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A multicenter assessment of single-cell models aligned to standard measures of cell health for prediction of acute hepatotoxicity

Assessing the potential of a new drug to cause drug-induced liver injury (DILI) is a challenge for the pharmaceutical industry. We therefore determined whether cell models currently used in safety assessment (HepG2, HepaRG, Upcyte and primary human hepatocytes in conjunction with basic but commonly...

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Autores principales: Sison-Young, Rowena L., Lauschke, Volker M., Johann, Esther, Alexandre, Eliane, Antherieu, Sébastien, Aerts, Hélène, Gerets, Helga H. J., Labbe, Gilles, Hoët, Delphine, Dorau, Martina, Schofield, Christopher A., Lovatt, Cerys A., Holder, Julie C., Stahl, Simone H., Richert, Lysiane, Kitteringham, Neil R., Jones, Robert P., Elmasry, Mohamed, Weaver, Richard J., Hewitt, Philip G., Ingelman-Sundberg, Magnus, Goldring, Chris E., Park, B. Kevin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5316403/
https://www.ncbi.nlm.nih.gov/pubmed/27344343
http://dx.doi.org/10.1007/s00204-016-1745-4
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author Sison-Young, Rowena L.
Lauschke, Volker M.
Johann, Esther
Alexandre, Eliane
Antherieu, Sébastien
Aerts, Hélène
Gerets, Helga H. J.
Labbe, Gilles
Hoët, Delphine
Dorau, Martina
Schofield, Christopher A.
Lovatt, Cerys A.
Holder, Julie C.
Stahl, Simone H.
Richert, Lysiane
Kitteringham, Neil R.
Jones, Robert P.
Elmasry, Mohamed
Weaver, Richard J.
Hewitt, Philip G.
Ingelman-Sundberg, Magnus
Goldring, Chris E.
Park, B. Kevin
author_facet Sison-Young, Rowena L.
Lauschke, Volker M.
Johann, Esther
Alexandre, Eliane
Antherieu, Sébastien
Aerts, Hélène
Gerets, Helga H. J.
Labbe, Gilles
Hoët, Delphine
Dorau, Martina
Schofield, Christopher A.
Lovatt, Cerys A.
Holder, Julie C.
Stahl, Simone H.
Richert, Lysiane
Kitteringham, Neil R.
Jones, Robert P.
Elmasry, Mohamed
Weaver, Richard J.
Hewitt, Philip G.
Ingelman-Sundberg, Magnus
Goldring, Chris E.
Park, B. Kevin
author_sort Sison-Young, Rowena L.
collection PubMed
description Assessing the potential of a new drug to cause drug-induced liver injury (DILI) is a challenge for the pharmaceutical industry. We therefore determined whether cell models currently used in safety assessment (HepG2, HepaRG, Upcyte and primary human hepatocytes in conjunction with basic but commonly used endpoints) are actually able to distinguish between novel chemical entities (NCEs) with respect to their potential to cause DILI. A panel of thirteen compounds (nine DILI implicated and four non-DILI implicated in man) were selected for our study, which was conducted, for the first time, across multiple laboratories. None of the cell models could distinguish faithfully between DILI and non-DILI compounds. Only when nominal in vitro concentrations were adjusted for in vivo exposure levels were primary human hepatocytes (PHH) found to be the most accurate cell model, closely followed by HepG2. From a practical perspective, this study revealed significant inter-laboratory variation in the response of PHH, HepG2 and Upcyte cells, but not HepaRG cells. This variation was also observed to be compound dependent. Interestingly, differences between donors (hepatocytes), clones (HepG2) and the effect of cryopreservation (HepaRG and hepatocytes) were less important than differences between the cell models per se. In summary, these results demonstrate that basic cell health endpoints will not predict hepatotoxic risk in simple hepatic cells in the absence of pharmacokinetic data and that a multicenter assessment of more sophisticated signals of molecular initiating events is required to determine whether these cells can be incorporated in early safety assessment. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00204-016-1745-4) contains supplementary material, which is available to authorized users.
