Two-electron quinone reductase (Aldo-keto Reductase 1C Isozyme) augments the oxidative DNA damage induced by quinones in diesel exhaust particles by accelerating redox cycling

Shigeru Yamano, Mie Shibata, Hideki Kita, Kimihiko Matsusue, Shizuo Narimatsu, Keiko Taguchi, Yoshito Kumagai

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

DNA cleavage by quinones contained in diesel exhaust particles (DEP) was examined in a cell-free system using supercoiled FX174 DNA as the target DNA. In the presence of Cu(II) and NADPH, 9,10phenanthrenequinone (PQ) caused the transformation of the supercoiled FX174 DNA into open circular and then linear forms in a concentration-dependent manner. This DNA damage by PQ was decreased by catalase, a superoxide anion scavenger and a Cu(I)specific chelator, but not by superoxide dismutase and a hydroxyl radical scavenger, suggesting that the ultimate reactive product responsible for the DNA scission may be Cu(I)-OOH generated from hydrogen peroxide and Cu(I) rather than hydroxyl radicals. In addition, 1,2-naphthoquinone (1,2-NQ) damaged DNA more severely than PQ, while 1,4-NQ and 9,10anthraquinone (AQ) did not induce significant DNA damage. When a purified aldo-keto reductase (AKR) 1C isozyme, which catalyzes the two-electron reduction of PQ, was included in the reaction mixture, the PQ-induced DNA damage became more extensive. Addition of the AKR1C isozyme also increased the 1,2-NQ-induced DNA damage and conferred the ability to cause DNA damage on 1,4-NQ, but had no effect on AQ. The severity of the DNA damage induced by DEP quinones was solely related to both NADPH consumption and reactive oxygen species (ROS) generation. These findings indicate that the generation of ROS via redox cycling of DEP quinones is a causative event in DNA scission and that the AKR1C isozyme accelerates the redox cycling of DEP quinones that are utilized as substrates, thereby resulting in the promotion of oxidative stress and DNA damage.

Original languageEnglish
Pages (from-to)107-114
Number of pages8
JournalJournal of Health Science
Volume57
Issue number1
DOIs
Publication statusPublished - 2011 Feb

Keywords

  • DNA scission
  • Quinone in diesel exhaust particle
  • Redox cycling
  • Two-electron reduction

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

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