361:
256:
505:
500:
86:
495:
752:
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-methylhydroxylation or by α-methylenehydroxylation. Both pathways produce the carcinogenic metabolized isoform of NNK, NNAL.
645:
29:
816:
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. The ERK1/2 and Akt pathways show consequential changes in levels of protein expression as
724:
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), especially when using an open flame, contains most of the NNK in
American blended tobaccos although
1412:
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
751:
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
838:
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
762:
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.
738:. Concentrations range from 0.22 to 9.84 μg/L. For the product that had the highest amount, if 1 ml is equivalent to 20 cigarettes, 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.
806:) 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.
1327:
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".
720:
NNK is both found in cured tobacco and is produced during its burning (pyrolysis). The amount of NNK delivered in cigarette smoke ranged from 30 to 280 ng/cigarette in one study and 12 to 110 ng/cigarette in another.
733:
e-Cigarette do not convert nicotine to NNK due to their lower operating temperatures. The amount of NNK delivered by e-cigarettes reaches 2.8 ng per 15 puffs (approximately 1 cigarette). NNK was found in 89% of Korean
513:
475:
1003:
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".
1538:
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".
1373:"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"
813:, 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.
1278:
Kim, Hyun-Ji; Shin, Ho-Sang (2013). "Determination of tobacco-specific nitrosamines in replacement liquids of electronic cigarettes by liquid chromatography–tandem mass spectrometry".
658:
1592:
400:
1499:"Tobacco carcinogen-induced cellular transformation increases activation of the phosphatidylinositol 3'-kinase/Akt pathway in vitro and in vivo"
1149:
798:
NNK activates μ en m-calpain kinase which induces lung metastasis via the ERK1/2 pathway. This pathway upregulates cellular myelocytomatosis (
735:
725:
Marlboro's "virginia blend" had the lowest levels of NNK per nicotine out of many tested with the exception of
Natural American Spirit.
817:
a result of NNK-activation in the cells, but further research is needed to fully understand the mechanism of NNK-activated pathways.
1617:
375:
65:
772:
859:
595:
976:
Castonguay, Andre; Hecht, Stephen S. (1985). "Synthesis of Carbon-14 Labeled 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone".
1039:
Djordjevic, M. V.; Stellman, S. D.; Zang, E (2000). "Doses of
Nicotine and Lung Carcinogens Delivered to Cigarette Smokers".
39:
1313:
1456:
Tsurutani, J.; Castillo, S. S.; Brognard, J.; Granville, C. A.; Zhang, C; Gills, J. J.; Sayyah, J.; Dennis, P. A. (2005).
685:
583:
665:
563:
1612:
591:
553:
308:
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In the reductive metabolism NNK undergoes either a carbonyl reduction or a pyridine N-oxidation, both producing NNAL.
579:
339:
161:
499:
1622:
1458:"Tobacco components stimulate Akt-dependent proliferation and NFkappaB-dependent survival in lung cancer cells"
890:
901:. Whether these effects have any relevance to human health is unknown and is a subject of ongoing research.
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251:
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1229:"Tobacco-Specific Nitrosamines in Electronic Cigarettes: Comparison between Liquid and Aerosol Levels"
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Gunduz, I.; Kondylis, A.; Jaccard, G.; Renaud, J.-M.; Hofer, R.; Ruffieux, L.; Gadani, F. (2016).
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1145:"Tobacco-specific N-nitrosamines NNN and NNK levels in cigarette brands between 2000 and 2014"
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Farsalinos, Konstantinos; Gillman, Gene; Poulas, Konstantinos; Voudris, Vassilis (2015).
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West, K. A.; Linnoila, I. R.; Belinsky, S. A.; Harris, C. C.; Dennis, P. A. (2004).
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Once NNK is activated, it initiates a cascade of signaling pathways (for example
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1163:
1144:
697:
384:
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
1434:
1188:"TSNA levels in machine-generated mainstream cigarette smoke: 35years of data"
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115:-Nitrosonornicotine ketone; 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone
953:
936:
776:
693:
1341:
843:(RAR-β). Studies showed that with a 100 mg/kg dose of NNK, several
809:
The ERK1/2 pathway also phosphorylates NF-κB causing an upregulation of
831:
795:), resulting in uncontrolled cellular proliferation and tumorigenesis.
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Except where otherwise noted, data are given for materials in their
537:
937:"Understanding tobacco smoke carcinogen NNK and lung tumorigenesis"
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International
Journal of Environmental Research and Public Health
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Appleton, Scott; Olegario, Raquel M.; Lipowicz, Peter J. (2013).
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873:, modification, and functional disruption which induce
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Journal of
Labelled Compounds and Radiopharmaceuticals
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derived from nicotine. It plays an important role in
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1077:Grana, R.; Benowitz, N.; Glantz, S. A. (2014).
136:
42:for grammar, style, cohesion, tone, or spelling
1371:Jin, Z.; Gao, F.; Flagg, T.; Deng, X. (2004).
1314:"VapeMail Ban - Brands Still Shipping in 2021"
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1136:
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8:
935:Akopyan, Gohar; Bonavida, Benjamin (2006).
