Aldehydes are the predominant forces inducing DNA damage and inhibiting DNA repair in tobacco smoke carcinogenesis

Abstract

Significance Tobacco smoke (TS) contains numerous carcinogens. Intriguingly, while TS itself is a weak carcinogen in animal models, many of the TS components, such as 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone (NNK) and polycyclic aromatic hydrocarbons (PAHs), are strong carcinogens. We found that TS induces mainly aldehyde-DNA adducts in mice and humans. TS reduces DNA repair activity and repair proteins in mouse lung. All of these TS-induced effects can be reduced by diet polyphenols. Aldehydes prevent PAHs and NNK from inducing DNA damage in human cells. We propose that, because they act to damage DNA, reduce DNA repair activity, and inhibit NNK and PAHs from becoming DNA-damaging agents, aldehydes are the major TS carcinogens. These insights allow for better TS cancer risk assessment and the design of effective preventive measures.