| Amiodarone impairs trafficking through late endosomes inducing a Niemann-Pick C-like phenotype. | |
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MedLine Citation:
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PMID: 21878321 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Patients treated with amiodarone accumulate lysobisphosphatidic acid (LBPA), also known as bis(monoacylglycero)phosphate, in airway secretions and develop in different tissues vacuoles and inclusion bodies thought to originate from endosomes. To clarify the origin of these changes, we studied in vitro the effects of amiodarone on endosomal activities like transferrin recycling, Shiga toxin processing, ESCRT-dependent lentivirus budding, fluid phase endocytosis, proteolysis and exosome secretion. Furthermore, since the accumulation of LBPA might point to a broader disturbance in lipid homeostasis, we studied the effect of amiodarone on the distribution of LBPA, unesterified cholesterol, sphingomyelin and glycosphyngolipids. Amiodarone analogues were also studied, including the recently developed derivative dronedarone. We found that amiodarone does not affect early endosomal activities, like transferrin recycling, Shiga toxin processing and lentivirus budding. Amiodarone, instead, interferes with late compartments of the endocytic pathway, blocking the progression of fluid phase endocytosis and causing fusion of organelles, collapse of lumenal structures, accumulation of undegraded substrates and amassing of different types of lipids. Not all late endocytic compartments are affected, since exosome secretion is spared. These changes recall the Niemann-Pick type-C phenotype (NPC), but originate by a different mechanism, since, differently from NPC, they are not alleviated by cholesterol removal. Studies with analogues indicate that basic pKa and high water-solubility at acidic pH are crucial requirements for the interference with late endosomes/lysosomes and that, in this respect, dronedarone is at least as potent as amiodarone. These findings may have relevance in fields unrelated to rhythm control. |
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Authors:
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Elena Piccoli; Matteo Nadai; Carla Mucignat Caretta; Valeria Bergonzini; Claudia Del Vecchio; Huy Riem Ha; Laurent Bigler; Daniele Dal Zoppo; Elisabetta Faggin; Andrea Pettenazzo; Rocco Orlando; Cristiano Salata; Arianna Calistri; Giorgio Palù; Aldo Baritussio |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-8-23 |
Journal Detail:
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Title: Biochemical pharmacology Volume: - ISSN: 1873-2968 ISO Abbreviation: - Publication Date: 2011 Aug |
Date Detail:
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Created Date: 2011-8-31 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0101032 Medline TA: Biochem Pharmacol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2011 Elsevier Inc. All rights reserved. |
Affiliation:
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Department of Histology, Microbiology and Medical Biotechnologies, University of Padova, via A. Gabelli 63, 35121, Italy. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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