic synthesis. [2]

Tobacco

NNK is both found in cured tobacco and is produced during its burning (pyrolysis). [3] The amount of NNK delivered in cigarette smoke ranged from 30 to 280 ng/cigarette in one study [4] and 12 to 110 ng/cigarette in another. [5]

Sun-cured tobaccos (a.k.a. "Oriental") contain very little NNK and other TSNAs due to low-nitrate soil, lack of nitrate fertilizer, and sun-curing. Flue-cured tobacco (a.k.a. "Virginia" tobacco [6] ), especially when using an open flame, contains most of the NNK in American blended tobaccos [7] although Marlboro's "virginia blend" had the lowest levels of NNK per nicotine out of many tested with the exception of Natural American Spirit. [8]

e-Cigarettes

e-Cigarette do not convert nicotine to NNK due to their lower operating temperatures. [9] The amount of NNK delivered by e-cigarettes reaches 2.8 ng per 15 puffs (approximately 1 cigarette). [5] NNK was found in 89% of Korean e-cigarette liquids. Concentrations range from 0.22 to 9.84 µg/L. [10] For the product that had the highest amount, if 1 ml is equival to 20 cigarettes, [11] there would be 9.84/20 = 0.5 ng NNK per e-cig cigarette dose. Cigarettes with 1 gram of tobacco average about 350 ng. [7]

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).[ citation needed ] 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-methylhydroxylation or by α-methylenehydroxylation. Both pathways produce the carcinogenic metabolized isoform of NNK, NNAL.[ citation needed ]

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

NNAL can be detoxified by glucuronidation producing a 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. [12]

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. [13]

The ERK1/2 pathway also phosphorylate NFκB causing an 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 pathways of NFκB. [14] [15]

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. [16] 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.[ citation needed ]

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.[ citation needed ]

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

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. [17] Whether these effects have any relevance to human health is unknown and is a subject of ongoing research.[ citation needed ]

See also

Related Research Articles

<span class="mw-page-title-main">Carcinogen</span> Substance, radionuclide, or radiation directly involved in causing cancer

A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis. This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive substances are considered carcinogens, but their carcinogenic activity is attributed to the radiation, for example gamma rays and alpha particles, which they emit. Common examples of non-radioactive carcinogens are inhaled asbestos, certain dioxins, and tobacco smoke. Although the public generally associates carcinogenicity with synthetic chemicals, it is equally likely to arise from both natural and synthetic substances. Carcinogens are not necessarily immediately toxic; thus, their effect can be insidious.

<span class="mw-page-title-main">Nicotine</span> Mild chemical stimulant naturally found in some plants

Nicotine is a naturally produced alkaloid in the nightshade family of plants and is widely used recreationally as a stimulant and anxiolytic. As a pharmaceutical drug, it is used for smoking cessation to relieve withdrawal symptoms. Nicotine acts as a receptor agonist at most nicotinic acetylcholine receptors (nAChRs), except at two nicotinic receptor subunits where it acts as a receptor antagonist.

<span class="mw-page-title-main">Nitrosamine</span> Organic compounds of the form >N–N=O

In organic chemistry, nitrosamines are organic compounds with the chemical structure R2N−N=O, where R is usually an alkyl group. They feature a nitroso group bonded to a deprotonated amine. Most nitrosamines are carcinogenic in nonhuman animals. A 2006 systematic review supports a "positive association between nitrite and nitrosamine intake and gastric cancer, between meat and processed meat intake and gastric cancer and oesophageal cancer, and between preserved fish, vegetable and smoked food intake and gastric cancer, but is not conclusive".

Toxication, toxification or toxicity exaltation is the conversion of a chemical compound into a more toxic form in living organisms or in substrates such as soil or water. The conversion can be caused by enzymatic metabolism in the organisms, as well as by abiotic chemical reactions. While the parent drug are usually less active, both the parent drug and its metabolite can be chemically active and cause toxicity, leading to mutagenesis, teratogenesis, and carcinogenesis. Different classes of enzymes, such as P450-monooxygenases, epoxide hydrolase, or acetyltransferases can catalyze the process in the cell, mostly in the liver.

