期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 115, 期 27, 页码 E6152-E6161出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1804869115
关键词
tobacco smoke carcinogenesis; aldehydes; DNA damage; DNA repair; polyphenols
资金
- NIH [1P01CA165980, R01CA190678, P30CA16087, ES00260]
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-(3pyridyl)-1-butanoe (NNK), and aldehydes in humans and mice. In mice, TS induces abundant aldehyde-induced gamma-hydroxy-propano-deoxyguanosine (gamma-OH-PdG) and alpha-methyl-gamma-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 gamma-OH-PdG and alpha-methyl-gamma-OH-PdG are the major adducts formed in tobacco smokers' buccal cells as well as the normal lung tissues of tobaccosmoking 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 O-6-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 aremajor TS carcinogens exerting dominant effect: Aldehydes induce mutagenic PdG adducts, impair DNA repair functions, and inhibit many procarcinogens in TS from becoming DNAdamaging agents.
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