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

Mao wen Weng, Hyun Wook Lee, Sung Hyun Park, Yu Hu, Hsing Tsui Wang, Lung Chi Chen, William N. Rom, William C. Huang, Herbert Lepor, Xue Ru Wu, Chung S. Yang, Moon shong Tang

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)E6152-E6161
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number27
DOIs
StatePublished - Jul 3 2018

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • Aldehydes
  • DNA damage
  • DNA repair
  • Polyphenols
  • Tobacco smoke carcinogenesis

Fingerprint

Dive into the research topics of 'Aldehydes are the predominant forces inducing DNA damage and inhibiting DNA repair in tobacco smoke carcinogenesis'. Together they form a unique fingerprint.

Cite this