Tobacco consumption is the main identifiable risk to
cancer, contributing to the majority of
tumors in upper aerodigestive tissues. The psychoactive compound responsible for tobacco
addiction, nicotine and the potent
carcinogens present at high concentrations either in cigarette mainstream
smoke or in smokeless tobacco products, 4-(methylnitrosamino)-1-(3-pyridyl)-butanone (NNK) and
N-nitrosonornicotine (NNN) can be metabolized by CYP2A6. CYP2A6 is expressed in many aerodigestive tissues with high interindividual variability. The CYP2A6 gene is highly polymorphic and CYP2A6 alleles coding for
enzymes with altered expression or metabolic capacity produce alterations in
nicotine metabolism in vivo and seem to influence smoking behavior. These polymorphisms may change the rate of NNK and NNN activation and, therefore, may influence
cancer risk associated with tobacco consumption. However, to date only a few and inconclusive studies have addressed the risk that a given CYP2A6 polymorphism presents for the development of tobacco-related
tumors. Most, but not all, show a reduced risk associated with alleles that result in decreased
enzyme activity. The overlapping substrate specificity and tissue expression between CYP2A6 and the highly similar CYP2A13 may add to the conflicting results observed. The intricate regulation of CYP2A6 and the variation of structurally different chemical compounds capable of inhibiting
CYP2A enzymes also add to the complexity. Finally, the interaction between polymorphisms of genes that code for CYP2A6, CYP2A13 and other potent
carcinogen-metabolizing CYP
enzymes may help to determine individuals that are at higher risk of developing
tumors associated with tobacco consumption.