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Mitogen-activated protein kinases are involved in hepatocanalicular dysfunction and cholestasis induced by oxidative stress

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dc.citation.titleArchives of Toxicologyes
dc.citation.volume91(6)es
dc.creatorToledo, Flavia D.
dc.creatorBasiglio, Cecilia Lorena
dc.creatorBarosso, Ismael R.
dc.creatorBoaglio, Andrea C.
dc.creatorZucchetti, Andrés E.
dc.creatorSanchez Pozzi, Enrique J.
dc.creatorRoma, Marcelo Gabriel
dc.date.accessioned2019-02-08T23:01:56Z
dc.date.available2019-02-08T23:01:56Z
dc.date.issued2017-06
dc.descriptionIn previous studies, we showed that the pro-oxidant model agent tert-butyl hydroperoxide (tBuOOH) induces alterations in hepatocanalicular secretory function by activating Ca2+-dependent protein kinase C isoforms (cPKC), via F-actin disorganization followed by endocytic internalization of canalicular transporters relevant to bile formation (Mrp2, Bsep). Since mitogen-activated protein kinases (MAPKs) may be downstream effectors of cPKC, we investigated here the involvement of the MAPKs of the ERK1/2, JNK1/2, and p38MAPK types in these deleterious effects. tBuOOH (100 µM, 15 min) increased the proportion of the active, phosphorylated forms of ERK1/2, JNK1/2, and p38MAPK, and panspecific PKC inhibition with bisindolylmaleimide-1 (100 nM) or selective cPKC inhibition with Gö6976 (1 μM) prevented the latter two events. In isolated rat hepatocyte couplets, tBuOOH (100 µM, 15 min) decreased the canalicular vacuolar accumulation of the fluorescent Bsep and Mrp2 substrates, cholylglycylamido fluorescein, and glutathione-methylfluorescein, respectively, and selective inhibitors of ERK1/2 (PD098059), JNK1/2 (SP600125), and p38MAPK (SB203580) partially prevented these alterations. In in situ perfused rat livers, these three MAPK inhibitors prevented tBuOOH (75 µM)-induced impairment of bile flow and the decrease in the biliary output of the Bsep and Mrp2 substrates, taurocholate, and dinitrophenyl-S-glutathione, respectively. The changes in Bsep/Mrp2 and F-actin localization induced by tBuOOH, as assessed by (immuno)fluorescence staining followed by analysis of confocal images, were prevented total or partially by the MAPK inhibitors. We concluded that MAPKs of the ERK1/2, JNK1/2, and p38MAPK types are all involved in cholestasis induced by oxidative stress, by promoting F-actin rearrangement and further endocytic internalization of canalicular transporters critical for bile formation.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: Basiglio, Cecilia Lorena. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina.es
dc.description.filFil: Barosso, Ismael R. 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: Zucchetti, Andrés E. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina.es
dc.description.filFil: Sanchez Pozzi, Enrique J. 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/pdf
dc.format.extent2391 - 2403es
dc.identifier.issn0340-5761es
dc.identifier.urihttp://hdl.handle.net/2133/13924
dc.language.isoenges
dc.publisherSpringeres
dc.relation.publisherversionhttp://dx.doi.org/10.1007/s00204-016-1898-1es
dc.relation.publisherversionhttps://link.springer.com/article/10.1007%2Fs00204-016-1898-1es
dc.rightsopenAccesses
dc.rights.holderUniversidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticases
dc.rights.holderToledo, Flavia D.es
dc.rights.holderBasiglio, Cecilia Lorenaes
dc.rights.holderBarosso, Ismael R.es
dc.rights.holderBoaglio, Andrea C.es
dc.rights.holderZucchetti, Andrés E.es
dc.rights.holderSanchez Pozzi, Enrique J.es
dc.rights.holderRoma, Marcelo Gabrieles
dc.rights.holderSpringeres
dc.rights.textAtribución-NoComercial-SinDerivadas 4.0 Internacional (CC BY-NC-ND 4.0)es
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectOxidative stresses
dc.subjectHepatocellular cholestasises
dc.subjectCanalicular transporterses
dc.subjectMitogen-activated protein kinaseses
dc.subjectActin cytoskeletones
dc.titleMitogen-activated protein kinases are involved in hepatocanalicular dysfunction and cholestasis induced by oxidative stresses
dc.typearticle
dc.typeartículo
dc.typepublishedVersion
dc.type.collectionarticulo
dc.type.versionpublishedVersiones

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