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    Paraquat increases cyanide-insensitive respiration in murine lung epithelial cells by activating an NAD(P)H:paraquat oxidoreductase : identification of the enzyme as thioredoxin reductase

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    Date
    2007-01-17
    Author
    Gray, Joshua P.  Concept link
    Heck, Diane E.  Concept link
    Mishin, Vladimir  Concept link
    Smith, Peter J. S.  Concept link
    Hong, Jun-Yan  Concept link
    Thiruchelvam, Mona  Concept link
    Cory-Slechta, Deborah A.  Concept link
    Laskin, Debra L.  Concept link
    Laskin, Jeffrey D.  Concept link
    Metadata
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    Citable URI
    https://hdl.handle.net/1912/2806
    As published
    https://doi.org/10.1074/jbc.M611817200
    DOI
    10.1074/jbc.M611817200
    Abstract
    Pulmonary fibrosis is one of the most severe consequences of exposure to paraquat, an herbicide that causes rapid alveolar inflammation and epithelial cell damage. Paraquat is known to induce toxicity in cells by stimulating oxygen utilization via redox cycling and the generation of reactive oxygen intermediates. However, the enzymatic activity mediating this reaction in lung cells is not completely understood. Using self-referencing microsensors, we measured the effects of paraquat on oxygen flux into murine lung epithelial cells. Paraquat (10–100 µM) was found to cause a 2–4-fold increase in cellular oxygen flux. The mitochondrial poisons cyanide, rotenone, and antimycin A prevented mitochondrial- but not paraquat-mediated oxygen flux into cells. In contrast, diphenyleneiodonium (10 µM), an NADPH oxidase inhibitor, blocked the effects of paraquat without altering mitochondrial respiration. NADPH oxidases, enzymes that are highly expressed in lung epithelial cells, utilize molecular oxygen to generate superoxide anion. We discovered that lung epithelial cells possess a distinct cytoplasmic diphenyleneiodonium-sensitive NAD(P)H:paraquat oxidoreductase. This enzyme utilizes oxygen, requires NADH or NADPH, and readily generates the reduced paraquat radical. Purification and sequence analysis identified this enzyme activity as thioredoxin reductase. Purified paraquat reductase from the cells contained thioredoxin reductase activity, and purified rat liver thioredoxin reductase or recombinant enzyme possessed paraquat reductase activity. Reactive oxygen intermediates and subsequent oxidative stress generated from this enzyme are likely to contribute to paraquat-induced lung toxicity.
    Description
    Author Posting. © American Society for Biochemistry and Molecular Biology, 2007. This article is posted here by permission of American Society for Biochemistry and Molecular Biology for personal use, not for redistribution. The definitive version was published in Journal of Biological Chemistry 282 (2007): 7939-7949, doi:10.1074/jbc.M611817200.
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    Suggested Citation
    Journal of Biological Chemistry 282 (2007): 7939-7949
     
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