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| {{Others|NNK (disambiguation)}} | |||
| {{chembox | |||
| {{copyedit|date=May 2024}} | |||
| | verifiedrevid = 360754152 | |||
| {{Chembox | |||
| | Name = nicotine-derived nitrosamine ketone (NNK) | |||
| | Verifiedfields = changed | |||
| | ImageFile = NNK_chemical_structure.png | |||
| | Watchedfields = changed | |||
| | ImageName = NNK | |||
| | Name = Nicotine-derived nitrosone (NNK) | |||
| | IUPACName = 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone | |||
| | verifiedrevid = 442050794 | |||
| <!-- Images --> | |||
| | ImageFile = NNK_chemical_structure.svg | |||
| | ImageSize = | |||
| | ImageAlt = | |||
| <!-- Names --> | |||
| | PIN = Methylnitrous amide | |||
| | OtherNames = ''N''-Nitrosonornicotine ketone; 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone | |||
| <!-- Sections --> | |||
| | Section1 = {{Chembox Identifiers | |||
| | CASNo_Ref = {{cascite|changed|??}} | |||
| | CASNo = 64091-91-4 | |||
| | PubChem = 47289 | |||
| | SMILES = CN(CCCC(=O)c1cccnc1)N=O | |||
| | 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 | |||
| | InChIKey=FLAQQSHRLBFIEZ-UHFFFAOYSA-N | |||
| | ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}} | |||
| | ChemSpiderID = 43038 | |||
| | Beilstein = 3548355 | |||
| | ChEBI_Ref = {{ebicite|correct|EBI}} | |||
| | ChEBI = 32692 | |||
| | ChEMBL_Ref = {{ebicite|correct|EBI}} | |||
| | ChEMBL = 2311069 | |||
| | UNII_Ref = {{fdacite|correct|FDA}} | |||
| | UNII = 7S395EDO61 | |||
| | KEGG_Ref = {{keggcite|correct|kegg}} | |||
| | KEGG = C16453 | |||
| | UNNumber = 2811 | |||
| }} | |||
| | Section2 = {{Chembox Properties | | Section2 = {{Chembox Properties | ||
| | C=10|H=13|N=3|O=2 | |||
| | Formula = {{{formula|C<sub>10</sub>H<sub>13</sub>N<sub>3</sub>O<sub>2</sub>}}} | |||
| | Appearance = | |||
| | MolarMass = 207.23 g/mol | |||
| | Density = | |||
| | MeltingPt = | |||
| | BoilingPt = | |||
| | Solubility = | |||
| }} | |||
| | Section3 = {{Chembox Hazards | |||
| | MainHazards = | |||
| | FlashPt = | |||
| | AutoignitionPt = | |||
| | GHSPictograms = {{GHS06}}{{GHS07}}{{GHS08}} | |||
| | GHSSignalWord = Danger | |||
| | HPhrases = {{H-phrases|301|302|317|351}} | |||
| | PPhrases = {{P-phrases|201|202|261|264|270|272|280|281|301+310|301+312|302+352|308+313|321|330|333+313|363|405|501}} | |||
| }} | }} | ||
| }} | }} | ||
| '''Nicotine-derived nitrosamine ketone''' ('''NNK''') is one of the key ] derived from nicotine. It plays an important role in ].<ref name=Akopyan>{{cite journal |last1=Akopyan |first1=Gohar |last2=Bonavida |first2=Benjamin |title=Understanding tobacco smoke carcinogen NNK and lung tumorigenesis |journal=International Journal of Oncology |volume=29 |issue=4 |pages=745–52 |year=2006 |pmid=16964372 |doi=10.3892/ijo.29.4.745 |doi-access=free }}</ref> The conversion of ] to NNK entails opening of the ] ring. | |||
| '''Nicotine-derived nitrosamine ketone''' ('''NNK'''), or '''4-(methylnitrosamino)- 1-(3-pyridyl)-1-butanone''', is a ] present in ] that is a potent procarcinogen. It is activated by ]. It is a ] of exposure to cigarette smoke. It is produced upon the ] of ]. | |||
| ==Synthesis and occurrence== | |||
| == See also == | |||
| NNK can be produced by standard methods of ].<ref>{{cite journal |last1=Castonguay |first1=Andre |last2=Hecht |first2=Stephen S. |title=Synthesis of Carbon-14 Labeled 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone |journal=Journal of Labelled Compounds and Radiopharmaceuticals |volume=22|year=1985 |pages=23–8 |doi=10.1002/jlcr.2580220104 }}</ref> | |||
| ===Tobacco=== | |||
| NNK is both found in cured tobacco and is produced during its burning (pyrolysis).<ref>{{cite journal |last1=Adams |first1=John D. |last2=Lee |first2=Suk Jong |last3=Vinchkoski |first3=Norma |last4=Castonguay |first4=Andre |last5=Hoffmann |first5=Dietrich |title=On the formation of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone during smoking |journal=Cancer Letters |volume=17 |issue=3 |pages=339–46 |year=1983 |pmid=6831390 |doi=10.1016/0304-3835(83)90173-8 }}</ref> The amount of NNK delivered in cigarette smoke ranged from 30 to 280 ng/cigarette in one study<ref>{{cite journal |doi=10.1093/jnci/92.2.106 |pmid=10639511 |title=Doses of Nicotine and Lung Carcinogens Delivered to Cigarette Smokers |journal=Journal of the National Cancer Institute |volume=92 |issue=2 |pages=106–11 |year=2000 |last1=Djordjevic |first1=M. V. |last2=Stellman |first2=S. D. |last3=Zang |first3=E }}</ref> and 12 to 110 ng/cigarette in another.<ref name=pmid24821826>{{cite journal |doi=10.1161/CIRCULATIONAHA.114.007667 |pmid=24821826 |pmc=4018182 |title=E-Cigarettes: A Scientific Review |journal=Circulation |volume=129 |issue=19 |pages=1972–86 |year=2014 |last1=Grana |first1=R. |last2=Benowitz |first2=N. |last3=Glantz |first3=S. A. }}</ref> | |||
