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. Synthesis and occurrence NNK can be produced by standard methods of organic synthesis. Tobacco NNK is both found in cured tobacco and is produced during its burning (pyrolysis). 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. 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. e-Cigarettes e-Cigarette do not convert nicotine to NNK due to their lower operating temperatures. The amount of NNK delivered by e-cigarettes reaches 2.8 ng per 15 puffs (approximately 1 cigarette). NNK was found in 89% of Korean e-cigarette liquids. Concentrations range 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. Biology Metabolism 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-methylhydroxylation or by α-methylenehydroxylation. Both pathways produce the carcinogenic metabolized isoform of NNK, NNAL. In the reductive metabolism NNK undergoes either a carbonyl reduction or a pyridine N-oxidation, both producing NNAL. NNAL can be detoxified by glucuronidation producing a non-carcinogenic compounds known as NNAL-Glucs. The glucuronidation can take place on the oxygen next to the ring (NNAL-O-Gluc), or it takes place on the nitrogen inside the ring(NNAL-N-Gluc). The NNAL-Glucs are then excreted by the kidneys into the