Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1782508830382358528 |
---|---|
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. |
format | Online Article Text |
id | pubmed-5316403 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT sisonyoungrowenal amulticenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT lauschkevolkerm amulticenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT johannesther amulticenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT alexandreeliane amulticenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT antherieusebastien amulticenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT aertshelene amulticenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT geretshelgahj amulticenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT labbegilles amulticenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT hoetdelphine amulticenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT doraumartina amulticenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT schofieldchristophera amulticenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT lovattcerysa amulticenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT holderjuliec amulticenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT stahlsimoneh amulticenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT richertlysiane amulticenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT kitteringhamneilr amulticenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT jonesrobertp amulticenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT elmasrymohamed amulticenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT weaverrichardj amulticenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT hewittphilipg amulticenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT ingelmansundbergmagnus amulticenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT goldringchrise amulticenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT parkbkevin amulticenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT sisonyoungrowenal multicenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT lauschkevolkerm multicenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT johannesther multicenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT alexandreeliane multicenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT antherieusebastien multicenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT aertshelene multicenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT geretshelgahj multicenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT labbegilles multicenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT hoetdelphine multicenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT doraumartina multicenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT schofieldchristophera multicenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT lovattcerysa multicenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT holderjuliec multicenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT stahlsimoneh multicenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT richertlysiane multicenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT kitteringhamneilr multicenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT jonesrobertp multicenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT elmasrymohamed multicenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT weaverrichardj multicenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT hewittphilipg multicenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT ingelmansundbergmagnus multicenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT goldringchrise multicenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity AT parkbkevin multicenterassessmentofsinglecellmodelsalignedtostandardmeasuresofcellhealthforpredictionofacutehepatotoxicity |