| Redox cycling and increased oxygen utilization contribute to diquat-induced oxidative stress and cytotoxicity in Chinese hamster ovary cells overexpressing NADPH-cytochrome P450 reductase. | |
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MedLine Citation:
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PMID: 21215309 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Diquat and paraquat are nonspecific defoliants that induce toxicity in many organs including the lung, liver, kidney, and brain. This toxicity is thought to be due to the generation of reactive oxygen species (ROS). An important pathway leading to ROS production by these compounds is redox cycling. In this study, diquat and paraquat redox cycling was characterized using human recombinant NADPH-cytochrome P450 reductase, rat liver microsomes, and Chinese hamster ovary (CHO) cells constructed to overexpress cytochrome P450 reductase (CHO-OR) and wild-type control cells (CHO-WT). In redox cycling assays with recombinant cytochrome P450 reductase and microsomes, diquat was 10-40 times more effective at generating ROS compared to paraquat (K(M)=1.0 and 44.2μM, respectively, for H(2)O(2) generation by diquat and paraquat using recombinant enzyme, and 15.1 and 178.5μM, respectively for microsomes). In contrast, at saturating concentrations, these compounds showed similar redox cycling activity (V(max)≈6.0nmol H(2)O(2)/min/mg protein) for recombinant enzyme and microsomes. Diquat and paraquat also redox cycle in CHO cells. Significantly more activity was evident in CHO-OR cells than in CHO-WT cells. Diquat redox cycling in CHO cells was associated with marked increases in protein carbonyl formation, a marker of protein oxidation, as well as cellular oxygen consumption, measured using oxygen microsensors; greater activity was detected in CHO-OR cells than in CHO-WT cells. These data demonstrate that ROS formation during diquat redox cycling can generate oxidative stress. Enhanced oxygen utilization during redox cycling may reduce intracellular oxygen available for metabolic reactions and contribute to toxicity. |
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Authors:
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Karma C Fussell; Ronald G Udasin; Joshua P Gray; Vladimir Mishin; Peter J S Smith; Diane E Heck; Jeffrey D Laskin |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2011-01-04 |
Journal Detail:
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Title: Free radical biology & medicine Volume: 50 ISSN: 1873-4596 ISO Abbreviation: Free Radic. Biol. Med. Publication Date: 2011 Apr |
Date Detail:
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Created Date: 2011-02-28 Completed Date: 2011-08-01 Revised Date: 2011-09-22 |
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: 874-82 Citation Subset: IM |
Copyright Information:
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Copyright © 2010 Elsevier Inc. All rights reserved. |
Affiliation:
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Pharmacology and Toxicology, Rutgers University, Piscataway, NJ 08854, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals CHO Cells Cricetinae Cricetulus Diquat / metabolism, pharmacology* Female Gene Expression Humans Hydrogen Peroxide / metabolism Liver / metabolism* Microsomes, Liver / metabolism NADPH-Ferrihemoprotein Reductase* / genetics, metabolism Oxidation-Reduction / drug effects Oxidative Stress / drug effects Oxygen / metabolism* Oxygen Consumption / drug effects Paraquat / metabolism, pharmacology* Protein Carbonylation / drug effects Rats Reactive Oxygen Species / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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AR055073/AR/NIAMS NIH HHS; CA093798/CA/NCI NIH HHS; ES005022/ES/NIEHS NIH HHS; R01 CA093798-05/CA/NCI NIH HHS; R01 CA093798-06/CA/NCI NIH HHS; R01 CA132624-02/CA/NCI NIH HHS; R01 CA132624-03/CA/NCI NIH HHS; R01 ES004738-17/ES/NIEHS NIH HHS; R01 ES004738-18/ES/NIEHS NIH HHS; R01 ES004738-19/ES/NIEHS NIH HHS; R01 GM034310-23/GM/NIGMS NIH HHS; U54AR055073/AR/NIAMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Reactive Oxygen Species; 2764-72-9/Diquat; 4685-14-7/Paraquat; 7722-84-1/Hydrogen Peroxide; 7782-44-7/Oxygen; EC 1.6.2.4/NADPH-Ferrihemoprotein Reductase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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