| 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<ref>{{Cite web|url=http://www.pmi.com/eng/our_products/pages/about_tobacco.aspx|title = Tobacco farming}}</ref>), especially when using an open flame, contains most of the NNK in American blended tobaccos<ref name=pmid26806560>{{cite journal |doi=10.1016/j.yrtph.2016.01.012 |pmid=26806560 |title=Tobacco-specific N-nitrosamines NNN and NNK levels in cigarette brands between 2000 and 2014 |journal=] |volume=76 |pages=113–20 |year=2016 |last1=Gunduz |first1=I. |last2=Kondylis |first2=A. |last3=Jaccard |first3=G. |last4=Renaud |first4=J.-M. |last5=Hofer |first5=R. |last6=Ruffieux |first6=L. |last7=Gadani |first7=F. |doi-access=free }}</ref> although Marlboro's "virginia blend" had the lowest levels of NNK per nicotine out of many tested with the exception of Natural American Spirit.<ref>{{cite journal |doi=10.1016/j.yrtph.2013.03.013 |pmid=23557986 |title=TSNA levels in machine-generated mainstream cigarette smoke: 35years of data |journal=Regulatory Toxicology and Pharmacology |volume=66 |issue=2 |pages=197–207 |year=2013 |last1=Appleton |first1=Scott |last2=Olegario |first2=Raquel M. |last3=Lipowicz |first3=Peter J. |doi-access=free }}</ref> | |||
| ===e-Cigarettes=== | |||
| e-Cigarette do not convert nicotine to NNK due to their lower operating temperatures.<ref>{{cite journal |last1=Farsalinos |first1=Konstantinos |last2=Gillman |first2=Gene |last3=Poulas |first3=Konstantinos |last4=Voudris |first4=Vassilis |title=Tobacco-Specific Nitrosamines in Electronic Cigarettes: Comparison between Liquid and Aerosol Levels |journal=International Journal of Environmental Research and Public Health |volume=12 |issue=8 |pages=9046–53 |year=2015 |pmid=26264016 |pmc=4555263 |doi=10.3390/ijerph120809046 |doi-access=free }}</ref> The amount of NNK delivered by e-cigarettes reaches 2.8 ng per 15 puffs (approximately 1 cigarette).<ref name=pmid24821826/> | |||
| NNK was found in 89% of Korean ]. Concentrations range from 0.22 to 9.84 μg/L.<ref>{{cite journal |last1=Kim |first1=Hyun-Ji |last2=Shin |first2=Ho-Sang |title=Determination of tobacco-specific nitrosamines in replacement liquids of electronic cigarettes by liquid chromatography–tandem mass spectrometry |journal=Journal of Chromatography A |volume=1291 |pages=48–55 |year=2013 |pmid=23602640 |doi=10.1016/j.chroma.2013.03.035 }}</ref> For the product that had the highest amount, if 1 ml is equivalent to 20 cigarettes,<ref>{{Cite web|url=http://www.electroniccigaretteconsumerreviews.com/how-much-nicotine-is-in-one-cigarette/|title = VapeMail Ban - Brands Still Shipping in 2021}}</ref> 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.<ref name=pmid26806560/> | |||
| == 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|date=April 2016}} | |||
| 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 ]. 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|date=April 2016}} | |||
| In the reductive metabolism NNK undergoes either a carbonyl reduction or a pyridine N-oxidation, both producing NNAL.{{citation needed|date=April 2016}} | |||
| NNAL can be detoxified by ] 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.<ref>{{cite journal |last1=Wiener |first1=D. |last2=Doerge |first2=D. R. |last3=Fang |first3=J. L. |last4=Upadhyaya |first4=P. |last5=Lazarus |first5=P |title=Characterization of N-glucuronidation of the lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) in human liver: importance of UDP-glucuronosyltransferase 1A4 |journal=Drug Metabolism and Disposition |volume=32 |issue=1 |pages=72–9 |year=2004 |pmid=14709623 |doi=10.1124/dmd.32.1.72 |s2cid=16712453 }}</ref> | |||
| === Signaling pathways === | |||
