Chemistry:Nitrosamine

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Short description: Organic compounds of the form >N–N=O
Structure of the nitrosamino group

In organic chemistry, nitrosamines (or more formally N-nitrosamines) are organic compounds with the chemical structure R
2N–N=O, where R is usually an alkyl group.[1] They feature a nitroso group (NO+
) bonded to a deprotonated amine. Most nitrosamines are carcinogenic in nonhuman animals.[2] 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".[3]

Chemistry

Metabolic activation of the nitrosamine NDMA converts it to the alkylating agent diazomethane[4]

The organic chemistry of nitrosamines is well developed with regard to their syntheses, their structures, and their reactions.[5][6] They usually are produced by the reaction of nitrous acid (HNO
2) and secondary amines, although other nitrosyl sources (e.g. N2O4, NOCl, RONO) have the same effect:[7] [math]\ce{ HONO + R2NH -> R2N-NO + H2O }[/math] The nitrous acid usually arises from protonation of a nitrite. This synthesis method is relevant to the generation of nitrosamines under some biological conditions.[citation needed] The nitrosation is also partially reversible; aryl nitrosamines rearrange to give a para-nitroso aryl amine in the Fischer-Hepp rearrangement.[8]

With regards to structure, the C
2N
2O core of nitrosamines is planar, as established by X-ray crystallography. The N-N and N-O distances are 132 and 126 pm, respectively in dimethylnitrosamine,[9] one of the simplest members of a large class of N-nitrosamines

Nitrosamines are not directly carcinogenic. Metabolic activation is required to convert them to the alkylating agents that modify bases in DNA, inducing mutations. The specific alkylating agents vary with the nitrosamine, but all are proposed to feature alkyldiazonium centers.[10][4]

History and occurrence

In 1956, two British scientists, John Barnes and Peter Magee, reported that a simple member of the large class of N-nitrosamines, dimethylnitrosamine, produced liver tumours in rats. Subsequent studies showed that approximately 90% of the 300 nitrosamines tested were carcinogenic in a wide variety of animals.[11]

Tobacco exposure

A common way ordinary consumers are exposed to nitrosamines is through tobacco use and cigarette smoke.[10] Tobacco-specific nitrosamines also can be found in American dip snuff, chewing tobacco, and to a much lesser degree, snus (127.9 ppm for American dip snuff compared to 2.8 ppm in Swedish snuff or snus).[12]

Dietary exposure

This section is transcluded from Nitrosamine formation during digestion. (edit | history)

Nitrosamine formation during digestion

Examples

Substance name CAS number Synonyms Molecular formula Physical appearance Carcinogenity category
N-Nitrosonornicotine 16543-55-8 NNN C9H11N3O Light yellow low-melting solid
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone[13] 64091-91-4 NNK, 4′-(nitrosomethylamino)-1-(3-pyridyl)-1-butanone C10H15N3O2 Light yellow oil
N-Nitrosodimethylamine 62-75-9 Dimethylnitrosamine, N,N-dimethylnitrosamine, NDMA, DMN C2H6N2O Yellow liquid EPA-B2; IARC-2A; OSHA carcinogen; TLV-A3
N-Nitrosodiethylamine 55-18-5 Diethylnitrosamide, diethylnitrosamine, N,N-diethylnitrosamine, N-ethyl-N-nitrosoethanamine, diethylnitrosamine, DANA, DENA, DEN, NDEA C4H10N2O Yellow liquid EPA-B2; IARC-2A
4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol 76014-81-8 NNAL
N-Nitrosoanabasine 37620-20-5 NAB C10H13N3O Yellow Oil IARC-3
N-Nitrosoanatabine 71267-22-6 NAT C10H11N3O Clear yellow-to-orange oil IARC-3

See also

Additional reading

  • Altkofer, Werner; Braune, Stefan; Ellendt, Kathi; Kettl-Grömminger, Margit; Steiner, Gabriele (2005). "Migration of nitrosamines from rubber products - are balloons and condoms harmful to the human health?". Molecular Nutrition & Food Research 49 (3): 235–238. doi:10.1002/mnfr.200400050. PMID 15672455. 
  • Proctor, Robert N. (2012). Golden Holocaust: Origins of the Cigarette Catastrophe and the Case for Abolition. Berkeley: University of California Press. ISBN 9780520950436. OCLC 784884555. 

