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{{DISPLAYTITLE:''N''-Nitrosonornicotine}} {{DISPLAYTITLE:''N''-Nitrosonornicotine}}
{{chembox {{chembox
| Watchedfields = changed
| verifiedrevid = 433365528 | verifiedrevid = 442050809
| Name = ''N''-Nitrosonornicotine | Name = ''N''-Nitrosonornicotine
| ImageFile = N-nitrosonornicotine-2D-skeletal.svg | ImageFile = N-nitrosonornicotine-2D-skeletal.svg
⚫ | PIN = 3-pyridine
| ImageSize = 200px
⚫ | IUPACName = 3-(1-Nitrosopyrrolidin-2-yl)pyridine
| OtherNames = | OtherNames =
| Section1 = {{Chembox Identifiers |Section1={{Chembox Identifiers
| Abbreviations = NNN | Abbreviations = NNN
| InChI = 1/C9H11N3O/c13-11-12-6-2-4-9(12)8-3-1-5-10-7-8/h1,3,5,7,9H,2,4,6H2/t9-/m0/s1 | InChI = 1/C9H11N3O/c13-11-12-6-2-4-9(12)8-3-1-5-10-7-8/h1,3,5,7,9H,2,4,6H2/t9-/m0/s1
Line 15: Line 15:
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = XKABJYQDMJTNGQ-VIFPVBQESA-N | StdInChIKey = XKABJYQDMJTNGQ-VIFPVBQESA-N
| CASNo_Ref = {{cascite|correct|??}}
| CASNo = 16543-55-8 | CASNo = 16543-55-8
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = X656TZ86DX
| PubChem = 27919 | PubChem = 27919
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
Line 23: Line 26:
| SMILES = O=NN2CCC2c1cnccc1 | SMILES = O=NN2CCC2c1cnccc1
}} }}
| Section2 = {{Chembox Properties |Section2={{Chembox Properties
| C=9 | H=11 | N=3 | O=1
| Formula = C<sub>9</sub>H<sub>11</sub>N<sub>3</sub>O
⚫ | Appearance = Oily yellow liquid
| MolarMass = 177.203 g/mol
⚫ | Appearance = oily yellow liquid
| Density = | Density =
| MeltingPtC = 47 | MeltingPtC = 47
| BoilingPtC = 154 | BoilingPtC = 154
| Solubility = soluble | Solubility = Soluble
}} }}
| Section3 = {{Chembox Hazards |Section3={{Chembox Hazards
| MainHazards = | MainHazards =
| FlashPt = 177 °C | FlashPtC = 177
| Autoignition = }} | AutoignitionPtC = }}
}} }}
'''''N''-Nitrosonornicotine''' ('''NNN''') is a ] produced during the curing and processing of ].


]
'''''N''-Nitrosonornicotine''' ('''NNN''') is a ] found in ] that has been classified by the ] as a ].<ref></ref>


==Toxicity==
Although no adequate studies of the relationship between exposure to NNN and human ] have been reported, there is sufficient evidence that NNN causes cancer in experimental animals.
It has been classified as a ].<ref>{{ cite web | url = http://monographs.iarc.fr/ENG/Classification/ClassificationsGroupOrder.pdf | title = Agents Classified by the IARC Monographs, Volumes 1–105 | publisher = IARC }}</ref> Although no adequate studies of the relationship between exposure to NNN and human ] have been reported, there is sufficient evidence that NNN causes cancer in experimental animals.<ref>{{cite journal |last1=Balbo |first1=Silvia |last2=James-Yi |first2=Sandra |last3=Johnson |first3=Charles S. |last4=O’Sullivan |first4=Michael G. |last5=Stepanov |first5=Irina |last6=Wang |first6=Mingyao |last7=Bandyopadhyay |first7=Dipankar |last8=Kassie |first8=Fekadu |last9=Carmella |first9=Steven |last10=Upadhyaya |first10=Pramod |last11=Hecht |first11=Stephen S. |title=(S)-N′-Nitrosonornicotine, a constituent of smokeless tobacco, is a powerful oral cavity carcinogen in rats |journal=Carcinogenesis |date=2013 |volume=34 |issue=9 |pages=2178–2183 |doi=10.1093/carcin/bgt162 |pmid=23671129 |pmc=3765046 }}</ref>


