|Molar mass||207.23 g/mol|
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
|what is: / ?)(|
Nicotine-derived nitrosamine ketone (NNK), also known as 4-(methylnitro-samino)-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.
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.” 
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. 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 an 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 urine. 
Once NNK is activated, NNK initiates a cascade of signaling pathways (for example ERK1/2, NFκB, PI3K/Akt, MAPK, FasL, K-ras), resulting in uncontrolled cellular proliferation and tumorigenesis. NNK activates µ en m-calpain kinase which induce lung metastatis via the ERK1/2 pathway. This pathway upregulate cellular myelocytomatosis (c-Myc) and B cell leukemia/lumphoma 2 (Bcl2) in which the two oncoprotein are involved in cellular proliferation, transformation and apoptosis. Also does NNK promotes cell survival via phosphorylation with cooperation of c-Myc and Bcl2 causing cellular migration, invasion and uncontrolled proliferation. The ERK1/2 pathway also phosphorylate NFκB causing a upregulation of cyclin D1, a G1 phase regulator protein. When NNK is present it directly involves cellular survival dependent on NFκB. Further studies are needed to better understand NNK cellular pathyways of NFκB. The phosphoinositide 3-kinase (PI3K/Akt) pathway is also an important contributor to NNK-induced cellular transformations and metastasis. This process ensures the proliferation and survival of tumorigenic cells. The ERK1/2 and Akt pathways show consequential changes in levels of protein expression as a result of NNK-activation in the cells, but further research is needed to fully understand the mechanism of NNK-activated pathways.
NNK is known as a mutagen, which means it causes a lot of polymorphisms in the human genome. Studies showed that NNK induced gene polymorphisms in cells that involve in cell growth, proliferation and differentiation. There are a lot of NNK dependent routes that involve cell proliferation. One of the many examples is the cellroute that coordinates the downregulation of retinoic acid receptor beta (RAR-β). Studies showed that with a dose of NNK of 100 mg/kg several point mutations were formed in the RAR-β gene and that induced tumorigenesis in the lungs. There were also found a lot more genes that were affected by the NNK compound such as sulfotransferase 1A1 (SULT1A1), tumor growth factor-beta (TGF-β) and angiotensin II (AT2). Summarizing NNK plays a very important role in gene silencing, modification and functional disruption which cause the early development of carcinogenesis. But the exact cause why it plays that important role is not yet clear. 
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