| Redox cycling of 9,10-phenanthraquinone to cause oxidative stress is terminated through its monoglucuronide conjugation in human pulmonary epithelial A549 cells. | |
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MedLine Citation:
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PMID: 18294972 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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 |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. Date: 2008-02-09 |
Journal Detail:
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Title: Free radical biology & medicine Volume: 44 ISSN: 0891-5849 ISO Abbreviation: Free Radic. Biol. Med. Publication Date: 2008 Apr |
Date Detail:
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Created Date: 2008-04-04 Completed Date: 2008-06-19 Revised Date: 2011-05-19 |
Medline Journal Info:
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Nlm Unique ID: 8709159 Medline TA: Free Radic Biol Med Country: United States |
Other Details:
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Languages: eng Pagination: 1645-55 Citation Subset: IM |
Affiliation:
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Doctoral Programs in Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Epithelial Cells / drug effects, metabolism* Glucuronosyltransferase / genetics, metabolism Hepatocytes / drug effects, metabolism Humans Intracellular Signaling Peptides and Proteins / genetics, metabolism Lung / drug effects, metabolism Male Metabolic Detoxication, Drug Mice Mice, Inbred C57BL Mice, Inbred ICR NF-E2-Related Factor 2 / genetics, metabolism Oxidation-Reduction Oxidative Stress / drug effects* Oxygen Consumption / drug effects Particulate Matter / pharmacokinetics*, toxicity Phenanthrenes / pharmacokinetics*, toxicity Substrate Specificity |
| Chemical | |
Reg. No./Substance:
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0/Intracellular Signaling Peptides and Proteins; 0/KEAP1 protein, human; 0/NF-E2-Related Factor 2; 0/Nfe2l2 protein, mouse; 0/Particulate Matter; 0/Phenanthrenes; 84-11-7/9,10-phenanthrenequinone; EC 2.4.1.-/UDP-glucuronosyltransferase, UGT1A6; EC 2.4.1.-/bilirubin uridine-diphosphoglucuronosyl transferase 1A10; EC 2.4.1.17/Glucuronosyltransferase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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