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dc.contributor.author Boaglio, Andrea Carolina
dc.contributor.author Zucchetti, Andrés Ernesto
dc.contributor.author Toledo, Flavia Daniela
dc.contributor.author Barosso, Ismael Ricardo
dc.contributor.author Sanchez Pozzi, Enrique Juan
dc.contributor.author Crocenzi, Fernando Ariel
dc.contributor.author Roma, Marcelo Gabriel
dc.date.available 2017-04-18T19:09:04Z
dc.date.issued 2012-11
dc.identifier.citation Boaglio, Andrea Carolina; Zucchetti, Andrés Ernesto; Toledo, Flavia Daniela; Barosso, Ismael Ricardo; Sanchez Pozzi, Enrique Juan; et al.; ERK1/2 and p38 MAPKs Are Complementarily Involved in Estradiol 17ß-d-Glucuronide-Induced Cholestasis: Crosstalk with cPKC and PI3K; Public Library Of Science; Plos One; 7; 11; 11-2012; 1-12; e49255
dc.identifier.uri http://hdl.handle.net/11336/15391
dc.description.abstract Objective: The endogenous, cholestatic metabolite estradiol 17ß-d-glucuronide (E217G) induces endocytic internalization of the canalicular transporters relevant to bile formation, Bsep and Mrp2. We evaluated here whether MAPKs are involved in this effect. Design: ERK1/2, JNK1/2, and p38 MAPK activation was assessed by the increase in their phosphorylation status. Hepatocanalicular function was evaluated in isolated rat hepatocyte couplets (IRHCs) by quantifying the apical secretion of fluorescent Bsep and Mrp2 substrates, and in isolated, perfused rat livers (IPRLs), using taurocholate and 2,4-dinitrophenyl-S-glutathione, respectively. Protein kinase participation in E217G-induced secretory failure was assessed by co-administering selective inhibitors. Internalization of Bsep/Mrp2 was assessed by confocal microscopy and image analysis. Results: E217G activated all kinds of MAPKs. The PI3K inhibitor wortmannin prevented ERK1/2 activation, whereas the cPKC inhibitor Gö6976 prevented p38 activation, suggesting that ERK1/2 and p38 are downstream of PI3K and cPKC, respectively. The p38 inhibitor SB203580 and the ERK1/2 inhibitor PD98059, but not the JNK1/2 inhibitor SP600125, partially prevented E217G-induced changes in transporter activity and localization in IRHCs. p38 and ERK1/2 co-inhibition resulted in additive protection, suggesting complementary involvement of these MAPKs. In IPRLs, E217G induced endocytosis of canalicular transporters and a rapid and sustained decrease in bile flow and biliary excretion of Bsep/Mrp2 substrates. p38 inhibition prevented this initial decay, and the internalization of Bsep/Mrp2. Contrarily, ERK1/2 inhibition accelerated the recovery of biliary secretion and the canalicular reinsertion of Bsep/Mrp2. Conclusions: cPKC/p38 MAPK and PI3K/ERK1/2 signalling pathways participate complementarily in E217G-induced cholestasis, through internalization and sustained intracellular retention of canalicular transporters, respectively.
dc.format application/pdf
dc.language.iso eng
dc.publisher Public Library Of Science
dc.rights info:eu-repo/semantics/openAccess
dc.rights.uri https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject Estradiol 17ß-D-glucuronide cholestasis;
dc.subject P38 MAPK
dc.subject ERK1/2
dc.subject Canalicular transporter internalization
dc.subject.classification Toxicología
dc.subject.classification Medicina Básica
dc.subject.classification CIENCIAS MÉDICAS Y DE LA SALUD
dc.title ERK1/2 and p38 MAPKs Are Complementarily Involved in Estradiol 17ß-d-Glucuronide-Induced Cholestasis: Crosstalk with cPKC and PI3K
dc.type info:eu-repo/semantics/article
dc.type info:ar-repo/semantics/artículo
dc.type info:eu-repo/semantics/publishedVersion
dc.date.updated 2017-04-18T14:03:41Z
dc.identifier.eissn 1932-6203
dc.journal.volume 7
dc.journal.number 11
dc.journal.pagination 1-12; e49255
dc.journal.pais Estados Unidos
dc.journal.ciudad San Francisco
dc.description.fil Fil: Boaglio, Andrea Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; Argentina
dc.description.fil Fil: Zucchetti, Andrés Ernesto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; Argentina
dc.description.fil Fil: Toledo, Flavia Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; Argentina
dc.description.fil Fil: Barosso, Ismael Ricardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; Argentina
dc.description.fil Fil: Sanchez Pozzi, Enrique Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; Argentina
dc.description.fil Fil: Crocenzi, Fernando Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; Argentina
dc.description.fil Fil: Roma, Marcelo Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; Argentina
dc.journal.title Plos One
dc.relation.alternativeid info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1371/journal.pone.0049255
dc.relation.alternativeid info:eu-repo/semantics/altIdentifier/url/http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0049255
dc.relation.alternativeid info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498151/


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