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dc.contributor.author
Zucchetti, Andrés Ernesto
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Barosso, Ismael Ricardo
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Boaglio, Andrea Carolina
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Luquita, Marcelo Gabriel
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Roma, Marcelo Gabriel
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Crocenzi, Fernando Ariel
dc.contributor.author
Sanchez Pozzi, Enrique Juan
dc.date.available
2016-06-09T16:01:05Z
dc.date.issued
2013-01
dc.identifier.citation
Zucchetti, Andrés Ernesto; Barosso, Ismael Ricardo; Boaglio, Andrea Carolina; Luquita, Marcelo Gabriel; Roma, Marcelo Gabriel; et al.; Hormonal Modulation of Hepatic cAMP Prevents Estradiol 17β-d-Glucuronide-Induced Cholestasis in Perfused Rat Liver; Springer; Digestive Disease and Sciences; 58; 6; 1-2013; 1602-1614
dc.identifier.issn
0163-2116
dc.identifier.uri
http://hdl.handle.net/11336/6120
dc.description.abstract
BACKGROUND: Estradiol-17β-D-glucuronide (E17G) induces cholestasis in vivo, endocytic internalization of the canalicular transporters multidrug resistance-associated protein 2 (Abcc2) and bile salt export pump (Abcb11) being a key pathomechanism. Cyclic AMP (cAMP) prevents cholestasis by targeting these transporters back to the canalicular membrane. In hepatocyte couplets, glucagon and salbutamol, both of which increase cAMP, prevented E17G action by stimulating the trafficking of these transporters by different mechanisms, namely: glucagon activates a protein kinase A-dependent pathway, whereas salbutamol activates an exchange-protein activated by cAMP (Epac)-mediated, microtubule-dependent pathway. METHODS: The present study evaluated whether glucagon and salbutamol prevent E17G-induced cholestasis in a more physiological model, i.e., the perfused rat liver (PRL). Additionally, the preventive effect of in vivo alanine administration, which induces pancreatic glucagon secretion, was evaluated. RESULTS: In PRLs, glucagon and salbutamol prevented E17G-induced decrease in both bile flow and the secretory activity of Abcc2 and Abcb11. Salbutamol prevention fully depended on microtubule integrity. On the other hand, glucagon prevention was microtubule-independent only at early time periods after E17G administration, but it was ultimately affected by the microtubule disrupter colchicine. Cholestasis was associated with endocytic internalization of Abcb11 and Abcc2, the intracellular carriers being partially colocalized with the endosomal marker Rab11a. This effect was completely prevented by salbutamol, whereas some transporter-containing vesicles remained colocalized with Rab11a after glucagon treatment. In vivo, alanine administration increased hepatic cAMP and accelerated the recovery of bile flow and Abcb11/Abcc2 transport function after E17G administration. The initial recovery afforded by alanine was microtubule-independent, but microtubule integrity was required to sustain this protective effect. CONCLUSION: We conclude that modulation of cAMP levels either by direct administration of cAMP modulators or by physiological manipulations leadings to hormone-mediated increase of cAMP levels (alanine administration), prevents estrogen-induced cholestasis in models with preserved liver architecture, through mechanisms similar to those arisen from in vitro studies.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Springer
dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
Colestasis
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Ampc
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Abcb11
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Abcc2
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Fisiología
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Medicina Básica
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CIENCIAS MÉDICAS Y DE LA SALUD
dc.title
Hormonal Modulation of Hepatic cAMP Prevents Estradiol 17β-d-Glucuronide-Induced Cholestasis in Perfused Rat Liver
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2016-06-08T17:57:13Z
dc.journal.volume
58
dc.journal.number
6
dc.journal.pagination
1602-1614
dc.journal.pais
Alemania
dc.journal.ciudad
Berlin
dc.description.fil
Fil: Zucchetti, Andrés Ernesto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); 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
dc.description.fil
Fil: Boaglio, Andrea Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentina
dc.description.fil
Fil: Luquita, Marcelo Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); 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
dc.description.fil
Fil: Crocenzi, Fernando Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); 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
dc.journal.title
Digestive Disease and Sciences
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/http://link.springer.com/article/10.1007/s10620-013-2558-4
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/10.1007/s10620-013-2558-4
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1007/s10620-013-2558-4
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