Tar is the name for the resinous, combusted particulate matter made by the burning of tobacco and other plant material in the act of smoking. Tar is toxic and damages the smoker's lungs over time through various biochemical and mechanical processes. Tar also damages the mouth by rotting and blackening teeth, damaging gums, and desensitizing taste buds. Tar includes the majority of mutagenic and carcinogenic agents in tobacco smoke. Polycyclic aromatic hydrocarbons (PAH), for example, are genotoxic and epoxidative.

<span class="mw-page-title-main">Smokeless tobacco</span> Tobacco product used by means other than smoking.

Smokeless tobacco is a tobacco product that is used by means other than smoking. Their use involves chewing, sniffing, or placing the product between gum and the cheek or lip. Smokeless tobacco products are produced in various forms, such as chewing tobacco, snuff, snus, and dissolvable tobacco products. Smokeless tobacco products typically contain over 3000 constituents. All smokeless tobacco products contain nicotine and are therefore highly addictive. Quitting smokeless tobacco use is as challenging as smoking cessation.

The MAPK/ERK pathway is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell.

In molecular biology, extracellular signal-regulated kinases (ERKs) or classical MAP kinases are widely expressed protein kinase intracellular signalling molecules that are involved in functions including the regulation of meiosis, mitosis, and postmitotic functions in differentiated cells. Many different stimuli, including growth factors, cytokines, virus infection, ligands for heterotrimeric G protein-coupled receptors, transforming agents, and carcinogens, activate the ERK pathway.

<span class="mw-page-title-main">DNA adduct</span> Segment of DNA bound to a cancer-causing chemical

In molecular genetics, a DNA adduct is a segment of DNA bound to a cancer-causing chemical. This process could lead to the development of cancerous cells, or carcinogenesis. DNA adducts in scientific experiments are used as biomarkers of exposure. They are especially useful in quantifying an organism's exposure to a carcinogen. The presence of such an adduct indicates prior exposure to a potential carcinogen, but it does not necessarily indicate the presence of cancer in the subject animal.

The PHLPP isoforms are a pair of protein phosphatases, PHLPP1 and PHLPP2, that are important regulators of Akt serine-threonine kinases and conventional/novel protein kinase C (PKC) isoforms. PHLPP may act as a tumor suppressor in several types of cancer due to its ability to block growth factor-induced signaling in cancer cells.

Third-hand smoke is contamination by tobacco smoke that lingers following the extinguishing of a cigarette, cigar, or other combustible tobacco product. First-hand smoke refers to what is inhaled into the smoker's own lungs, while second-hand smoke is a mixture of exhaled smoke and other substances leaving the smoldering end of the cigarette that enters the atmosphere and can be inhaled by others. Third-hand smoke or "THS" is a neologism coined by a research team from the Dana–Farber/Harvard Cancer Center, where "third-hand" is a reference to the smoking residue on surfaces after "second-hand smoke" has cleared out.

<span class="mw-page-title-main">MAPK1</span> Protein-coding gene in the species Homo sapiens

Mitogen-activated protein kinase 1, (MAPK 1), also known as ERK2, is an enzyme that in humans is encoded by the MAPK1 gene.

<span class="mw-page-title-main">MAPK7</span> Protein-coding gene in the species Homo sapiens

Mitogen-activated protein kinase 7 also known as MAP kinase 7 is an enzyme that in humans is encoded by the MAPK7 gene.

<span class="mw-page-title-main">MAP3K3</span> Protein-coding gene in the species Homo sapiens

Mitogen-activated protein kinase kinase kinase 3 is an enzyme that in humans is encoded by the MAP3K3 gene, which is located on the long arm of chromosome 17 (17q23.3).

<span class="mw-page-title-main">CYP2A13</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450 2A13 is a protein that in humans is encoded by the CYP2A13 gene.

Tobacco-specific nitrosamines (TSNAs) comprise one of the most important groups of carcinogens in tobacco products, particularly cigarettes and fermented dipping snuff.

