Nitrosamine

Nitrosamines (or more formally N-Nitrosamines) are organic compounds of the chemical structure R2N−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.[2]

Not to be confused with Nitroamine.
Structure of the nitrosamino group

Chemistry
Metabolic activation of the nitrosamine NDMA, involving its conversion to an alkylating agent[3]

The organic chemistry of nitrosamines is well developed with regard to their syntheses, their structures, and their reactions.[4][5] They are usually produced by the reaction of nitrous acid (HNO2) and secondary amines.

HONO + R2NH → R2N-NO + H2O

The nitrous acid usually arises from protonation of nitrite. This synthesis method is relevant to the generation of nitrosamines under some biological conditions.

With regards to structure, the C2N2O 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.[6]

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.[7][3]

History and occurrence

In 1956, two British scientists, John Barnes and Peter Magee, reported that 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.[8]

A common way ordinary consumers are exposed to nitrosamines is through cigarette smoke.[7] Tobacco-specific nitrosamines can also 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).[9]

Nitrosamines are produced by the reaction of nitrites and secondary amines. Nitrites are used as food preservatives, e.g. cured meats. Secondary amines arise by the degradation of proteins (food).[10]

Nitrite and nitrosamine intake are associated with risk of gastric cancer and oesophageal cancer.[11] In the 1970s, an elevated frequency of liver cancer was found in Norwegian farm animals. The farm animals had been fed on herring meal, which was preserved using sodium nitrite. The sodium nitrite had reacted with dimethylamine in the fish and produced dimethylnitrosamine.[12]

Inhibition

Endogenous nitrosamine formation can be inhibited by ascorbic acid.[13] In the case of formation of carcinogenic nitrosamines in the stomach from dietary nitrite (used as processed meat preservative), ascorbic acid markedly decreases nitrosamine formation in the absence of fat in the meal; but when 10% fat is present, this reverses the effect such that ascorbic acid then markedly increases nitrosamine formation.[14][15]

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[16] 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. 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.
  4. 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.
  5. Vogel, A. I. (1962). Practical Organic Chemistry (3rd ed.). Impression. p. 1074.
  6. Krebs, Bernt; Mandt, Jürgen (1975). "Kristallstruktur des N-Nitrosodimethylamins". Chemische Berichte. 108 (4): 1130–1137. doi:10.1002/cber.19751080419.
  7. 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.
  8. Advances in Agronomy. Academic Press. 2013-01-08. p. 159. ISBN 978-0-12-407798-0.
  9. 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". Cite journal requires |journal= (help)
  10. Honikel, Karl-Otto (2008). "The use and control of nitrate and nitrite for the processing of meat products". Meat Science. 78 (1–2): 68–76. doi:10.1016/j.meatsci.2007.05.030. PMID 22062097.
  11. Jakszyn, P; Gonzalez, CA (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. PMC 4087738. PMID 16865769.
  12. Joyce I. Boye; Yves Arcand (2012-01-10). Green Technologies in Food Production and Processing. Springer Science & Business Media. p. 573. ISBN 978-1-4614-1586-2.
  13. Tannenbaum SR, Wishnok JS, Leaf CD (1991). "Inhibition of nitrosamine formation by ascorbic acid". The American Journal of Clinical Nutrition. 53 (1 Suppl): 247S–250S. Bibcode:1987NYASA.498..354T. doi:10.1111/j.1749-6632.1987.tb23774.x. PMID 1985394. S2CID 41045030. Retrieved 2015-06-06. Evidence now exists that ascorbic acid is a limiting factor in nitrosation reactions in people.
  14. Combet, E.; Paterson, S; Iijima, K; Winter, J; Mullen, W; Crozier, A; Preston, T; McColl, K. E. (2007). "Fat transforms ascorbic acid from inhibiting to promoting acid-catalysed N-nitrosation". Gut. 56 (12): 1678–1684. doi:10.1136/gut.2007.128587. PMC 2095705. PMID 17785370.
  15. Combet, E; El Mesmari, A; Preston, T; Crozier, A; McColl, K. E. (2010). "Dietary phenolic acids and ascorbic acid: Influence on acid-catalyzed nitrosative chemistry in the presence and absence of lipids". Free Radical Biology and Medicine. 48 (6): 763–771. doi:10.1016/j.freeradbiomed.2009.12.011. PMID 20026204.
  16. 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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