==Sources==
NNN is found in a variety of tobacco products including ], ], ]s, and ]s. It is present in smoke from cigars and cigarettes, in the ] of people who chew ] with tobacco, and in the saliva of oral-snuff users. NNN is produced by the ] of nicotine during the curing, ageing, processing, and smoking of tobacco. Roughly half of the NNN originates in the unburnt tobacco, with the remainder being formed during burning.
NNN is found in a variety of tobacco products including ] like ] and ],<ref>{{ cite web | author = Balbo, S. | url = http://www.aacr.org/home/public--media/aacr-press-releases.aspx?d=2740 | title = Strong Oral Carcinogen Identified in Smokeless Tobacco | publisher = American Association for Cancer Research | date = April 2, 2012 | url-status = dead | archive-url = https://web.archive.org/web/20120611122215/http://www.aacr.org/home/public--media/aacr-press-releases.aspx?d=2740 | archive-date = June 11, 2012 }}</ref> ]s, and ]s. It is present in smoke from cigars and cigarettes, in the ] of people who chew ] with tobacco, and in the saliva of oral-snuff and e-cigarette<ref>{{cite journal |date=July 2018 |title=Presence of the Carcinogen N'-Nitrosonornicotine in Saliva of E-cigarette Users |journal=Chem. Res. Toxicol. |volume=31 |issue=8 |pages=731–738 |doi=10.1021/acs.chemrestox.8b00089 |pmid=30019582 |last1=Bustamante |first1=Gabriela |last2=Ma |first2=Bin |last3=Yakovlev |first3=Galina |last4=Yershova |first4=Katrina |last5=Le |first5=Chap |last6=Jensen |first6=Joni |last7=Hatsukami |first7=Dorothy K. |last8=Stepanov |first8=Irina |pmc=8556657 }}</ref> users. NNN is produced by the ] of ] during the curing, aging, processing, and smoking of tobacco.<ref>{{ cite journal |author1=Siminszky, B. |author2=Gavilano, L. |author3=Bowen, S. W. |author4=Dewey, R. E. | title = Conversion of nicotine to nornicotine in ''Nicotiana tabacum'' is mediated by CYP82E4, a cytochrome P450 monooxygenase | journal = Proceedings of the National Academy of Sciences | year = 2005 | volume = 102 | issue = 41 | pages = 14919–14924 | doi = 10.1073/pnas.0506581102 | pmid = 16192354 | pmc = 1253577 |bibcode=2005PNAS..10214919S |doi-access=free }}</ref> Roughly half of the NNN originates in the unburnt tobacco, with the remainder being formed during burning.


NNN can be produced in the acidic environment of the stomach in users of oral nicotine replacement therapies, due to the combination of dietary/endogenous nitrates, and nornicotine (either present as a minor metabolite of nicotine, or as an impurity in the product).{{Citation needed|date=October 2021}}
Some of the NNN present in the ] of tobacco users is produced ]ly from ] in saliva and tobacco ]s including ].

==Mechanism of action==
NNN is metabolized by ], which adds a hydroxy group to either the 2' or 5' carbon on the 5-membered ring. 2'-hydroxylation appears more prevalent in humans, while 5'-hydroxylation is more prevalent in non-primate animals.<ref>{{Cite journal|last1=Zarth|first1=Adam T.|last2=Upadhyaya|first2=Pramod|last3=Yang|first3=Jing|last4=Hecht|first4=Stephen S.|date=2016-03-21|title=DNA Adduct Formation from Metabolic 5′-Hydroxylation of the Tobacco-Specific Carcinogen N′-Nitrosonornicotine in Human Enzyme Systems and in Rats|journal=Chemical Research in Toxicology|volume=29|issue=3|pages=380–389|doi=10.1021/acs.chemrestox.5b00520|issn=0893-228X|pmc=4805523|pmid=26808005}}</ref> Upon hydroxylation, the 5-membered ring opens up, allowing the compound to bind to the base of one of the nucleotides.
]

