title: A multicenter assessment of single-cell models aligned to standard measures of cell health for prediction of acute hepatotoxicity.
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.
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Sherrington Building, Ashton Street, Liverpool, L69 3GE, UK.
authors.forename: Rowena L
authors.initials: RL
authors.lastname: Sison-Young
authors.affiliation: Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, SE-171 77, Stockholm, Sweden.
authors.forename: Volker M
authors.initials: VM
authors.lastname: Lauschke
authors.affiliation: Early Non-Clinical Safety, Merck KGaA, Frankfurter Str. 250, 64293, Darmstadt, Germany.
authors.forename: Esther
authors.initials: E
authors.lastname: Johann
authors.affiliation: KaLy-Cell, 20A rue du Général Leclerc, 67115, Plobsheim, France.
authors.forename: Eliane
authors.initials: E
authors.lastname: Alexandre
authors.affiliation: Université de Lille 2, EA 4483, Lille, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Antherieu
authors.affiliation: Biologie Servier, 905 Rue de Saran, 45520, Gidy, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Aerts
authors.affiliation: UCB BioPharma SPRL, Non-Clinical Development, Chemin du Foriest, 1420, Braine-l'Alleud, Belgium.
authors.forename: Helga H J
authors.initials: HHJ
authors.lastname: Gerets
authors.affiliation: Sanofi-Aventis Recherche and Développement, Drug Safety Evaluation, Alfortville, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Labbe
authors.affiliation: Sanofi-Aventis Recherche and Développement, Drug Safety Evaluation, Alfortville, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Hoët
authors.affiliation: Sanofi-Aventis Deutschland GmbH, R&D DSAR, Preclinical Safety FF, Industriepark Hoechst, Building H823, Room 104, 65926, Frankfurt am Main, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Dorau
authors.affiliation: GSK, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Schofield
authors.affiliation: GSK, David Jack Centre for R&D, Park Road, Ware, Hertfordshire, SG12 0DP, UK.
authors.forename: Cerys A
authors.initials: CA
authors.lastname: Lovatt
authors.affiliation: GSK, David Jack Centre for R&D, Park Road, Ware, Hertfordshire, SG12 0DP, UK.
authors.forename: Julie C
authors.initials: JC
authors.lastname: Holder
authors.affiliation: 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.
authors.forename: Simone H
authors.initials: SH
authors.lastname: Stahl
authors.affiliation: KaLy-Cell, 20A rue du Général Leclerc, 67115, Plobsheim, France.|Université de Franche-Comté, EA 4267, 25030, Besançon, France.
authors.forename: Lysiane
authors.initials: L
authors.lastname: Richert
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Sherrington Building, Ashton Street, Liverpool, L69 3GE, UK.
authors.forename: Neil R
authors.initials: NR
authors.lastname: Kitteringham
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Sherrington Building, Ashton Street, Liverpool, L69 3GE, UK.|North Western Hepatobiliary Unit, Aintree University Hospital NHS Foundation Trust, Longmoor Lane, Liverpool, L9 7AL, UK.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Jones
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Sherrington Building, Ashton Street, Liverpool, L69 3GE, UK.|North Western Hepatobiliary Unit, Aintree University Hospital NHS Foundation Trust, Longmoor Lane, Liverpool, L9 7AL, UK.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Elmasry
authors.affiliation: Biologie Servier, 905 Rue de Saran, 45520, Gidy, France.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Weaver
authors.affiliation: Early Non-Clinical Safety, Merck KGaA, Frankfurter Str. 250, 64293, Darmstadt, Germany.
authors.forename: Philip G
authors.initials: PG
authors.lastname: Hewitt
authors.affiliation: Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, SE-171 77, Stockholm, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Ingelman-Sundberg
authors.affiliation: 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.
authors.forename: Chris E
authors.initials: CE
authors.lastname: Goldring
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Sherrington Building, Ashton Street, Liverpool, L69 3GE, UK.
authors.forename: B Kevin
authors.initials: BK
authors.lastname: Park
mesh_terms: D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D015925:Cryopreservation; D056945:Hep G2 Cells / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D015203:Reproducibility of Results; D023382:Toxicity Tests, Acute / Q000379:methods* / Q000592:standards
keywords: Acute; Cytotoxicity; Hepatocytes; Pharmaceuticals; Predictive toxicology; Toxicity