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Hepatic cells derived from human skin progenitors show a typical phospholipidotic response upon exposure to amiodarone

Tijdschriftbijdrage - Tijdschriftartikel

Phospholipidosis is a metabolic disorder characterized by intracellular accumulation of phospholipids. It can be caused by short-term or chronic exposure to cationic amphiphilic drugs (CADs). These compounds bind to phospholipids, leading to inhibition of their degradation and consequently to their accumulation in lysosomes. Drug-induced phospholipidosis (DIPL) is frequently at the basis of discontinuation of drug development and post-market drug withdrawal. Therefore, reliable human-relevant in vitro models must be developed to speed up the identification of compounds that are potential inducers of phospholipidosis. Here, hepatic cells derived from human skin (hSKP-HPC) were evaluated as an in vitro model for DIPL. These cells were exposed over time to amiodarone, a CAD known to induce phospholipidosis in humans. Transmission electron microscopy revealed the formation of the typical lamellar inclusions in the cell cytoplasm. Increase of phospholipids was already detected after 24 h exposure to amiodarone, whereas a significant increase of neutral lipid vesicles could be observed after 72 h. At the transcriptional level, the modulation of genes involved in DIPL was detected. These results provide a valuable indication of the applicability of hSKP-HPC for the quick assessment of drug-induced phospholipidosis in vitro, early in the drug development process.

Tijdschrift: Toxicol Lett
ISSN: 0378-4274
Volume: 284
Pagina's: 184-194
Jaar van publicatie:2018
Trefwoorden:Amiodarone/toxicity, Cell Differentiation/drug effects, Cells, Cultured, Drug Evaluation, Preclinical/methods, Drug-Related Side Effects and Adverse Reactions, Flow Cytometry, Gene Expression/drug effects, Hep G2 Cells, Hepatocytes/drug effects, Humans, Lipidoses/chemically induced, Lysosomes/drug effects, Male, Phospholipids/genetics, Skin/cytology, Stem Cells/cytology
  • ORCID: /0000-0003-0635-7740/work/76984571
  • ORCID: /0000-0002-4078-4896/work/76554771
  • ORCID: /0000-0001-8399-5872/work/70477644
  • ORCID: /0000-0003-2927-6791/work/61725245
  • ORCID: /0000-0002-6685-7299/work/58116024
  • DOI: https://doi.org/10.1016/j.toxlet.2017.11.014
  • WoS Id: 000425265800022
  • Scopus Id: 85040360667
  • PubMed Id: 29248575
BOF-keylabel:ja
BOF-publication weight:1
CSS-citation score:1
Auteurs:International
Authors from:Higher Education
Toegankelijkheid:Open