N-Nitrosonornicotine

Last updated
N-Nitrosonornicotine
N-nitrosonornicotine-2D-skeletal.svg
Names
Preferred IUPAC name
3-[(2S)-1-Nitrosopyrrolidin-2-yl]pyridine
Identifiers
3D model (JSmol)
AbbreviationsNNN
ChemSpider
ECHA InfoCard 100.230.123 OOjs UI icon edit-ltr-progressive.svg
KEGG
PubChem CID
UNII
  • InChI=1S/C9H11N3O/c13-11-12-6-2-4-9(12)8-3-1-5-10-7-8/h1,3,5,7,9H,2,4,6H2/t9-/m0/s1 Yes check.svgY
    Key: XKABJYQDMJTNGQ-VIFPVBQESA-N Yes check.svgY
  • InChI=1/C9H11N3O/c13-11-12-6-2-4-9(12)8-3-1-5-10-7-8/h1,3,5,7,9H,2,4,6H2/t9-/m0/s1
    Key: XKABJYQDMJTNGQ-VIFPVBQEBO
  • O=NN2CCC[C@H]2c1cnccc1
Properties
C9H11N3O
Molar mass 177.207 g·mol−1
AppearanceOily yellow liquid
Melting point 47 °C (117 °F; 320 K)
Boiling point 154 °C (309 °F; 427 K)
Soluble
Hazards
Flash point 177 °C (351 °F; 450 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

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

Contents

Toxicity

It has been classified as a Group 1 carcinogen. [1] Although no adequate studies of the relationship between exposure to NNN and human cancer have been reported, there is sufficient evidence that NNN causes cancer in experimental animals. [2]

Sources

NNN is found in a variety of tobacco products including smokeless tobacco like chewing tobacco and snuff, [3] cigarettes, and cigars. It is present in smoke from cigars and cigarettes, in the saliva of people who chew betel quid with tobacco, and in the saliva of oral-snuff and e-cigarette [4] users. NNN is produced by the nitrosation of nornicotine during the curing, aging, processing, and smoking of tobacco. [5] 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).[ citation needed ]

Mechanism of action

NNN is metabolized by cytochrome P450, 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. [6] 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.png

Synthesis

Endogenous Formation of Tobacco-specific N-nitrosamines (TSNA).jpg

NNN is a derivative of nicotine that is produced in the curing of tobacco, 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. [7] 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. [8]

The nitrosonium group forms from nitrous acid (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. [9] Nitrous acid becomes protonated on its hydroxy group to form nitrosooxonium. This compound then splits off to form nitrosonium and water. [10]

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. [11] 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. [12] However, in mice, the median lethal dose (LD50) is 1g/kg. [13]

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). [14]

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">Nicotine</span> Mild chemical stimulant produced by some plants

Nicotine is a naturally produced alkaloid in the nightshade family of plants and is widely used recreationally as a stimulant and anxiolytic. As a pharmaceutical drug, it is used for smoking cessation to relieve withdrawal symptoms. Nicotine acts as a receptor agonist at most nicotinic acetylcholine receptors (nAChRs), except at two nicotinic receptor subunits where it acts as a receptor antagonist.

<span class="mw-page-title-main">Gutka</span> Tobacco preparation chewed in South Asia

Gutka, ghutka, guṭkha or betel quid is a chewing tobacco preparation made of crushed areca nut, tobacco, catechu, paraffin wax, slaked lime and sweet or savory flavourings, in India, Pakistan, other Asian countries, and North America.

<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">Snus</span> Moist tobacco product placed under the upper lip, used in the Nordic countries.

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 similarly to American dipping tobacco, snus does not typically result in the need for spitting and, unlike naswar, snus is steam-pasteurized.

<span class="mw-page-title-main">Cotinine</span> Alkaloid found in tobacco. used as a biomarker for exposure to tobacco smoke.