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spelling pubmed-53164032017-03-03 A multicenter assessment of single-cell models aligned to standard measures of cell health for prediction of acute hepatotoxicity Sison-Young, Rowena L. Lauschke, Volker M. Johann, Esther Alexandre, Eliane Antherieu, Sébastien Aerts, Hélène Gerets, Helga H. J. Labbe, Gilles Hoët, Delphine Dorau, Martina Schofield, Christopher A. Lovatt, Cerys A. Holder, Julie C. Stahl, Simone H. Richert, Lysiane Kitteringham, Neil R. Jones, Robert P. Elmasry, Mohamed Weaver, Richard J. Hewitt, Philip G. Ingelman-Sundberg, Magnus Goldring, Chris E. Park, B. Kevin Arch Toxicol Organ Toxicity and Mechanisms Assessing the potential of a new drug to cause drug-induced liver injury (DILI) is a challenge for the pharmaceutical industry. We therefore determined whether cell models currently used in safety assessment (HepG2, HepaRG, Upcyte and primary human hepatocytes in conjunction with basic but commonly used endpoints) are actually able to distinguish between novel chemical entities (NCEs) with respect to their potential to cause DILI. A panel of thirteen compounds (nine DILI implicated and four non-DILI implicated in man) were selected for our study, which was conducted, for the first time, across multiple laboratories. None of the cell models could distinguish faithfully between DILI and non-DILI compounds. Only when nominal in vitro concentrations were adjusted for in vivo exposure levels were primary human hepatocytes (PHH) found to be the most accurate cell model, closely followed by HepG2. From a practical perspective, this study revealed significant inter-laboratory variation in the response of PHH, HepG2 and Upcyte cells, but not HepaRG cells. This variation was also observed to be compound dependent. Interestingly, differences between donors (hepatocytes), clones (HepG2) and the effect of cryopreservation (HepaRG and hepatocytes) were less important than differences between the cell models per se. In summary, these results demonstrate that basic cell health endpoints will not predict hepatotoxic risk in simple hepatic cells in the absence of pharmacokinetic data and that a multicenter assessment of more sophisticated signals of molecular initiating events is required to determine whether these cells can be incorporated in early safety assessment. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00204-016-1745-4) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2016-06-25 2017 /pmc/articles/PMC5316403/ /pubmed/27344343 http://dx.doi.org/10.1007/s00204-016-1745-4 Text en © The Author(s) 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Organ Toxicity and Mechanisms
Sison-Young, Rowena L.
Lauschke, Volker M.
Johann, Esther
Alexandre, Eliane
Antherieu, Sébastien
Aerts, Hélène
Gerets, Helga H. J.
Labbe, Gilles
Hoët, Delphine
Dorau, Martina
Schofield, Christopher A.
Lovatt, Cerys A.
Holder, Julie C.
Stahl, Simone H.
Richert, Lysiane
Kitteringham, Neil R.
Jones, Robert P.
Elmasry, Mohamed
Weaver, Richard J.
Hewitt, Philip G.
Ingelman-Sundberg, Magnus
Goldring, Chris E.
Park, B. Kevin
A multicenter assessment of single-cell models aligned to standard measures of cell health for prediction of acute hepatotoxicity
title A multicenter assessment of single-cell models aligned to standard measures of cell health for prediction of acute hepatotoxicity
title_full A multicenter assessment of single-cell models aligned to standard measures of cell health for prediction of acute hepatotoxicity
title_fullStr A multicenter assessment of single-cell models aligned to standard measures of cell health for prediction of acute hepatotoxicity
title_full_unstemmed A multicenter assessment of single-cell models aligned to standard measures of cell health for prediction of acute hepatotoxicity
title_short A multicenter assessment of single-cell models aligned to standard measures of cell health for prediction of acute hepatotoxicity
title_sort multicenter assessment of single-cell models aligned to standard measures of cell health for prediction of acute hepatotoxicity
topic Organ Toxicity and Mechanisms
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5316403/
https://www.ncbi.nlm.nih.gov/pubmed/27344343
http://dx.doi.org/10.1007/s00204-016-1745-4
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