N-Nitrosonornicotine

N-Nitrosonornicotine (NNN) is a tobacco-specific nitrosamine produced during the curing and processing of tobacco.

N-Nitrosonornicotine
Names
Preferred IUPAC name
3-[(2S)-1-Nitrosopyrrolidin-2-yl]pyridine
Identifiers
3D model (JSmol)
Abbreviations NNN
ChemSpider
ECHA InfoCard 100.230.123
KEGG
UNII
  • InChI=1S/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 checkY
    Key: XKABJYQDMJTNGQ-VIFPVBQESA-N checkY
  • 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
    Key: XKABJYQDMJTNGQ-VIFPVBQEBO
  • O=NN2CCC[C@H]2c1cnccc1
Properties
C9H11N3O
Molar mass 177.207 g·mol−1
Appearance Oily yellow liquid
Melting point 47 °C (117 °F; 320 K)
Boiling point 154 °C (309 °F; 427 K)
Soluble
Hazards
Flash point 177 °C (351 °F; 450 K)
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

Toxicity

It has been classified as a Group 1 carcinogen.[1] Although no adequate studies of the relationship between exposure to NNN and human cancer have been reported, there is sufficient evidence that NNN causes cancer in experimental animals.[2]

Sources

NNN is found in a variety of tobacco products including smokeless tobacco like chewing tobacco and snuff,[3] cigarettes, and cigars. It is present in smoke from cigars and cigarettes, in the saliva of people who chew betel quid with tobacco, and in the saliva of oral-snuff and e-cigarette[4] users. NNN is produced by the nitrosation of nornicotine during the curing, aging, processing, and smoking of tobacco.[5] 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).

Mechanism of action

NNN is metabolized by cytochrome P450, 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.[6] 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 curing of tobacco, 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.[7] From there, Nornicotine undergoes nitrosation (the conversion of organic compounds into nitroso derivatives by gaining a nitrosonium (N=O) group) on that same nitrogen, converting it to NNN.[8]

The nitrosonium group forms from nitrous acid (HNO2) 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.[9] Nitrous acid becomes protonated on its hydroxy group to form nitrosooxonium. This compound then splits off to form nitrosonium and water.[10]

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.[11] 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.[12] However, in mice, the median lethal dose (LD50) is 1g/kg.[13]

In cigarette smoke, NNN has been found in levels between 2.2-6.6 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).[14]

References
  1. "Agents Classified by the IARC Monographs, Volumes 1–105" (PDF). IARC.
  2. Balbo, Silvia; James-Yi, Sandra; Johnson, Charles S.; O’Sullivan, Michael G.; Stepanov, Irina; Wang, Mingyao; Bandyopadhyay, Dipankar; Kassie, Fekadu; Carmella, Steven; Upadhyaya, Pramod; Hecht, Stephen S. (2013). "(S)-N′-Nitrosonornicotine, a constituent of smokeless tobacco, is a powerful oral cavity carcinogen in rats". Carcinogenesis. 34 (9): 2178–2183. doi:10.1093/carcin/bgt162. PMC 3765046. PMID 23671129.
  3. Balbo, S. (April 2, 2012). "Strong Oral Carcinogen Identified in Smokeless Tobacco". American Association for Cancer Research. Archived from the original on June 11, 2012.
  4. Bustamante, Gabriela; Ma, Bin; Yakovlev, Galina; Yershova, Katrina; Le, Chap; Jensen, Joni; Hatsukami, Dorothy K.; Stepanov, Irina (July 2018). "Presence of the Carcinogen N'-Nitrosonornicotine in Saliva of E-cigarette Users". Chem. Res. Toxicol. 31 (8): 731–738. doi:10.1021/acs.chemrestox.8b00089. PMC 8556657. PMID 30019582.
  5. Siminszky, B.; Gavilano, L.; Bowen, S. W.; Dewey, R. E. (2005). "Conversion of nicotine to nornicotine in Nicotiana tabacum is mediated by CYP82E4, a cytochrome P450 monooxygenase". Proceedings of the National Academy of Sciences. 102 (41): 14919–14924. Bibcode:2005PNAS..10214919S. doi:10.1073/pnas.0506581102. PMC 1253577. PMID 16192354.
  6. Zarth, Adam T.; Upadhyaya, Pramod; Yang, Jing; Hecht, Stephen S. (2016-03-21). "DNA Adduct Formation from Metabolic 5′-Hydroxylation of the Tobacco-Specific Carcinogen N′-Nitrosonornicotine in Human Enzyme Systems and in Rats". Chemical Research in Toxicology. 29 (3): 380–389. doi:10.1021/acs.chemrestox.5b00520. ISSN 0893-228X. PMC 4805523. PMID 26808005.
  7. Dong-yun, Hao (1996). "Nicotine N-demethylase in cell-free preparations from tobacco cell cultures". Phytochemistry. 42 (2): 325–329. doi:10.1016/0031-9422(95)00868-3.
  8. Stepanov, Irina; Carmella, Steven G.; Briggs, Anna; Hertsgaard, Louise; Lindgren, Bruce; Hatsukami, Dorothy; Hecht, Stephen S. (2009-11-01). "Presence of the Carcinogen N′-Nitrosonornicotine in the Urine of Some Users of Oral Nicotine Replacement Therapy Products". Cancer Research. 69 (21): 8236–8240. doi:10.1158/0008-5472.CAN-09-1084. ISSN 0008-5472. PMC 2783463. PMID 19843845.
  9. "oxyacid - Nitrous acid and nitrite salts | chemical compound". Encyclopedia Britannica. Retrieved 2017-05-06.
  10. Vogel, Arthur Israel (1962). Practical Organic Chemistry (3rd ed.). London: Longman Group Limited.
  11. "N-NITROSONORNICOTINE - National Library of Medicine HSDB Database". toxnet.nlm.nih.gov. Retrieved 2017-04-23.
  12. "New Jersey Department of Health and Senior Services Hazardous Substance Fact Sheet: N-Nitrosonornicotine" (PDF). nj.gov/health.
  13. Pubchem. "N'-Nitrosonornicotine | C9H11N3O - PubChem". pubchem.ncbi.nlm.nih.gov. Retrieved 2017-04-26.
  14. Hecht, Stephen S. (2017-05-05). "It is time to regulate carcinogenic tobacco-specific nitrosamines in cigarette tobacco". Cancer Prevention Research (Philadelphia, Pa.). 7 (7): 639–647. doi:10.1158/1940-6207.CAPR-14-0095. ISSN 1940-6207. PMC 4135519. PMID 24806664.
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