![Nitrosamine Formulae V](https://upload.wikimedia.org/wikipedia/commons/a/a9/Nitrosamine_Formulae_V.1.svg)
In
organic chemistry
Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, and reactions of organic compounds and organic materials, i.e., matter in its various forms that contain carbon atoms.Clayden, J.; ...
, nitrosamines (or more formally ''N''-Nitrosamines) are
organic compound
In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. The ...
s with the
chemical structure
A chemical structure determination includes a chemist's specifying the molecular geometry and, when feasible and necessary, the electronic structure of the target molecule or other solid. Molecular geometry refers to the spatial arrangement of at ...
, where R is usually an
alkyl group
In organic chemistry, an alkyl group is an alkane missing one hydrogen.
The term ''alkyl'' is intentionally unspecific to include many possible substitutions.
An acyclic alkyl has the general formula of . A cycloalkyl is derived from a cycloalk ...
. They feature a
nitroso
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 (e.g., nitrosoalkanes; ), ''S''-nitroso ...
group () bonded to a deprotonated
amine
In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituen ...
. Most nitrosamines are
carcinogen
A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis (the formation of cancer). This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive substan ...
ic in nonhuman animals. 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".
Chemistry
![Ndma activ](https://upload.wikimedia.org/wikipedia/commons/4/46/Ndma_activ.svg)
The organic chemistry of nitrosamines is well developed with regard to their syntheses, their structures, and their reactions. They usually are produced by the reaction of
nitrous acid
Nitrous acid (molecular formula ) is a weak and monoprotic acid known only in Solution (chemistry), solution, in the gas phase and in the form of nitrite () salts. Nitrous acid is used to make diazonium salts from amines. The resulting diazoni ...
() and secondary amines.
:
HONO + R2NH -> R2N-NO + H2O
The nitrous acid usually arises from protonation of a
nitrite
The nitrite polyatomic ion, ion has the chemical formula . Nitrite (mostly sodium nitrite) is widely used throughout chemical and pharmaceutical industries. The nitrite anion is a pervasive intermediate in the nitrogen cycle in nature. The name ...
. This synthesis method is relevant to the generation of nitrosamines under some biological conditions.
With regards to structure, the core of nitrosamines is planar, as established by
X-ray crystallography
X-ray crystallography is the experimental science determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to diffract into many specific directions. By measuring the angles ...
. The N-N and N-O distances are 132 and 126 pm, respectively in
dimethylnitrosamine, 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 agent
Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion, or a carbene (or their equivalents). Alkylating agents are reagents for effecting al ...
s that modify bases in DNA, inducing mutations. The specific alkylating agents vary with the nitrosamine, but all are proposed to feature
alkyldiazonium
Diazonium compounds or diazonium salts are a group of organic compounds sharing a common functional group where R can be any organic group, such as an alkyl or an aryl, and X is an inorganic or organic anion, such as a halide.
General propert ...
centers.
[
]
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 tumour
A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
s in rats. Subsequent studies showed that approximately 90% of the 300 nitrosamines tested were carcinogen
A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis (the formation of cancer). This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive substan ...
ic in a wide variety of animals.
Tobacco exposure
A common way ordinary consumers are exposed to nitrosamines is through tobacco use and cigarette smoke.[ ]Tobacco-specific nitrosamines
Tobacco-specific nitrosamines (TSNAs) comprise one of the most important groups of carcinogens in tobacco products, particularly cigarettes (traditional and electronic) and fermented dipping snuff.
Background
These nitrosamine carcinogens are for ...
also can be found in American dip snuff, chewing tobacco
Chewing tobacco is a type of smokeless tobacco product that is placed between the cheek and lower gum to draw out its flavor. Some users chew it, others do not. It consists of coarsely chopped aged tobacco that is flavored and often sweetened; ...
, and to a much lesser degree, snus
Snus ( , ) is a tobacco product, originating from a variant of dry snuff in early 18th-century Sweden. It is placed between the upper lip and gum for extended periods, as a form of sublabial administration. Snus is not fermented. Although used s ...
(127.9 ppm for American dip snuff compared to 2.8 ppm in Swedish snuff or snus).
Dietary exposure
Nitrosamines are produced by the reaction of nitrite
The nitrite polyatomic ion, ion has the chemical formula . Nitrite (mostly sodium nitrite) is widely used throughout chemical and pharmaceutical industries. The nitrite anion is a pervasive intermediate in the nitrogen cycle in nature. The name ...
s and secondary amine
In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituen ...
s. Nitrites are used as food preservatives, e.g. cured meats. Secondary amines arise by the degradation of protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
s (food).