708:NNK can be produced by standard methods of
1540:Annals of the New York Academy of Sciences
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66:Learn how and when to remove this message
1041:Journal of the National Cancer Institute
847:were formed in the RAR-β gene, inducing
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1192:Regulatory Toxicology and Pharmacology
1150:Regulatory Toxicology and Pharmacology
245:
387:Key: FLAQQSHRLBFIEZ-UHFFFAOYSA-N
212:
192:
7:
854:Other genes affected by NNK include
1415:Toxicology and Applied Pharmacology
1079:"E-Cigarettes: A Scientific Review"
869:NNK plays a very important role in
678:Nicotine-derived nitrosamine ketone
287:
271:
1560:10.1111/j.1749-6632.1993.tb39174.x
802:) and B cell leukemia/lymphoma 2 (
14:
1095:10.1161/CIRCULATIONAHA.114.007667
941:International Journal of Oncology
79:Nicotine-derived nitrosone (NNK)
1546:(1): 186–201, discussion 201–2.
885:Chemical compounds derived from
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84:
27:
1377:Journal of Biological Chemistry
1330:Drug Metabolism and Disposition
860:transforming growth factor beta
639:(at 25 °C , 100 kPa).
696:to NNK entails opening of the
447:
429:
1:
1516:10.1158/0008-5472.CAN-03-3241
686:tobacco-specific nitrosamines
1292:10.1016/j.chroma.2013.03.035
1018:10.1016/0304-3835(83)90173-8
1280:Journal of Chromatography A
1205:10.1016/j.yrtph.2013.03.013
1164:10.1016/j.yrtph.2016.01.012
841:retinoic acid receptor beta
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1435:10.1016/j.taap.2004.09.019
758:NNAL can be detoxified by
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1618:IARC Group 1 carcinogens
834:, which means it causes
704:Synthesis and occurrence
554:Precautionary statements
1246:10.3390/ijerph120809046
990:10.1002/jlcr.2580220104
408:CN(CCCC(=O)c1cccnc1)N=O
1390:10.1074/jbc.M404056200
887:cruciferous vegetables
1475:10.1093/carcin/bgi072
1053:10.1093/jnci/92.2.106
954:10.3892/ijo.29.4.745
692:. The conversion of
684:) is one of the key
99:Preferred IUPAC name
18:NNK (disambiguation)
16:For other uses, see
1613:3-Pyridyl compounds
1552:1993NYASA.686..186C
1427:2005ToxAP.205..133H
1342:10.1124/dmd.32.1.72
736:e-cigarette liquids
465: g·mol
174:Beilstein Reference
103:Methylnitrous amide
80:
830:NNK is known as a
767:Signaling pathways
666:Infobox references
78:
46:You can assist by
1127:"Tobacco farming"
710:organic synthesis
674:Chemical compound
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528:Hazard statements
340:CompTox Dashboard
162:Interactive image
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1608:Nitrosamines
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911:Toxification
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729:e-Cigarettes
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121:Identifiers
112:
110:Other names
62:
53:
40:copy editing
38:may require
37:
1336:(1): 72–9.
1083:Circulation
698:pyrrolidine
514:Signal word
417:Properties
252:100.164.147
194:CHEBI:32692
1602:Categories
1157:: 113–20.
917:References
897:by NNK in
881:Inhibition
747:Metabolism
488:Pictograms
458:Molar mass
318:7S395EDO61
225:ChemSpider
149:3D model (
138:64091-91-4
128:CAS Number
48:editing it
1286:: 48–55.
821:Pathology
811:cyclin D1
616:P333+P313
604:P308+P313
600:P302+P352
596:P301+P312
592:P301+P310
479:labelling
329:UN number
1576:43880163
1525:14744754
1484:15790591
1443:15893541
1399:15210690
1358:16712453
1350:14709623
1300:23602640
1265:26264016
1214:23557986
1173:26806560
1113:24821826
1061:10639511
984:: 23–8.
963:16964372
905:See also
826:Toxicity
781:PI3K/Akt
694:nicotine
470:Hazards
179:3548355
56:May 2024
1568:8512247
1548:Bibcode
1423:Bibcode
1256:4555263
1104:4018182
1026:6831390
866:(AT2).
832:mutagen
742:Biology
716:Tobacco
659:what is
657: (
463:207.233
285:PubChem
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401:SMILES
273:C16453
205:ChEMBL
93:Names
1572:S2CID
1354:S2CID
804:Bcl-2
800:c-Myc
793:K-Ras
777:NF-κB
376:InChI
333:2811
298:47289
234:43038
185:ChEBI
151:JSmol
1593:MSDS
1564:PMID
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1296:PMID
1284:1291
1261:PMID
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1169:PMID
1109:PMID
1057:PMID
1022:PMID
959:PMID
891:EGCG
889:and
789:FasL
785:MAPK
628:P501
624:P405
620:P363
612:P330
608:P321
588:P281
584:P280
580:P272
576:P270
572:P264
568:P261
564:P202
560:P201
546:H351
542:H317
538:H302
534:H301
309:UNII
264:KEGG
1556:doi
1544:686
1511:doi
1470:doi
1431:doi
1419:205
1385:doi
1381:279
1338:doi
1288:doi
1251:PMC
1241:doi
1200:doi
1159:doi
1099:PMC
1091:doi
1087:129
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682:NNK
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