Physiological concentrations of unconjugated bilirubin prevent oxidative stress-induced hepatocanalicular dysfunction and cholestasis

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dc.citation.titleArchives of Toxicologyes
dc.citation.volume88(2)es
dc.creatorBasiglio, Cecilia Lorena
dc.creatorToledo, Flavia D.
dc.creatorBoaglio, Andrea C.
dc.creatorArriaga, Sandra Mónica María
dc.creatorOchoa, Justina E.
dc.creatorSánchez Pozzi, Enrique Juan
dc.creatorMottino, Aldo D.
dc.creatorRoma, Marcelo Gabriel
dc.date.accessioned2018-01-29T21:00:05Z
dc.date.available2018-01-29T21:00:05Z
dc.date.issued2014-02
dc.descriptionBilirubin is an endogenous antioxidant with cytoprotective properties, and several studies highlight its potential in the treatment of pro-oxidant diseases. We demonstrated that oxidative stress (OS), a key feature in most hepatopathies, induces cholestasis by actin cytoskeleton disarrangement and further endocytic internalization of key canalicular transporters, such as the bile salt export pump (Bsep) and the multidrug resistance-associated protein 2 (Mrp2). He re, we evaluated the capability of physiological concentrations of unconjugated bilirubin (UB) to limit OS and the impairment in biliary secretory function induced by the model pro-oxidant agent, tert-butylhydroperoxide (tBuOOH). UB fully prevented the formation of reactive oxygen species (ROS) and membrane lipid peroxidation induced by tBuOOH in isolated rat hepatocytes. In the isolated rat hepatocyte couplet model, UB (17.1 µM) prevented the endocytic internalization of Bsep and Mrp2 and the impairment in their secretory function induced by tBuOOH. UB also prevented actin disarrangement, as evaluated by both plasma membrane bleb formation and actin fluorescent staining. Finally, UB prevented tBuOOH-induced cPKC activation. Experiments in isolated perfused rat livers showed that UB prevents the increase in oxidized glutathione biliary excretion and the drop in bile flow and the biliary excretion of specific Bsep and Mrp2 substrates. We conclude that physiological concentrations of UB are sufficient to prevent the biliary secretory failure induced by OS, by counteracting actin disarrangement and the consequent internalization of canalicular transporters relevant to normal bile formation. This reveals an important role for UB in preserving biliary secretory function under OS conditions.es
dc.description.filFil: Basiglio, Cecilia Lorena. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina.es
dc.description.filFil: Toledo, Flavia D. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina.es
dc.description.filFil: Boaglio, Andrea C. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina.es
dc.description.filFil: Arriaga, Sandra Mónica María. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Área Bioquímica Clínica; Argentina.es
dc.description.filFil: Ochoa, Justina E. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina.es
dc.description.filFil: Sánchez Pozzi, Enrique J. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina.es
dc.description.filFil: Mottino, Aldo D. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina.es
dc.description.filFil: Roma, Marcelo Gabriel. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina.es
dc.description.sponsorshipAgencia Nacional de Promoción Científica y Tecnológica (ANPCyT)es
dc.description.sponsorshipConsejo Nacional de Investigaciones Científicas y Técnicas (CONICET)es
dc.formatapplication/octet-stream
dc.format.extent501-514es
dc.identifier.issn0340-5761es
dc.identifier.urihttp://hdl.handle.net/2133/10482
dc.language.isoenges
dc.publisherSpringeres
dc.relation.publisherversionhttps://link.springer.com/article/10.1007%2Fs00204-013-1143-0es
dc.relation.publisherversionhttps://doi.org/10.1007/s00204-013-1143-0es
dc.rightsopenAccesses
dc.rights.holderSpringeres
dc.rights.holderUniversidad Nacional de Rosarioes
dc.rights.holderBasiglio, Cecilia Lorenaes
dc.rights.holderToledo, Flavia D.es
dc.rights.holderBoaglio, Andrea C.es
dc.rights.holderArriaga, Sandra Mónica Maríaes
dc.rights.holderOchoa, Justina E.es
dc.rights.holderSánchez Pozzi, Enrique J.es
dc.rights.holderMottino, Aldo D.es
dc.rights.holderRoma, Marcelo Gabrieles
dc.rights.textAttribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0*
dc.subjectUnconjugated Bilirubines
dc.subjectOxidative Stresses
dc.subjectHepatocellular Cholestasises
dc.subjectCanalicular Transporterses
dc.titlePhysiological concentrations of unconjugated bilirubin prevent oxidative stress-induced hepatocanalicular dysfunction and cholestasises
dc.typearticle
dc.typeartículo
dc.typepublishedVersion
dc.type.collectionarticulo
dc.type.versionpublishedVersiones

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PHYSIOLOGICAL CONCENTRATIONS OF UNCONJUGATED BILIRUBIN PREVENT OXIDATIVE STRESS-INDUCED HEPATOCANALICULAR DYSFUNCTION AND CHOLESTASIS.pdf
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