Nitrosamine

Last updated
Structure of the nitrosamino group Nitrosamine Formulae V.1.svg
Structure of the nitrosamino group

In organic chemistry, nitrosamines (or more formally N-nitrosamines) are organic compounds with 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 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]

Contents

Chemistry

Metabolic activation of the nitrosamine NDMA converts it to the alkylating agent diazomethane Ndma activ.svg
Metabolic activation of the nitrosamine NDMA converts it to the alkylating agent diazomethane

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]

Dietary exposure

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]

For example, during the 1970s, certain Norwegian farm animals began exhibiting elevated levels of liver cancer. These animals had been fed herring meal preserved with sodium nitrite. The sodium nitrite had reacted with dimethylamine in the fish and produced dimethylnitrosamine. [18]

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]

Medication impurities

There have been recalls for various medications due to the presence of nitrosamine impurities. There have been recalls for angiotensin II receptor blockers, ranitidine, valsartan and others.

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]

Examples

Substance name CAS number SynonymsMolecular formulaPhysical appearanceCarcinogenity category
N-Nitrosonornicotine 16543-55-8NNNC9H11N3OLight yellow low-melting solid
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone [30] 64091-91-4NNK, 4′-(nitrosomethylamino)-1-(3-pyridyl)-1-butanoneC10H15N3O2Light yellow oil
N-Nitrosodimethylamine 62-75-9Dimethylnitrosamine, N,N-dimethylnitrosamine, NDMA, DMNC2H6N2OYellow liquidEPA-B2; IARC-2A; OSHA carcinogen; TLV-A3
N-Nitrosodiethylamine 55-18-5Diethylnitrosamide, diethylnitrosamine, N,N-diethylnitrosamine, N-ethyl-N-nitrosoethanamine, diethylnitrosamine, DANA, DENA, DEN, NDEAC4H10N2OYellow liquid EPA-B2; IARC-2A
4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol76014-81-8NNAL
N-Nitrosoanabasine37620-20-5NABC10H13N3OYellow Oil IARC-3
N-Nitrosoanatabine71267-22-6NATC10H11N3OClear yellow-to-orange oilIARC-3

See also

Additional reading

Related Research Articles

<span class="mw-page-title-main">Carcinogen</span> Substance, radionuclide, or radiation directly involved in causing cancer

A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis. This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive substances are considered carcinogens, but their carcinogenic activity is attributed to the radiation, for example gamma rays and alpha particles, which they emit. Common examples of non-radioactive carcinogens are inhaled asbestos, certain dioxins, and tobacco smoke. Although the public generally associates carcinogenicity with synthetic chemicals, it is equally likely to arise from both natural and synthetic substances. Carcinogens are not necessarily immediately toxic; thus, their effect can be insidious.

<span class="mw-page-title-main">Ham</span> Pork from a leg cut that has been preserved by wet or dry curing, with or without smoking

Ham is pork from a leg cut that has been preserved by wet or dry curing, with or without smoking. As a processed meat, the term "ham" includes both whole cuts of meat and ones that have been mechanically formed.

<span class="mw-page-title-main">Mutagen</span> Physical or chemical agent that increases the rate of genetic mutation

In genetics, a mutagen is a physical or chemical agent that permanently changes genetic material, usually DNA, in an organism and thus increases the frequency of mutations above the natural background level. As many mutations can cause cancer in animals, such mutagens can therefore be carcinogens, although not all necessarily are. All mutagens have characteristic mutational signatures with some chemicals becoming mutagenic through cellular processes.

<span class="mw-page-title-main">Nitrate</span> Polyatomic ion (NO₃, charge –1) found in explosives and fertilisers

Nitrate is a polyatomic ion with the chemical formula NO−
3. Salts containing this ion are called nitrates. Nitrates are common components of fertilizers and explosives. Almost all inorganic nitrates are soluble in water. An example of an insoluble nitrate is bismuth oxynitrate.

A preservative is a substance or a chemical that is added to products such as food products, beverages, pharmaceutical drugs, paints, biological samples, cosmetics, wood, and many other products to prevent decomposition by microbial growth or by undesirable chemical changes. In general, preservation is implemented in two modes, chemical and physical. Chemical preservation entails adding chemical compounds to the product. Physical preservation entails processes such as refrigeration or drying. Preservative food additives reduce the risk of foodborne infections, decrease microbial spoilage, and preserve fresh attributes and nutritional quality. Some physical techniques for food preservation include dehydration, UV-C radiation, freeze-drying, and refrigeration. Chemical preservation and physical preservation techniques are sometimes combined.

<span class="mw-page-title-main">Sodium nitrate</span> Chemical compound

Sodium nitrate is the chemical compound with the formula NaNO
3. This alkali metal nitrate salt is also known as Chile saltpeter to distinguish it from ordinary saltpeter, potassium nitrate. The mineral form is also known as nitratine, nitratite or soda niter.

