Chapter 5 Molecular Mechanisms of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone-Induced Lung Carcinogenesis

Our understanding of the molecular mechanisms of NNK-induced pulmonary carcinogenesis in rodents has increased substantially in the past 5-10 years. NNK requires metabolic activation to elicit its carcinogenic properties. Both DNA alkylation pathways are important to the carcinogenic properties of this potent lung carcinogen. The DNA methylation pathway is well-characterized and is a critical pathway for the elicitation of NNK-induced pulmonary tumors in A/J mice. The pyridyloxobutylation pathway likely contributes to the mutagenic properties in this animal model by influencing the repair of the mutagenic O⁶-mG through several possible mechanisms. The pyridyloxobutylion pathway appears to play an important role in the initiation of lung tumors in rats. Now that specific pyridyloxobutyl DNA adducts have been characterized, more specific details regarding the mutagenic properties of this pathway can be acquired. It is clear that multiple pyridyloxobutyl DNA adducts contribute to the overall mutagenic properties of this compound. Which adduct(s) is (are) more important will likely depend on particular situations. For example, O⁶-pobG is likely responsible for the GC to AT transitional mutations triggered by the pyridyloxobutylation pathway. So this adduct may be responsible for GC to AT mutations observed in activated K-ras associated with pyridyloxobutylating agents. Other adducts, like O²-pobdT, are likely responsible for other mutations (i.e., AT to TA transversion). It is important that the mutational specificity of these newly identified adducts be determined. Recent data also indicate the importance of defining the role the aldehyde metabolites of NNK play in the mechanism of tumor induction of this compound. These compounds are likely to enhance as well as contribute to the mutagenic properties of the alkylation pathways. It is also clear from the accumulating data that NNK is an effective promoter of cells which have been initiated by its genotoxic metabolites. Further investigations into the biochemical mechanisms of tumor promotion by this potent carcinogen will provide insights into possible chemoprevention strategies. The identification of all the important steps in the activation, formation, and cellular responses to NNK and its metabolites are critical for our application of the laboratory animal studies to humans for adequate risk assessment. While most lung cancers are attributed to smoking, only 15% of smokers get lung cancer [184]. Genetic variations in the proteins involved in every step in this process likely influence a person's risk. Therefore, genetic susceptibility is likely to be critical in the determination of lung cancer risk in humans. Therefore, it is critical that we establish the biochemical details of NNK-induced carcinogenesis so that we can determine the genetic factors responsible for increased risk in susceptible populations.