Nitrite and nitrosamine intake are associated with risk of gastric cancer
Stomach cancer, also known as gastric cancer, is a cancer that develops from the lining of the stomach. Most cases of stomach cancers are gastric carcinomas, which can be divided into a number of subtypes, including gastric adenocarcinomas. Lymph ...
and oesophageal cancer
Esophageal cancer is cancer arising from the esophagus—the food pipe that runs between the throat and the stomach. Symptoms often include difficulty in swallowing and weight loss. Other symptoms may include pain when swallowing, a hoarse voice ...
.
Adverse reaction with dimethylamine
During the 1970s, an elevated frequency of liver cancer was found in Norwegian
Norwegian, Norwayan, or Norsk may refer to:
*Something of, from, or related to Norway, a country in northwestern Europe
* Norwegians, both a nation and an ethnic group native to Norway
* Demographics of Norway
*The Norwegian language, including ...
farm animals after the farm animals had been fed on herring
Herring are forage fish, mostly belonging to the family of Clupeidae.
Herring often move in large schools around fishing banks and near the coast, found particularly in shallow, temperate waters of the North Pacific and North Atlantic Oceans, i ...
meal that was preserved using sodium nitrite
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 ...
. The sodium nitrite had reacted with dimethylamine
Dimethylamine is an organic compound with the formula (CH3)2NH. This secondary amine is a colorless, flammable gas with an ammonia-like odor. Dimethylamine is commonly encountered commercially as a solution in water at concentrations up to aroun ...
in the fish and produced dimethylnitrosamine, which was determined to be carcinogenic during the studies of the 1950s.
Opposing reactions with ascorbic acid
Endogenous nitrosamine formation can be affected by ascorbic acid
Vitamin C (also known as ascorbic acid and ascorbate) is a water-soluble vitamin found in citrus and other fruits and vegetables, also sold as a dietary supplement and as a topical 'serum' ingredient to treat melasma (dark pigment spots) an ...
, either inhibiting its formation or increasing its formation, depending upon whether ascorbic acid is consumed in conjunction with it as opposed to the effect being reversed by factors related to dietary fat consumed at the same time.
In the case of formation of carcinogenic nitrosamines in the stomach from dietary nitrite (used as a processed meat preservative), ascorbic acid markedly decreases nitrosamine formation in the absence of fat in the meal, through inhibition. However, when 10% of the meal is fat, the effect is reversed, such that ascorbic acid then markedly ''increases'' nitrosamine formation. A yeast study has shown that N-nitrosamines can perturb amino acid metabolism and mitochondrial function.[Ogbede, J.U., Giaever, G. & Nislow, C. A genome-wide portrait of pervasive drug contaminants. Sci Rep 11, 12487 (2021). https://doi.org/10.1038/s41598-021-91792-1]
Examples
See also
* Angiotensin II receptor blocker recalls
* Hydrazines
Hydrazines (R2N−NR2) are a class of chemical compounds with two nitrogen atoms linked via a covalent bond and which carry from one up to four alkyl or aryl substituents. Hydrazines can be considered as derivatives of the inorganic hydrazine (H ...
derived from these nitrosamines, e.g. UDMH
Unsymmetrical dimethylhydrazine (UDMH; 1,1-dimethylhydrazine, НДМГ or codenamed Geptil) is a chemical compound with the formula H2NN(CH3)2 that is used as a rocket propellant. It is a colorless liquid, with a sharp, fishy, ammonia-like smell ...
, are also carcinogenic.
* Possible health hazards of pickled vegetables
* Ranitidine cancer-causing impurities
* Tobacco-specific nitrosamines
Tobacco-specific nitrosamines (TSNAs) comprise one of the most important groups of carcinogens in tobacco products, particularly cigarettes (traditional and electronic) and fermented dipping snuff.
Background
These nitrosamine carcinogens are for ...
* Valsartan recalls
Additional reading
*
*
References
External links
*
Oregon State University, Linus Pauling Institute article on Nitrosamines and cancer, including info on history of meat laws
Risk factors in Pancreatic Cancer
{{Authority control
Nitrogen cycle
Functional groups
Garde manger
Carcinogens
IARC Group 1 carcinogens