Dissolvable tobacco is a tobacco product that, unlike ordinary chewing tobacco, dissolves in the mouth. Major tobacco manufacturers that sell dissolvable tobacco products include R. J. Reynolds Tobacco Company and Star Scientific. The move of the major players into the smokeless tobacco market is attributed to smoke-free laws in the United States. Research into health effects of this and other new tobacco products was among the reasons of the establishment of the Tobacco Products Scientific Advisory Committee of the Food and Drug Administration in 2009.

<span class="mw-page-title-main">PI3K/AKT/mTOR pathway</span> Cell cycle regulation pathway

The PI3K/AKT/mTOR pathway is an intracellular signaling pathway important in regulating the cell cycle. Therefore, it is directly related to cellular quiescence, proliferation, cancer, and longevity. PI3K activation phosphorylates and activates AKT, localizing it in the plasma membrane. AKT can have a number of downstream effects such as activating CREB, inhibiting p27, localizing FOXO in the cytoplasm, activating PtdIns-3ps, and activating mTOR which can affect transcription of p70 or 4EBP1. There are many known factors that enhance the PI3K/AKT pathway including EGF, shh, IGF-1, insulin, and CaM. Both leptin and insulin recruit PI3K signalling for metabolic regulation. The pathway is antagonized by various factors including PTEN, GSK3B, and HB9.

The use of electronic cigarettes (vaping) carries health risks. The risk depends on the fluid and varies according to design and user behavior. In the United Kingdom, vaping is considered by some to be around 95% less harmful than tobacco after a controversial landmark review by Public Health England.

<span class="mw-page-title-main">Smoker's macrophages</span>

Smoker’s macrophages are alveolar macrophages whose characteristics, including appearance, cellularity, phenotypes, immune response, and other functions, have been affected upon the exposure to cigarettes. These altered immune cells are derived from several signaling pathways and are able to induce numerous respiratory diseases. They are involved in asthma, chronic obstructive pulmonary diseases (COPD), pulmonary fibrosis, and lung cancer. Smoker’s macrophages are observed in both firsthand and secondhand smokers, so anyone exposed to cigarette contents, or cigarette smoke extract (CSE), would be susceptible to these macrophages, thus in turns leading to future complications.

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. ↑ 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: 23–8. doi:10.1002/jlcr.2580220104.
  3. ↑ 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.
  4. ↑ Djordjevic, M. V.; Stellman, S. D.; Zang, E (2000). "Doses of Nicotine and Lung Carcinogens Delivered to Cigarette Smokers". Journal of the National Cancer Institute. 92 (2): 106–11. doi:10.1093/jnci/92.2.106. PMID   10639511.
  5. 1 2 Grana, R.; Benowitz, N.; Glantz, S. A. (2014). "E-Cigarettes: A Scientific Review". Circulation. 129 (19): 1972–86. doi:10.1161/CIRCULATIONAHA.114.007667. PMC   4018182 . PMID   24821826.
  6. ↑ "Tobacco farming".
  7. 1 2 Gunduz, I.; Kondylis, A.; Jaccard, G.; Renaud, J.-M.; Hofer, R.; Ruffieux, L.; Gadani, F. (2016). "Tobacco-specific N-nitrosamines NNN and NNK levels in cigarette brands between 2000 and 2014". Regulatory Toxicology and Pharmacology . 76: 113–20. doi: 10.1016/j.yrtph.2016.01.012 . PMID   26806560.
  8. ↑ Appleton, Scott; Olegario, Raquel M.; Lipowicz, Peter J. (2013). "TSNA levels in machine-generated mainstream cigarette smoke: 35years of data". Regulatory Toxicology and Pharmacology. 66 (2): 197–207. doi: 10.1016/j.yrtph.2013.03.013 . PMID   23557986.
  9. ↑ 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   4555263 . PMID   26264016.
  10. ↑ 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.
  11. ↑ "VapeMail Ban - Brands Still Shipping in 2021".
  12. ↑ 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. S2CID   16712453.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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 (1): 186–201, discussion 201–2. Bibcode:1993NYASA.686..186C. doi:10.1111/j.1749-6632.1993.tb39174.x. PMID   8512247. S2CID   43880163.
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