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

研究成果: Article査読

50 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)1645-1655
ページ数11
ジャーナルFree Radical Biology and Medicine
44
8
DOI
出版ステータスPublished - 2008 4月 15
外部発表はい

ASJC Scopus subject areas

  • 生化学
  • 生理学(医学)

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