== Synthesis ==
]NNN is a derivative of nicotine that is produced in the ], in the burning of tobacco (such as with cigarettes), and in the acidic conditions of the stomach. Nicotine is converted into nornicotine via nicotine N-demethylase (NND), an enzyme found in the tobacco plant that works by removing the methyl group from the nitrogen on the 5-membered ring of nicotine.<ref>{{Cite journal|title=Nicotine N-demethylase in cell-free preparations from tobacco cell cultures |language=en|doi=10.1016/0031-9422(95)00868-3|volume=42|issue=2|journal=Phytochemistry|pages=325–329 | last1 = Dong-yun | first1 = Hao|year=1996}}</ref> From there, Nornicotine undergoes nitrosation (the conversion of organic compounds into nitroso derivatives by gaining a ] (N=O) group) on that same nitrogen, converting it to NNN.<ref>{{Cite journal|last1=Stepanov|first1=Irina|last2=Carmella|first2=Steven G.|last3=Briggs|first3=Anna|last4=Hertsgaard|first4=Louise|last5=Lindgren|first5=Bruce|last6=Hatsukami|first6=Dorothy|last7=Hecht|first7=Stephen S.|date=2009-11-01|title=Presence of the Carcinogen N′-Nitrosonornicotine in the Urine of Some Users of Oral Nicotine Replacement Therapy Products|url= |journal=Cancer Research|language=en|volume=69|issue=21|pages=8236–8240|doi=10.1158/0008-5472.CAN-09-1084|issn=0008-5472|pmc=2783463|pmid=19843845}}</ref>

The nitrosonium group forms from ] (HNO<sub>2</sub>) under acidic conditions present in the tobacco curing process. It can also be formed in the stomach when stomach acid reacts with nitrite ions that are typically used as a salt to preserve red meats and inhibit bacterial growth.<ref>{{Cite news|url=https://www.britannica.com/science/oxyacid/Nitrous-acid-and-nitrite-salts|title=oxyacid - Nitrous acid and nitrite salts {{!}} chemical compound|work=Encyclopedia Britannica|access-date=2017-05-06|language=en}}</ref> Nitrous acid becomes protonated on its hydroxy group to form nitrosooxonium. This compound then splits off to form nitrosonium and water.<ref>{{Cite book|title=Practical Organic Chemistry|last=Vogel|first=Arthur Israel|publisher=Longman Group Limited|year=1962|location=London|edition=3rd}}</ref>

== Symptoms ==
Symptoms of NNN are similar to those of nicotine poisoning and include irritation at the point of absorption (for example, the gums when dipping tobacco is used), nausea and vomiting, sleep disturbances, headache, and chest pain.<ref>{{Cite web|url=https://toxnet.nlm.nih.gov/cgi-bin/sis/search/a?dbs+hsdb:@term+@DOCNO+5114|title=N-NITROSONORNICOTINE - National Library of Medicine HSDB Database|website=toxnet.nlm.nih.gov|access-date=2017-04-23}}</ref> The substance is also a known carcinogen, meaning that any exposure to the substance can lead to cancer and is proven to cause esophageal and nasal cancer in animals. There is no known "safe" levels of NNN ingestion in humans due to its carcinogenic activity.<ref>{{Cite web|url=http://nj.gov/health/eoh/rtkweb/documents/fs/2900.pdf|title=New Jersey Department of Health and Senior Services Hazardous Substance Fact Sheet: N-Nitrosonornicotine|website=nj.gov/health}}</ref> However, in mice, the ] (LD<sub>50</sub>) is 1g/kg.<ref>{{Cite web|url=https://pubchem.ncbi.nlm.nih.gov/compound/N_-Nitrosonornicotine#section=Non-Human-Toxicity-Values|title=N'-Nitrosonornicotine {{!}} C9H11N3O - PubChem|last=Pubchem|website=pubchem.ncbi.nlm.nih.gov|language=en|access-date=2017-04-26}}</ref>

In cigarette smoke, NNN has been found in levels between 2.2 and 6.6 parts per million (ppm). The FDA has put limits of nitrosamines in other consumable products (such as cured meats) at levels below 10 parts per billion (ppb).<ref>{{Cite journal|last=Hecht|first=Stephen S.|date=2017-05-05|title=It is time to regulate carcinogenic tobacco-specific nitrosamines in cigarette tobacco|journal=Cancer Prevention Research (Philadelphia, Pa.)|volume=7|issue=7|pages=639–647|doi=10.1158/1940-6207.CAPR-14-0095|issn=1940-6207|pmc=4135519|pmid=24806664}}</ref>


== References == == References ==

{{Reflist}} {{Reflist}}

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{{DEFAULTSORT:Nitrosonornicotine, N-}} {{DEFAULTSORT:Nitrosonornicotine, N-}}
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