Title: Aldehydes are the predominant forces inducing DNA damage and inhibiting DNA repair in tobacco smoke carcinogenesis.
Authors: Weng, Mao-Wen; Lee, Hyun-Wook; Park, Sung-Hyun; Hu, Yu; Wang, Hsing-Tsui; Chen, Lung-Chi; Rom, William N; Huang, William C; Lepor, Herbert; Wu, Xue-Ru; Yang, Chung S; Tang, Moon-Shong
Published In Proc Natl Acad Sci U S A, (2018 07 03)
Abstract: Tobacco smoke (TS) contains numerous cancer-causing agents, with polycyclic aromatic hydrocarbons (PAHs) and nitrosamines being most frequently cited as the major TS human cancer agents. Many lines of evidence seriously question this conclusion. To resolve this issue, we determined DNA adducts induced by the three major TS carcinogens: benzo(a)pyrene (BP), 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanoe (NNK), and aldehydes in humans and mice. In mice, TS induces abundant aldehyde-induced γ-hydroxy-propano-deoxyguanosine (γ-OH-PdG) and α-methyl-γ-OH-PdG adducts in the lung and bladder, but not in the heart and liver. TS does not induce the BP- and NNK-DNA adducts in lung, heart, liver, and bladder. TS also reduces DNA repair activity and the abundance of repair proteins, XPC and OGG1/2, in lung tissues. These TS effects were greatly reduced by diet with polyphenols. We found that γ-OH-PdG and α-methyl-γ-OH-PdG are the major adducts formed in tobacco smokers' buccal cells as well as the normal lung tissues of tobacco-smoking lung cancer patients, but not in lung tissues of nonsmokers. However, the levels of BP- and NNK-DNA adducts are the same in lung tissues of smokers and nonsmokers. We found that while BP and NNK can induce BPDE-dG and O6-methyl-dG adducts in human lung and bladder epithelial cells, these inductions can be inhibited by acrolein. Acrolein also can reduce DNA repair activity and repair proteins. We propose a TS carcinogenesis paradigm. Aldehydes are major TS carcinogens exerting dominant effect: Aldehydes induce mutagenic PdG adducts, impair DNA repair functions, and inhibit many procarcinogens in TS from becoming DNA-damaging agents.
PubMed ID: 29915082
MeSH Terms: Aldehydes/toxicity*; Animals; Benzo(a)pyrene/toxicity*; Carcinogens/toxicity*; Cell Line; Cell Transformation, Neoplastic*/chemically induced; Cell Transformation, Neoplastic*/genetics; Cell Transformation, Neoplastic*/metabolism; Cell Transformation, Neoplastic*/pathology; DNA Damage*; DNA Repair/drug effects*; Humans; Lung Neoplasms*/chemically induced; Lung Neoplasms*/genetics; Lung Neoplasms*/metabolism; Lung Neoplasms*/pathology; Mice; Nitrosamines/toxicity*; Tobacco Smoke Pollution/adverse effects*; Tobacco Smoking*/adverse effects; Tobacco Smoking*/pathology