The nitrite ion has the chemical formula NO−
2. Nitrite is widely used throughout chemical and pharmaceutical industries. The nitrite anion is a pervasive intermediate in the nitrogen cycle in nature. The name nitrite also refers to organic compounds having the –ONO group, which are esters of nitrous acid.

<span class="mw-page-title-main">Sodium nitrite</span> Chemical compound

Sodium nitrite is an inorganic compound with the chemical formula NaNO2. It is a white to slightly yellowish crystalline powder that is very soluble in water and is hygroscopic. From an industrial perspective, it is the most important nitrite salt. It is a precursor to a variety of organic compounds, such as pharmaceuticals, dyes, and pesticides, but it is probably best known as a food additive used in processed meats and (in some countries) in fish products.

<span class="mw-page-title-main">Processed meat</span> Type of meat

Processed meat is considered to be any meat that has been modified in order to either improve its taste or to extend its shelf life. Methods of meat processing include salting, curing, fermentation, smoking, boiling, frying, and/or the addition of chemical preservatives. Processed meat is usually composed of pork or beef or, less frequently, poultry. It can also contain offal or meat by-products such as blood. Processed meat products include bacon, ham, sausages, salami, corned beef, jerky, hot dogs, lunch meat, canned meat, chicken nuggets, and meat-based sauces. Meat processing includes all the processes that change fresh meat with the exception of simple mechanical processes such as cutting, grinding or mixing.

Nitrosation is a process of converting organic compounds into nitroso derivatives, i.e., compounds containing the R-NO functionality.

<i>N</i>-Nitrosonornicotine Chemical compound

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

<span class="mw-page-title-main">Nitroso</span> Class of functional groups with a –N=O group attached

In organic chemistry, nitroso refers to a functional group in which the nitric oxide group is attached to an organic moiety. As such, various nitroso groups can be categorized as C-nitroso compounds, S-nitroso compounds, N-nitroso compounds, and O-nitroso compounds.

<span class="mw-page-title-main">Curing (food preservation)</span> Food preservation and flavouring processes based on drawing moisture out of the food by osmosis

Curing is any of various food preservation and flavoring processes of foods such as meat, fish and vegetables, by the addition of salt, with the aim of drawing moisture out of the food by the process of osmosis. Because curing increases the solute concentration in the food and hence decreases its water potential, the food becomes inhospitable for the microbe growth that causes food spoilage. Curing can be traced back to antiquity, and was the primary method of preserving meat and fish until the late 19th century. Dehydration was the earliest form of food curing. Many curing processes also involve smoking, spicing, cooking, or the addition of combinations of sugar, nitrate, and nitrite.

<span class="mw-page-title-main">Heterocyclic amine</span> Any heterocyclic compound having at least one nitrogen heteroatom

Heterocyclic amines, also sometimes referred to as HCAs, are chemical compounds containing at least one heterocyclic ring, which by definition has atoms of at least two different elements, as well as at least one amine (nitrogen-containing) group. Typically it is a nitrogen atom of an amine group that also makes the ring heterocyclic, though compounds exist in which this is not the case. The biological functions of heterocyclic amines vary, including vitamins and carcinogens. Carcinogenic heterocyclic amines are created by high temperature cooking of meat and smoking of plant matter like tobacco. Some well known heterocyclic amines are niacin, nicotine, and the nucleobases that encode genetic information in DNA.

<span class="mw-page-title-main">DNA adduct</span> Segment of DNA bound to a cancer-causing chemical

In molecular genetics, a DNA adduct is a segment of DNA bound to a cancer-causing chemical. This process could lead to the development of cancerous cells, or carcinogenesis. DNA adducts in scientific experiments are used as biomarkers of exposure. They are especially useful in quantifying an organism's exposure to a carcinogen. The presence of such an adduct indicates prior exposure to a potential carcinogen, but it does not necessarily indicate the presence of cancer in the subject animal.

<i>N</i>-Nitrosodiethylamine Chemical compound

N-Nitrosodiethylamine (NDEA) is an organic compound with the formula Et2NNO (Et = C2H5). A member of the nitrosamines, it is a light-sensitive, volatile, clear yellow oil that is soluble in water, lipids, and other organic solvents. It has an amine or aromatic odor. It is used as gasoline and lubricant additive, antioxidant, and stabilizer for industry materials. When heated to decomposition, N-nitrosodiethylamine emits toxic fumes of nitrogen oxides. N-Nitrosodiethylamine affects DNA integrity, probably by alkylation, and is used in experimental research to induce liver tumorigenesis. It is carcinogenic and mutagenic. NDEA has also been found to perturb amino acid biosynthesis including arginine, as well as DNA damage repair and mitochondrial genome maintenance in yeast.

<span class="mw-page-title-main">Semustine</span> Chemical compound

Semustine is an alkylating nitrosourea compound used in chemotherapy treatment of various types of tumours. Due to its lipophilic property, semustine can cross the blood-brain barrier for the chemotherapy of brain tumours, where it interferes with DNA replication in the rapidly-dividing tumour cells. Semustine, just as lomustine, is administered orally. Evidence has been found that treatment with semustine can cause acute leukaemia as a delayed effect in very rare cases.

