In
organic chemistry, nitrosamines (or more formally N-nitrosamines) are
organic compounds with the
chemical structureR2N−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
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 (HNO2) and secondary amines, although other
nitrosyl sources (e.g. N 2O 4, NOCl,
RONO) have the same effect:[7]
HONO + R2NH → R2N-NO + H2O
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 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,[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]
Nitroso compounds react with
primary amines in acidic environments to form
nitrosamines, which human metabolism converts to mutagenic
diazo compounds. Small amounts of nitro and nitroso compounds form during meat
curing; the toxicity of these compounds
preserves the meat against
bacterial infection. After curing completes, the concentration of these compounds appears to degrade over time. Their presence in finished products has been tightly regulated since several food-poisoning cases in the early 20th century,[13] but consumption of large quantities of processed meats can still cause a slight elevation in
gastric and
oesophageal cancer risk today.[14][15][16][17]
The effects of nitroso compounds vary dramatically across the gastrointestinal tract, and with diet. Nitroso compounds present in stool do not induce nitrosamine formation, because stool has neutral
pH.[19][20]Stomach acid does cause nitrosamine compound formation, but the process is inhibited when amine concentration is low (e.g. a low-protein diet or no fermented food). The process may also be inhibited in the case of high
vitamin C (ascorbic acid) concentration (e.g. high-fruit diet).[21][22][23] However, when 10% of the meal is fat, the effect reverses, and ascorbic acid markedly increases nitrosamine formation.[24][25]
The US
Food and Drug Administration published guidance about the control of nitrosamine impurities in medicines.[26][27]Health Canada published guidance about nitrosamine impurities in medications[28] and a list of established acceptable intake limits of nitrosamine impurities in medications.[29]
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.
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PMID15672455.
Proctor, Robert N. (2012). Golden Holocaust: Origins of the Cigarette Catastrophe and the Case for Abolition. Berkeley: University of California Press.
ISBN9780520950436.
OCLC784884555.
^Krebs, Bernt; Mandt, Jürgen (1975). "Kristallstruktur des N-Nitrosodimethylamins". Chemische Berichte. 108 (4): 1130–1137.
doi:
10.1002/cber.19751080419.
^
abHecht, Stephen S. (1998). "Biochemistry, Biology, and Carcinogenicity of Tobacco-Specific N-Nitrosamines". Chemical Research in Toxicology. 11 (6): 559–603.
doi:
10.1021/tx980005y.
PMID9625726.
^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}}: Cite journal requires |journal= (
help)
^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.
PMID20026204.
^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