Cotinine is an alkaloid found in tobacco and is also the predominant metabolite of nicotine. An anagram of the word "nicotine", it is used as a biomarker for exposure to tobacco smoke. Cotinine is currently being studied as a treatment for depression, PTSD, schizophrenia, Alzheimer's disease and Parkinson's disease. Cotinine was developed as an antidepressant as a fumaric acid salt, cotinine fumarate, to be sold under the brand name Scotine but it was never marketed.

<span class="mw-page-title-main">Nitrosamine</span> Organic compounds of the form >N–N=O

In organic chemistry, nitrosamines are organic compounds with the chemical structure R2N−N=O, where R is usually an alkyl group. They feature a nitroso group bonded to a deprotonated amine. Most nitrosamines are carcinogenic 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".

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

Dipping tobacco is a type of finely ground or shredded, moistened smokeless tobacco product. It is commonly and idiomatically known as "dip". Dipping tobacco is used by placing a pinch, or "dip", of tobacco between the lip and the gum. The act of using it is called dipping. Dip is colloquially called "chaw", "snuff", "rub", or "fresh leaf" among other terms; because of this, it is sometimes confused with other tobacco products—namely nasal/dry snuff.

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

Nicotine-derived nitrosamine ketone (NNK) is one of the key tobacco-specific nitrosamines derived from nicotine. It plays an important role in carcinogenesis. The conversion of nicotine to NNK entails opening of the pyrrolidine ring.

<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">Health effects of tobacco</span> Circumstances, mechanisms, and factors of tobacco consumption on human health

Tobacco products, especially when smoked or used orally, have negative effects on human health, and concerns about these effects have existed for a long time. Research has focused primarily on cigarette smoking.

<span class="mw-page-title-main">Smokeless tobacco</span> Tobacco product used by means other than smoking.

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 chewing tobacco, snuff, snus, and dissolvable tobacco products. Smokeless tobacco products typically contain over 3000 constituents. All smokeless tobacco products contain nicotine and are therefore highly addictive. Quitting smokeless tobacco use is as challenging as smoking cessation.

<i>Nicotiana tabacum</i> Species of plant

Nicotiana tabacum, or cultivated tobacco, is an annually grown herbaceous plant of the Nicotiana genus. The plant is tropical in origin, is commonly grown throughout the world, and is often found in cultivation. It grows to heights between 1 and 2 meters. Research is ongoing into its ancestry among wild Nicotiana species, but it is believed to be a hybrid of Nicotiana sylvestris, Nicotiana tomentosiformis, and possibly Nicotiana otophora. It is the most commonly grown of all plants in the genus Nicotiana, the plants' leaves commercially grown to be processed into tobacco.

<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.

<span class="mw-page-title-main">Snuff (tobacco)</span> Smokeless tobacco type

Snuff is a type of smokeless tobacco product made from finely ground or pulverized tobacco leaves. It is snorted or "sniffed" into the nasal cavity, delivering a swift hit of nicotine and a lasting flavored scent. Traditionally, it is sniffed or inhaled lightly after a pinch of snuff is either placed onto the back surface of the hand, held pinched between thumb and index finger, or held by a specially made "snuffing" device.

Third-hand smoke is contamination by tobacco smoke that lingers following the extinguishing of a cigarette, cigar, or other combustible tobacco product. First-hand smoke refers to what is inhaled into the smoker's own lungs, while second-hand smoke is a mixture of exhaled smoke and other substances leaving the smoldering end of the cigarette that enters the atmosphere and can be inhaled by others. Third-hand smoke or "THS" is a neologism coined by a research team from the Dana–Farber/Harvard Cancer Center, where "third-hand" is a reference to the smoking residue on surfaces after "second-hand smoke" has cleared out.

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

<i>Duboisia hopwoodii</i> Species of plant

Duboisia hopwoodii is a shrub native to the arid interior region of Australia. Common names include pituri, pitchuri thornapple or pitcheri.

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

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.

References

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