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Arch Toxicol. 2017 Mar;91(3):1385-1400. doi: 10.1007/s00204-016-1745-4. Epub 2016 Jun 25.

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

Author information

1
MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Sherrington Building, Ashton Street, Liverpool, L69 3GE, UK.
2
Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, SE-171 77, Stockholm, Sweden.
3
Early Non-Clinical Safety, Merck KGaA, Frankfurter Str. 250, 64293, Darmstadt, Germany.
4
KaLy-Cell, 20A rue du Général Leclerc, 67115, Plobsheim, France.
5
Université de Lille 2, EA 4483, Lille, France.
6
Biologie Servier, 905 Rue de Saran, 45520, Gidy, France.
7
UCB BioPharma SPRL, Non-Clinical Development, Chemin du Foriest, 1420, Braine-l'Alleud, Belgium.
8
Sanofi-Aventis Recherche and Développement, Drug Safety Evaluation, Alfortville, France.
9
Sanofi-Aventis Deutschland GmbH, R&D DSAR, Preclinical Safety FF, Industriepark Hoechst, Building H823, Room 104, 65926, Frankfurt am Main, Germany.
10
GSK, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK.
11
GSK, David Jack Centre for R&D, Park Road, Ware, Hertfordshire, SG12 0DP, UK.
12
AstraZeneca, Innovative Medicines and Early Development, Drug Safety and Metabolism, ADME Transporters, Unit 310 - Darwin Building, Cambridge Science Park, Milton Road, Cambridge, CB4 0FZ, UK.
13
Université de Franche-Comté, EA 4267, 25030, Besançon, France.
14
North Western Hepatobiliary Unit, Aintree University Hospital NHS Foundation Trust, Longmoor Lane, Liverpool, L9 7AL, UK.
15
MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Sherrington Building, Ashton Street, Liverpool, L69 3GE, UK. chrissy@liverpool.ac.uk.

Abstract

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.

KEYWORDS:

Acute; Cytotoxicity; Hepatocytes; Pharmaceuticals; Predictive toxicology; Toxicity

PMID:
27344343
PMCID:
PMC5316403
DOI:
10.1007/s00204-016-1745-4
[Indexed for MEDLINE]
Free PMC Article

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