| Once NNK is activated, it initiates a cascade of signaling pathways (for example ], ], ], ], ], ]), resulting in uncontrolled cellular proliferation and tumorigenesis.<ref name=Akopyan/> | |||
| NNK activates μ en m-calpain kinase which induces lung metastasis via the ERK1/2 pathway. This pathway upregulates cellular myelocytomatosis (]) and B cell leukemia/lymphoma 2 (]) in which the two oncoproteins are involved in cellular proliferation, transformation and apoptosis. Also NNK promotes cell survival via phosphorylation with cooperation of c-Myc and Bcl-2 causing cellular migration, invasion and uncontrolled proliferation.<ref>{{cite journal |last1=Jin |first1=Z. |last2=Gao |first2=F. |last3=Flagg |first3=T. |last4=Deng |first4=X. |title=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=Journal of Biological Chemistry |volume=279 |issue=38 |pages=40209–19 |year=2004 |pmid=15210690 |doi=10.1074/jbc.M404056200 |doi-access=free }}</ref> | |||
| The ERK1/2 pathway also phosphorylates NF-κB causing an upregulation of ], a G1 phase regulator protein. When NNK is present it directly involves cellular survival dependent on NF-κB. Further studies are needed to better understand NNK cellular pathways of NF-κB.<ref>{{cite journal |last1=Ho |first1=Y |last2=Chen |first2=C |last3=Wang |first3=Y |last4=Pestell |first4=R |last5=Albanese |first5=C |last6=Chen |first6=R |last7=Chang |first7=M |last8=Jeng |first8=J |last9=Lin |first9=S |last10=Liang |first10=Y |title=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 |journal=Toxicology and Applied Pharmacology |volume=205 |issue=2 |pages=133–48 |year=2005 |pmid=15893541 |doi=10.1016/j.taap.2004.09.019 |bibcode=2005ToxAP.205..133H }}</ref><ref>{{cite journal |last1=Tsurutani |first1=J. |last2=Castillo |first2=S. S. |last3=Brognard |first3=J. |last4=Granville |first4=C. A. |last5=Zhang |first5=C |last6=Gills |first6=J. J. |last7=Sayyah |first7=J. |last8=Dennis |first8=P. A. |title=Tobacco components stimulate Akt-dependent proliferation and NFkappaB-dependent survival in lung cancer cells |journal=Carcinogenesis |volume=26 |issue=7 |pages=1182–95 |year=2005 |pmid=15790591 |doi=10.1093/carcin/bgi072 |doi-access=free }}</ref> | |||
| 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.<ref>{{cite journal |last1=West |first1=K. A. |last2=Linnoila |first2=I. R. |last3=Belinsky |first3=S. A. |last4=Harris |first4=C. C. |last5=Dennis |first5=P. A. |title=Tobacco carcinogen-induced cellular transformation increases activation of the phosphatidylinositol 3'-kinase/Akt pathway in vitro and in vivo |journal=Cancer Research |volume=64 |issue=2 |pages=446–51 |year=2004 |pmid=14744754 |doi=10.1158/0008-5472.CAN-03-3241 |doi-access=free }}</ref> | |||
| 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|date=April 2016}} | |||
| == Pathology == | |||
| === Toxicity === | |||
| NNK is known as a ], which means it causes ] 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 ] (RAR-β). Studies showed that with a 100 mg/kg dose of NNK, several ] were formed in the RAR-β gene, inducing ] in the lungs.{{citation needed|date=April 2016}} | |||
| Other genes affected by NNK include ] 1A1 (SULT1A1), ] (TGF-β), and ] (AT2).{{citation needed|date=April 2016}} | |||
| NNK plays a very important role in ], modification, and functional disruption which induce ].<ref name=Akopyan/> | |||
| === Inhibition === | |||
| Chemical compounds derived from ]s and ] inhibit lung ] by NNK in ]s.<ref name=pmid8512247>{{cite journal |last1=Chung |first1=F.-L. |last2=Morse |first2=M. A. |last3=Eklind |first3=K. I. |last4=Xu |first4=Y. |title=Inhibition of the Tobacco-Specific Nitrosamine-Induced Lung Tumorigenesis by Compounds Derived from Cruciferous Vegetables and Green Tea |journal=Annals of the New York Academy of Sciences |volume=686 |issue= 1|pages=186–201; discussion 201–2 |year=1993 |pmid=8512247 |doi=10.1111/j.1749-6632.1993.tb39174.x |bibcode=1993NYASA.686..186C |s2cid=43880163 }}</ref> Whether these effects have any relevance to human health is unknown and is a subject of ongoing research.{{citation needed|date=April 2016}} | |||
| == See also == | |||
| * ] | * ] | ||
| ==References== | == References == | ||
| {{Unreferenced|date =September 2007}} | |||
| {{reflist}} | {{reflist}} | ||
| ==External links== | == External links == | ||
| * | * | ||
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