Nitrosamine

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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. [8] The nitrosation is also reversible, particularly in acidic solutions of nucleophiles. [9] Aryl nitrosamines rearrange to give a para-nitroso aryl amine in the Fischer-Hepp rearrangement. [10]

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, [11] 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. [12] [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. [13]

Tobacco exposure

A common way ordinary consumers are exposed to nitrosamines is through tobacco use and cigarette smoke. [12] 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). [14]

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, [15] but consumption of large quantities of processed meats can still cause a slight elevation in gastric and oesophageal cancer risk today. [16] [17] [18] [19]

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. [20]

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. [21] [22] 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). [23] [24] [25] However, when 10% of the meal is fat, the effect reverses, and ascorbic acid markedly increases nitrosamine formation. [26] [27]

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. [28] [29] Health Canada published guidance about nitrosamine impurities in medications [30] and a list of established acceptable intake limits of nitrosamine impurities in medications. [31]

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 [32] 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 agent that promotes the development of cancer. Carcinogens can include synthetic chemicals, naturally occurring substances, physical agents such as ionizing and non-ionizing radiation, and biologic agents such as viruses and bacteria. Most carcinogens act by creating mutations in DNA that disrupt a cell's normal processes for regulating growth, leading to uncontrolled cellular proliferation. This occurs when the cell's DNA repair processes fail to identify DNA damage allowing the defect to be passed down to daughter cells. The damage accumulates over time. This is typically a multi-step process during which the regulatory mechanisms within the cell are gradually dismantled allowing for unchecked cellular division.

<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 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.

<span class="mw-page-title-main">Nitrosation and nitrosylation</span> Process of converting organic compounds into nitroso derivatives

Nitrosation and nitrosylation are two names for the process of converting organic compounds or metal complexes into nitroso derivatives, i.e., compounds containing the R−NO functionality. The synonymy arises because the R-NO functionality can be interpreted two different ways, depending on the physico-chemical environment:

<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">Alkyl nitrite</span> Organic compounds of the form R–O–N=O

In organic chemistry, alkyl nitrites are a group of organic compounds based upon the molecular structure R−O−N=O, where R represents an alkyl group. Formally they are alkyl esters of nitrous acid. They are distinct from nitro compounds.

<span class="mw-page-title-main">Fischer–Hepp rearrangement</span> Organic reaction applied to aromatic nitroso and nitrosamine compounds

In organic chemistry, the Fischer–Hepp rearrangement is a rearrangement reaction in which an aromatic N-nitroso or secondary nitrosamine converts to a carbon nitroso compound:

<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.

<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.

Tobacco-specific nitrosamines (TSNAs) comprise one of the most important groups of carcinogens in tobacco products, particularly cigarettes and fermented dipping snuff.

<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

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  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.
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  20. ↑ 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.
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  26. ↑ 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.
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  29. ↑ https://www.fda.gov/media/141720/download [ bare URL ]
  30. ↑ "Nitrosamine impurities in medications: Guidance". Health Canada . 4 April 2022. Retrieved 29 March 2024.
  31. ↑ "Nitrosamine impurities in medications: Established acceptable intake limits". Health Canada . 15 March 2024. Retrieved 29 March 2024.
  32. ↑ 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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