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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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dc.contributor.author Gray, Joshua P.
dc.contributor.author Heck, Diane E.
dc.contributor.author Mishin, Vladimir
dc.contributor.author Smith, Peter J. S.
dc.contributor.author Hong, Jun-Yan
dc.contributor.author Thiruchelvam, Mona
dc.contributor.author Cory-Slechta, Deborah A.
dc.contributor.author Laskin, Debra L.
dc.contributor.author Laskin, Jeffrey D.
dc.date.accessioned 2009-04-24T18:10:34Z
dc.date.available 2009-04-24T18:10:34Z
dc.date.issued 2007-01-17
dc.identifier.citation Journal of Biological Chemistry 282 (2007): 7939-7949 en
dc.identifier.uri http://hdl.handle.net/1912/2806
dc.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. en
dc.description.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. en
dc.description.sponsorship This work was supported in part by National Institutes of Health Grants U54AR055073, ES006897, CA100994, CA093798, ES003647, ES010791, ES004738, GM034310, RR001395, and ES005022. en
dc.format.mimetype application/pdf
dc.language.iso en_US en
dc.publisher American Society for Biochemistry and Molecular Biology en
dc.relation.uri http://dx.doi.org/10.1074/jbc.M611817200
dc.title 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 en
dc.type Article en
dc.identifier.doi 10.1074/jbc.M611817200


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