4.5 Article

α,β-Unsaturated Aldehyde-Induced Delays in Nucleotide Excision Repair and the Contribution of Reactive Oxygen Species

期刊

CHEMICAL RESEARCH IN TOXICOLOGY
卷 31, 期 2, 页码 145-155

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AMER CHEMICAL SOC
DOI: 10.1021/acs.chemrestox.7b00304

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资金

  1. Smoking Research Foundation
  2. JSPS KAKENHI [JP15H02828]
  3. Grants-in-Aid for Scientific Research [15H02828] Funding Source: KAKEN

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Aldehydes are widespread environmental and industrial compounds to which humans are frequently exposed. Despite their significant health risk, the mechanisms underlying aldehyde toxicity are poorly understand. We recently demonstrated that cigarette sidestream smoke (CSS) inhibited nucleotide excision repair (NER), and this was attributed to aldehydes in CSS. In the present study, we examined the influence of saturated and unsaturated aldehydes on NER The human keratinocyte cell line, HaCaT, was treated with aldehydes and then exposed to UVB. Saturated aldehydes did not show toxicity, whereas alpha,beta-unsaturated aldehydes caused cell death, which was markedly enhanced by UV exposure. The speed of NER was examined by the detection of pyrimidine (6-4) pyrimidone photoproducts (6-4PPs) using ELISA and local UV irradiation assay. The repair of 6-4PPs was markedly reduced by alpha,beta-unsaturated aldehydes, but not by saturated aldehydes, and this was attributed to a delay in the recruitment of repair proteins (TFIIH and XPG) to DNA damage sites. Reactive oxygen species (ROS) were produced after a treatment with alpha,beta-unsaturated aldehydes, and hydrogen peroxide (H2O2) inhibited the repair of 6-4PPs, similar to alpha,beta-unsaturated aldehydes. H2O2 inhibited the accumulation of XPA and XPG at DNA damage sites, whereas TFIIH showed the same recruitment with or without H2O2. These results suggest that an exposure to alpha,beta-unsaturated aldehydes, not saturated aldehydes inhibits NER by delaying the recruitment of NER proteins to DNA damage sites, and alpha,beta-unsaturated aldehyde-induced ROS production may partially play a role in this process.

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