Tobacco-Specific Nitrosamine “4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)”: Toxicological Mechanisms, Carcinogenicity, and Chemopreventive Approaches

The tobacco-specific nitrosamine, 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone has been identified as potent lung carcinogen in laboratory animals. Bioactivation of nicotine-derived nitrosamine ketone occurs via cytochrome P450-mediated hydroxylation of carbon atoms adjacent to the nitrosamino group, generating reactive methylating and pyridyloxobutylating intermediates. NNK can be metabolically reduced to NNAL, which retains carcinogenic potential and undergoes similar activation. Like NNK, NNAL also requires the metabolic activation to DNA alkylating agents. When NNAL is methyl hydroxylated, pyridinyl-hydroxy-butyl DNA adducts are formed, and methylene hydroxylation results in DNA methyl adducts. NNK's metabolic complexity leads to a variety of DNA lesions, increasing its overall carcinogenic potency. From this angle, the chemistry and genotoxic properties of many DNA adduct generated from NNK are discussed. Adducts that contribute to the genotoxic effects of NNK include the gene targeted for mutation, amounts and genetic variants of critical repair enzymes. NNK, present in modern smokeless tobacco products, plays a central role in cancer risk among users. The mechanisms by which NNK induces cancer in humans are discussed in this paper, along with the factors influencing NNK development at various phases of tobacco manufacturing.