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

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dc.creator Basiglio, Cecilia Lorena
dc.creator Toledo, Flavia D.
dc.creator Boaglio, Andrea C.
dc.creator Arriaga, Sandra Mónica María
dc.creator Ochoa, Justina E.
dc.creator Sánchez Pozzi, Enrique J.
dc.creator Mottino, Aldo D.
dc.creator Roma, Marcelo G.
dc.date.accessioned 2018-01-29T21:00:05Z
dc.date.available 2018-01-29T21:00:05Z
dc.date.issued 2014-02
dc.identifier.issn 0340-5761 es
dc.identifier.uri http://hdl.handle.net/2133/10482
dc.description Bilirubin 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.sponsorship Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT) es
dc.description.sponsorship Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) es
dc.format application/octet-stream
dc.format.extent 501-514 es
dc.language.iso eng es
dc.publisher Springer es
dc.rights openAccess es
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/2.5/ar/ *
dc.subject Unconjugated Bilirubin es
dc.subject Oxidative Stress es
dc.subject Hepatocellular Cholestasis es
dc.subject Canalicular Transporters es
dc.title Physiological concentrations of unconjugated bilirubin prevent oxidative stress-induced hepatocanalicular dysfunction and cholestasis es
dc.type article
dc.type artículo
dc.type publishedVersion
dc.rights.holder Springer es
dc.rights.holder Universidad Nacional de Rosario es
dc.rights.holder Basiglio, Cecilia Lorena es
dc.rights.holder Toledo, Flavia D. es
dc.rights.holder Boaglio, Andrea C. es
dc.rights.holder Arriaga, Sandra Mónica María es
dc.rights.holder Ochoa, Justina E. es
dc.rights.holder Sánchez Pozzi, Enrique J. es
dc.rights.holder Mottino, Aldo D. es
dc.rights.holder Roma, Marcelo G. es
dc.relation.publisherversion https://link.springer.com/article/10.1007%2Fs00204-013-1143-0 es
dc.relation.publisherversion https://doi.org/10.1007/s00204-013-1143-0 es
dc.citation.title Archives of Toxicology es
dc.citation.volume 88(2) es
dc.description.fil Fil: Basiglio, Cecilia Lorena. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina. es
dc.description.fil Fil: Toledo, Flavia D. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina. es
dc.description.fil Fil: Boaglio, Andrea C. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina. es
dc.description.fil Fil: Arriaga, Sandra Mónica María. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Área Bioquímica Clínica; Argentina. es
dc.description.fil Fil: Ochoa, Justina E. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina. es
dc.description.fil Fil: Sánchez Pozzi, Enrique J. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina. es
dc.description.fil Fil: Mottino, Aldo D. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina. es
dc.description.fil Fil: Roma, Marcelo G. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina. es
dc.type.collection articulo
dc.type.version publishedVersion es


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