''N''-Nitrosonornicotine (NNN) is a

tobacco-specific nitrosamine 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 fo ...

produced during the curing and processing of

tobacco Tobacco is the common name of several plants in the genus '' Nicotiana'' of the family Solanaceae, and the general term for any product prepared from the cured leaves of these plants. More than 70 species of tobacco are known, but the ...

Toxicity

It has been classified as a Group 1 carcinogen. Although no adequate studies of the relationship between exposure to NNN and human

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

have been reported, there is sufficient evidence that NNN causes cancer in experimental animals.

Sources

NNN is found in a variety of tobacco products including

smokeless tobacco Smokeless tobacco is a tobacco product that is used by means other than smoking. Their use involves chewing, sniffing, or placing the product between gum and the cheek or lip. Smokeless tobacco products are produced in various forms, such as che ...

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

snuff Snuff may refer to: Tobacco * Snuff (tobacco), fine-ground tobacco, sniffed into the nose ** Moist snuff or dipping tobacco ** Creamy snuff, an Indian tobacco paste Media and entertainment * Snuff film, a type of film that shows a murder Literat ...

cigarette A cigarette is a narrow cylinder containing a combustible material, typically tobacco, that is rolled into thin paper for smoking. The cigarette is ignited at one end, causing it to smolder; the resulting smoke is orally inhaled via the opp ...

s, and

cigar A cigar is a rolled bundle of dried and fermented tobacco leaves made to be smoked. Cigars are produced in a variety of sizes and shapes. Since the 20th century, almost all cigars are made of three distinct components: the filler, the binder l ...

s. It is present in smoke from cigars and cigarettes, in the

saliva Saliva (commonly referred to as spit) is an extracellular fluid produced and secreted by salivary glands in the mouth. In humans, saliva is around 99% water, plus electrolytes, mucus, white blood cells, epithelial cells (from which DNA can be ...

of people who chew

betel quid Betel nut chewing, also called betel quid chewing or areca nut chewing, is a practice in which areca nuts (also called "betel nuts") are chewed together with slaked lime and betel leaves for their stimulant and narcotic effects. The practice ...

with tobacco, and in the saliva of oral-snuff and e-cigarette users. NNN is produced by the

nitrosation Nitrosation is a process of converting organic compounds into nitroso derivatives, i.e. compounds containing the R-NO functionality. ''C''-Nitroso compounds ''C''-Nitroso compounds, such as nitrosobenzene, are typically prepared by oxidation of ...

nornicotine Nornicotine is an alkaloid found in various plants including ''Nicotiana'', the tobacco plant. It is chemically similar to nicotine, but does not contain a methyl group. It is a precursor to the carcinogen ''N''-nitrosonornicotine that is produc ...

during the curing, aging, processing, and smoking of tobacco. Roughly half of the NNN originates in the unburnt tobacco, with the remainder being formed during burning. NNN can be produced in the acidic environment of the stomach in users of oral nicotine replacement therapies, due to the combination of dietary/endogenous nitrates, and nornicotine (either present as a minor metabolite of nicotine, or as an impurity in the product).

Mechanism of action

NNN is metabolized by

cytochrome P450 Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...

, which adds a hydroxy group to either the 2' or 5' carbon on the 5-membered ring. 2'-hydroxylation appears more prevalent in humans, while 5'-hydroxylation is more prevalent in non-primate animals. Upon hydroxylation, the 5-membered ring opens up, allowing the compound to bind to the base of one of the nucleotides. NNN_Mechanism_of_Action

Synthesis

Endogenous_Formation_of_Tobacco-specific_N-nitrosamines_(TSNA)

NNN is a derivative of nicotine that is produced in the

curing of tobacco In nearly all instances where tobacco is to be used for smoking or chewing, it is necessary to cure the tobacco directly after it's harvested. Tobacco curing is also known as ''color curing'', because tobacco leaves are cured with the intention of ...

, in the burning of tobacco (such as with cigarettes), and in the acidic conditions of the stomach. Nicotine is converted into nornicotine via nicotine N-demethylase (NND), an enzyme found in the tobacco plant that works by removing the methyl group from the nitrogen on the 5-membered ring of nicotine. From there, Nornicotine undergoes nitrosation (the conversion of organic compounds into nitroso derivatives by gaining a nitrosonium (N=O) group) on that same nitrogen, converting it to NNN. The nitrosonium group forms from

nitrous acid Nitrous acid (molecular formula ) is a weak and monoprotic acid known only in solution, in the gas phase and in the form of nitrite () salts. Nitrous acid is used to make diazonium salts from amines. The resulting diazonium salts are reagent ...

(HNO₂) under acidic conditions present in the tobacco curing process. It can also be formed in the stomach when stomach acid reacts with nitrite ions that are typically used as a salt to preserve red meats and inhibit bacterial growth. Nitrous acid becomes protonated on its hydroxy group to form nitrosooxonium. This compound then splits off to form nitrosonium and water.

Symptoms

Symptoms of NNN are similar to those of nicotine poisoning and include irritation at the point of absorption (for example, the gums when dipping tobacco is used), nausea and vomiting, sleep disturbances, headache, and chest pain. The substance is also a known carcinogen, meaning that any exposure to the substance can lead to cancer and is proven to cause esophageal and nasal cancer in animals. There is no known "safe" levels of NNN ingestion in humans due to its carcinogenic activity. However, in mice, the

median lethal dose In toxicology, the median lethal dose, LD50 (abbreviation for "lethal dose, 50%"), LC50 (lethal concentration, 50%) or LCt50 is a toxic unit that measures the lethal dose of a toxin, radiation, or pathogen. The value of LD50 for a substance is the ...

(LD₅₀) is 1g/kg. In cigarette smoke, NNN has been found in levels between 2.2-6.6 parts per million (ppm). The FDA has put limits of nitrosamines in other consumable products (such as cured meats) at levels below 10 parts per billion (ppb).

References

__FORCETOC__ {{DEFAULTSORT:Nitrosonornicotine, N- 3-Pyridyl compounds Nitrosamines Pyrrolidines IARC Group 1 carcinogens