Redox cycling of 9,10-phenanthraquinone to cause oxidative stress is terminated through its monoglucuronide conjugation in human pulmonary epithelial A549 cells

Keiko Taguchi, Megumi Shimada, Sayako Fujii, Daigo Sumi, Xiaoqing Pan, Shigeru Yamano, Takahito Nishiyama, Akira Hiratsuka, Masayuki Yamamoto, Arthur K. Cho, John R. Froines, Yoshito Kumagai

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

9,10-Phenanthraquinone (PQ), a component of airborne particulate matter, causes marked cellular protein oxidation and cytotoxicity through a two-electron reduction to 9,10-dihydroxyphenanthrene (PQH2), which is associated with the propagation of reactive oxygen species (K. Taguchi et al., Free Radic. Biol. Med. 43:789-799, 2007). In the present study, we explored a biotransformation pathway for the detoxification of PQ. Exposure of human pulmonary epithelial A549 cells to PQ resulted in a time-dependent appearance of an unknown metabolite in the medium that was identified as the monoglucuronide of PQH2 (PQHG). Whereas a variety of isozymes of uridine 5′-diphosphate glucuronosyltransferase (UGTs) are responsible for PQHG formation, UGT1A10 and UGT1A6 were particularly effective catalysts for glucuronide conjugation. In cell-free systems, PQ exhibited a rapid thiol oxidation and subsequent oxygen consumption in the presence of dithiothreitol, whereas PQHG did not. Unlike the parent compound, PQHG completely lost the ability to oxidize cellular proteins and cause cell death in A549 cells. In addition, deletion of the transcription factor Nrf2 decreased PQHG formation and increased PQ-mediated toxicity of mouse primary hepatocytes. Thus, we conclude that PQHG is a metabolite of PQ, generated through PQH2, that terminates its redox cycling and transports it to extracellular space.

Original languageEnglish
Pages (from-to)1645-1655
Number of pages11
JournalFree Radical Biology and Medicine
Volume44
Issue number8
DOIs
Publication statusPublished - 2008 Apr 15
Externally publishedYes

Keywords

  • 9,10-Phenanthraquinone
  • Detoxification
  • Free radicals
  • Glucuronidation
  • Redox activity

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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