"Oriental") contain very little NNK and other TSNAs due to low-nitrate soil, lack of nitrate fertilizer, and sun-curing.

Beside the CYP family NNK can also be activated by metabolic genes, like myeloperoxidase (MPO) and epoxide hydrolase (EPHX1).

[12] Once NNK is activated, it initiates a cascade of signaling pathways (for example ERK1/2, NF-κB, PI3K/Akt, MAPK, FasL, K-Ras), resulting in uncontrolled cellular proliferation and tumorigenesis.

[1] NNK activates μ en m-calpain kinase which induces lung metastasis via the ERK1/2 pathway.

Also NNK promotes cell survival via phosphorylation with cooperation of c-Myc and Bcl-2 causing cellular migration, invasion and uncontrolled proliferation.

Studies showed that with a 100 mg/kg dose of NNK, several point mutations were formed in the RAR-β gene, inducing tumorigenesis in the lungs.

[citation needed] Other genes affected by NNK include sulfotransferase 1A1 (SULT1A1), transforming growth factor beta (TGF-β), and angiotensin II (AT2).

[citation needed] NNK plays a very important role in gene silencing, modification, and functional disruption which induce carcinogenesis.

[1] Chemical compounds derived from cruciferous vegetables and EGCG inhibit lung tumorigenesis by NNK in animal models.