6-<i>O</i>-Methylguanine Chemical compound

6-O-Methylguanine is a derivative of the nucleobase guanine in which a methyl group is attached to the oxygen atom. It base-pairs to thymine rather than cytosine, causing a G:C to A:T transition in DNA.

In biochemistry, nitrosamines are a class of compounds that can form during food digestion. The presence of their precursors, nitrites, in cured meats, is controversial, because of a small connection to cancer risk.

<i>N</i>-Nitrosomorpholine Chemical compound

N-Nitrosomorpholine is an organic compound which is known to be a carcinogen and mutagen.

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 . PMC   7885798 . 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 . PMC   4087738 . PMID   16865769.
  4. 1 2 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. Vol. 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
  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
  9. ↑ Krebs, Bernt; Mandt, Jürgen (1975). "Kristallstruktur des N-Nitrosodimethylamins". Chemische Berichte. 108 (4): 1130–1137. doi:10.1002/cber.19751080419.
  10. 1 2 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.
  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".{{cite journal}}: Cite journal requires |journal= (help)
  13. ↑ Honikel, K. O. (2008). "The use an control of nitrate and nitrite for the processing of meat products" (PDF). Meat Science. 78 (1–2): 68–76. doi:10.1016/j.meatsci.2007.05.030. PMID   22062097.
  14. ↑ Lunn, J.C.; Kuhnle, G.; Mai, V.; Frankenfeld, C.; Shuker, D.E.G.; Glen, R. C.; Goodman, J.M.; Pollock, J.R.A.; Bingham, S.A. (2006). "The effect of haem in red and processed meat on the endogenous formation of N-nitroso compounds in the upper gastrointestinal tract". Carcinogenesis. 28 (3): 685–690. doi:10.1093/carcin/bgl192. PMID   17052997.
  15. ↑ Bastide, Nadia M.; Pierre, Fabrice H.F.; Corpet, Denis E. (2011). "Heme Iron from Meat and Risk of Colorectal Cancer: A Meta-analysis and a Review of the Mechanisms Involved". Cancer Prevention Research. 4 (2): 177–184. doi: 10.1158/1940-6207.CAPR-10-0113 . PMID   21209396. S2CID   4951579.
  16. ↑ Bastide, Nadia M.; Chenni, Fatima; Audebert, Marc; Santarelli, Raphaelle L.; Taché, Sylviane; Naud, Nathalie; Baradat, Maryse; Jouanin, Isabelle; Surya, Reggie; Hobbs, Ditte A.; Kuhnle, Gunter G.; Raymond-Letron, Isabelle; Gueraud, Françoise; Corpet, Denis E.; Pierre, Fabrice H.F. (2015). "A Central Role for Heme Iron in Colon Carcinogenesis Associated with Red Meat Intake". Cancer Research. 75 (5): 870–879. doi: 10.1158/0008-5472.CAN-14-2554 . PMID   25592152. S2CID   13274953.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ Lee, L; Archer, MC; Bruce, WR (October 1981). "Absence of volatile nitrosamines in human feces". Cancer Res. 41 (10): 3992–4. PMID   7285009.
  20. ↑ Kuhnle, GG; Story, GW; Reda, T; et al. (October 2007). "Diet-induced endogenous formation of nitroso compounds in the GI tract". Free Radic. Biol. Med. 43 (7): 1040–7. doi:10.1016/j.freeradbiomed.2007.03.011. PMID   17761300.
  21. ↑ Mirvish, SS; Wallcave, L; Eagen, M; Shubik, P (July 1972). "Ascorbate–nitrite reaction: possible means of blocking the formation of carcinogenic N-nitroso compounds". Science. 177 (4043): 65–8. Bibcode:1972Sci...177...65M. doi:10.1126/science.177.4043.65. PMID   5041776. S2CID   26275960.
  22. ↑ Mirvish, SS (October 1986). "Effects of vitamins C and E on N-nitroso compound formation, carcinogenesis, and cancer". Cancer. 58 (8 Suppl): 1842–50. doi:10.1002/1097-0142(19861015)58:8+<1842::aid-cncr2820581410>3.0.co;2-#. PMID   3756808. S2CID   196379002.
  23. ↑ 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.
  24. ↑ 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.
  25. ↑ 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.
  26. ↑ "Control of Nitrosamine Impurities in Human Drugs". U.S. Food and Drug Administration (FDA). 24 February 2021.
  27. ↑ https://www.fda.gov/media/141720/download
  28. ↑ "Nitrosamine impurities in medications: Guidance". Health Canada . 4 April 2022. Retrieved 29 March 2024.
  29. ↑ "Nitrosamine impurities in medications: Established acceptable intake limits". Health Canada . 15 March 2024. Retrieved 29 March 2024.
  30. ↑ 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
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.