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The utility of a differentiated preclinical liver model, HepaRG cells, in investigating delayed toxicity via inhibition of mitochondrial-replication induced by fialuridine.
Jolly, Carol E; Douglas, Oisin; Kamalian, Laleh; Jenkins, Rosalind E; Beckett, Alison J; Penman, Sophie L; Williams, Dominic P; Monshouwer, Mario; Simic, Damir; Snoeys, Jan; Park, B Kevin; Chadwick, Amy E.
Afiliación
  • Jolly CE; MRC Centre for Drug Safety Science, The Department of Pharmacology and Therapeutics, The University of Liverpool, Ashton Street, Liverpool L69 3GE, UK.
  • Douglas O; MRC Centre for Drug Safety Science, The Department of Pharmacology and Therapeutics, The University of Liverpool, Ashton Street, Liverpool L69 3GE, UK.
  • Kamalian L; MRC Centre for Drug Safety Science, The Department of Pharmacology and Therapeutics, The University of Liverpool, Ashton Street, Liverpool L69 3GE, UK.
  • Jenkins RE; MRC Centre for Drug Safety Science, The Department of Pharmacology and Therapeutics, The University of Liverpool, Ashton Street, Liverpool L69 3GE, UK.
  • Beckett AJ; Cellular and Molecular Physiology, The University of Liverpool, Crown Street, Liverpool L69 3BX, UK.
  • Penman SL; MRC Centre for Drug Safety Science, The Department of Pharmacology and Therapeutics, The University of Liverpool, Ashton Street, Liverpool L69 3GE, UK.
  • Williams DP; Innovative Medicines and Early Development, Drug Safety and Metabolism, Translational Safety, AstraZeneca, Cambridge, UK.
  • Monshouwer M; Pharmacokinetics Dynamics and Metabolism, Janssen Research and Development, Beerse, Belgium.
  • Simic D; Mechanistic and Investigative Toxicology, Janssen Research and Development, Spring House, PA, USA.
  • Snoeys J; Pharmacokinetics Dynamics and Metabolism, Janssen Research and Development, Beerse, Belgium.
  • Park BK; MRC Centre for Drug Safety Science, The Department of Pharmacology and Therapeutics, The University of Liverpool, Ashton Street, Liverpool L69 3GE, UK.
  • Chadwick AE; MRC Centre for Drug Safety Science, The Department of Pharmacology and Therapeutics, The University of Liverpool, Ashton Street, Liverpool L69 3GE, UK. Electronic address: Amy.Chadwick@liverpool.ac.uk.
Toxicol Appl Pharmacol ; 403: 115163, 2020 09 15.
Article en En | MEDLINE | ID: mdl-32730777
During its clinical development fialuridine caused liver toxicity and the death of five patients. This case remains relevant due to the continued development of mechanistically-related compounds against a back-drop of simple in vitro models which remain limited for the preclinical detection of such delayed toxicity. Here, proteomic investigation of a differentiated, HepaRG, and proliferating, HepG2 cell model was utilised to confirm the presence of the hENT1 transporter, thymidine kinase-1 and -2 (TK1, TK2) and thymidylate kinase, all essential in order to reproduce the cellular activation and disposition of fialuridine in the clinic. Acute metabolic modification assays could only identify mitochondrial toxicity in HepaRG cells following extended dosing, 2 weeks. Toxic effects were observed around 10 µM, which is within a range of 10-15 X approximate Cmax. HepaRG cell death was accompanied by a significant decrease in mitochondrial DNA content, indicative of inhibition of mitochondrial replication, and a subsequent reduction in mitochondrial respiration and the activity of mitochondrial respiratory complexes, not replicated in HepG2 cells. The structural epimer of fialuridine, included as a pharmacological negative control, was shown to have no cytotoxic effects in HepaRG cells up to 4 weeks. Overall, these comparative studies demonstrate the HepaRG model has translational relevance for fialuridine toxicity and therefore may have potential in investigating the inhibition of mitochondrial replication over prolonged exposure for other toxicants.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Antivirales / Arabinofuranosil Uracilo / Hepatocitos / Mitocondrias Límite: Humans Idioma: En Revista: Toxicol Appl Pharmacol Año: 2020 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
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PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Antivirales / Arabinofuranosil Uracilo / Hepatocitos / Mitocondrias Límite: Humans Idioma: En Revista: Toxicol Appl Pharmacol Año: 2020 Tipo del documento: Article Pais de publicación: Estados Unidos