References

  1. ↑ Beard, Jessica C.; Swager, Timothy M. (21 January 2021). "An Organic Chemist's Guide to N-Nitrosamines: Their Structure, Reactivity, and Role as Contaminants". The Journal of Organic Chemistry 86 (3): 2037–2057. doi:10.1021/acs.joc.0c02774. PMID 33474939. 
  2. ↑ Yang, Chung S.; Yoo, Jeong-Sook H.; Ishizaki, Hiroyuki; Hong, Junyan (1990). "Cytochrome P450IIe1: Roles in Nitrosamine Metabolism and Mechanisms of Regulation". Drug Metabolism Reviews 22 (2–3): 147–159. doi:10.3109/03602539009041082. PMID 2272285. 
  3. ↑ Jakszyn, Paula; Gonzalez, Carlos (2006). "Nitrosamine and related food intake and gastric and oesophageal cancer risk: A systematic review of the epidemiological evidence". World Journal of Gastroenterology 12 (27): 4296–4303. doi:10.3748/wjg.v12.i27.4296. PMID 16865769. 
  4. ↑ 4.0 4.1 Tricker, A.R.; Preussmann, R. (1991). "Carcinogenic N-Nitrosamines in the Diet: Occurrence, Formation, Mechanisms and Carcinogenic Potential". Mutation Research/Genetic Toxicology 259 (3–4): 277–289. doi:10.1016/0165-1218(91)90123-4. PMID 2017213. 
  5. ↑ Anselme, Jean-Pierre (1979). "The Organic Chemistry of N-Nitrosamines: A Brief Review". N-Nitrosamines. ACS Symposium Series. 101. pp. 1–12. doi:10.1021/bk-1979-0101.ch001. ISBN 0-8412-0503-5. 
  6. ↑ Vogel, A. I. (1962). Practical Organic Chemistry (3rd ed.). Impression. p. 1074. 
  7. ↑ Smith, Michael B.; March, Jerry (2007), Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (6th ed.), New York: Wiley-Interscience, pp. 846-847, ISBN 978-0-471-72091-1, https://books.google.com/books?id=JDR-nZpojeEC&printsec=frontcover 
  8. ↑ Smith, Michael B.; March, Jerry (2007), Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (6th ed.), New York: Wiley-Interscience, p. 739, ISBN 978-0-471-72091-1, https://books.google.com/books?id=JDR-nZpojeEC&printsec=frontcover 
  9. ↑ Krebs, Bernt; Mandt, Jürgen (1975). "Kristallstruktur des N-Nitrosodimethylamins". Chemische Berichte 108 (4): 1130–1137. doi:10.1002/cber.19751080419. 
  10. ↑ 10.0 10.1 Hecht, Stephen S. (1998). "Biochemistry, Biology, and Carcinogenicity of Tobacco-Specific N-Nitrosamines". Chemical Research in Toxicology 11 (6): 559–603. doi:10.1021/tx980005y. PMID 9625726. 
  11. ↑ Advances in Agronomy. Academic Press. 2013-01-08. p. 159. ISBN 978-0-12-407798-0. https://books.google.com/books?id=lMrEEB3rhV8C&pg=PA159. 
  12. ↑ Gregory N. Connolly; Howard Saxner (August 21, 2001). Informational Update Research on Tobacco Specific Nitrosamines (TSNAs) in Oral Snuff and a Request to Tobacco Manufacturers to Voluntarily Set Tolerance Limits For TSNAs in Oral Snuff. 
  13. ↑ Hecht, Steven S.; Borukhova, Anna; Carmella, Steven G. "Tobacco specific nitrosamines" Chapter 7; of "Nicotine safety and toxicity" Society for Research on Nicotine and Tobacco; 1998 - 203 pages

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