Nicotine-derived nitrosamine ketone
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IUPAC name
4-[Methyl(nitroso)amino]-1-(3-pyridinyl)-1-butanone
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| Other names
N-Nitrosonornicotine ketone; 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone
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3D model (JSmol)
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| ChEBI | |
| ChemSpider | |
| ECHA InfoCard | 100.164.147 |
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| Properties | |
| C10H13N3O2 | |
| Molar mass | 207.23 g·mol−1 |
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Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Nicotine-derived nitrosamine ketone (NNK), also known as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, is one of the key tobacco-specific nitrosamines which play an important role in carcinogenesis.
NNK is a compound that is naturally synthesized in tobacco leaves that are exposed to light: the pyrrolidine ring in the nicotine opens and turns the nicotine into NNK. Most of the NNK found in tobacco smoke originates from nicotine burning.
It can also be formed synthetically by taking the following steps:
The potent carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is present in tobacco and tobacco smoke. [Carbonyl14C]NNK (6) was synthesized in 27% overall yield. [Carboxyl-14C] nicotinic acid was esterified with benzyl alcohol and the ester was alkylated by 3-lithio-N-methylpyrrolidin-2-one. The resulting keto-lactam was hydrolyzed and decarboxylated by treatment with boiling hydrochloric acid. Nitrosation at pH 4.0 gave [carbonyl-14C]NNK. Carbonyl reduction of [carbonyl-14C]NNK with either sodium borohydride or cultured rat liver slices gave [carbinol-14C] 4-(methylnitrosamino)-1-(3-pyridyl) butan-1-ol.
Sun-cured tobaccos (a.k.a. "Oriental") contain very little NNK and other TSNAs due to low-nitrate soil, lack of nitrate fertilizer, and sun-curing. Flue-cured tobacco (a.k.a. "Virginia" tobacco), especially when using an open flame, contains most of the NNK in American blended tobaccos although Marlboro's "virginia blend" had the lowest levels of NNK per nicotine out of many tested with the exception of Natural American Spirit.
NNK was found in 89% of Korean e-cigarette liquids tested in concentrations from 0.22 to 9.84 µg/L. For the product that had the highest amount, if 1 ml is equival to 20 cigarettes, there would be 9.84/20 = 0.5 ng NNK per e-cig cigarette dose. Cigarettes with 1 gram of tobacco average about 350 ng. It is believed that none of the nicotine in an e-cigarette is converted to NNK due to the lower vaporization temperature. The amount of NNK delivered in cigarette smoke ranged from 30 to 280 ng/cigarette in one study and 12 to 110 ng/cigarette in another. The amount of NNK delivered by e-cigarettes was found to range from non-detectable to 2.8 ng per 15 puffs (approximately 1 cigarette).
NNK is initially a procarcinogen that needs activation to exert its effects. The activation of NNK is done by enzymes of the cytochrome pigment (CYP) multigene family. These enzymes catalyze hydroxylation reactions. Beside the CYP family NNK can also be activated by metabolic genes, like myeloperoxidase (MPO) and epoxide hydrolase (EPHX1). NNK can be activated by two different routes, the oxidative path and the reductive path. In the oxidative metabolism NNK undergoes an α-hydroxylation catalyzed by cytochrome P450. This reaction can be done by two pathways namely by α-methylhydoxylation or by α-methylenehydroxylation. Both pathways produce the carcinogenic metabolized isoform of NNK, NNAL.
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