ArticleArchives of toxicology2017
A multicenter assessment of single-cell models aligned to standard measures of cell health for prediction of acute hepatotoxicity.
Article in Archives of toxicology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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The trial behind it
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Who cites it
46 citing papers in PubMed.
- A metabolomic analysis of thiol response for standard and modified N-acetyl cysteine treatment regimens in patients with acetaminophen overdose.Clinical and translational science · 2021Trial
- Article
- Single-cell transcriptomics of acetaminophen-induced responses in human 2D and 3D liver microtissues.Archives of toxicology · 2026Article
- Genipin rewires endogenous amino acid metabolism and induces hepatocellular necroptosis by activation of the TNF-necrosome signaling axis.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- Evaluation of the Immortalized Primary Human Hepatocyte Cell Line Fa2N-4 as a Model for Metabolic Dysfunction-Associated Steatotic Liver Disease.Gastro hep advances · 2026Article
- Primary Human Tissue Models for Metabolic Dysfunction-Associated Liver Disease - toward Streamlining Drug Discovery with Patient-Derived Assays.Advanced biology · 2025Review
- Article
- A Review on New Frontiers in Drug-Drug Interaction Predictions and Safety Evaluations with In Vitro Cellular Models.Pharmaceutics · 2025Review
- MechanisticComputational and structural biotechnology journal · 2025Article
- Limitations of acetaminophen as a reference hepatotoxin for the evaluation of in vitro liver models.Toxicological sciences : an official journal of the Society of Toxicology · 2025Article
- Compound Absorption in Polymer Devices Impairs the Translatability of Preclinical Safety Assessments.Advanced healthcare materials · 2024Article
- A network-based transcriptomic landscape of HepG2 cells uncovering causal gene-cytotoxicity interactions underlying drug-induced liver injury.Toxicological sciences : an official journal of the Society of Toxicology · 2024Article
- Review
- The evolving role of investigative toxicology in the pharmaceutical industry.Nature reviews. Drug discovery · 2023Review
- Detection of Hepatic Drug Metabolite-Specific T-Cell Responses Using a Human Hepatocyte, Immune Cell Coculture System.Chemical research in toxicology · 2023Article
- Identification of flucloxacillin-modified hepatocellular proteins: implications in flucloxacillin-induced liver injury.Toxicological sciences : an official journal of the Society of Toxicology · 2023Article
- Optimisation of the HepaRG cell line model for drug toxicity studies using two different cultivation conditions: advantages and limitations.Archives of toxicology · 2022Article
- Oxidative-stress and long-term hepatotoxicity: comparative study in Upcyte human hepatocytes and hepaRG cells.Archives of toxicology · 2022Article
- Metabolically Improved Stem Cell Derived Hepatocyte-Like Cells Support HBV Life Cycle and Are a Promising Tool for HBV Studies and Antiviral Drug Screenings.Biomedicines · 2022Article
- Adult Stem Cell Therapy as Regenerative Medicine for End-Stage Liver Disease.Advances in experimental medicine and biology · 2022Article
Corrections and comments
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Authors and funding
23 authors.
Funding
No grant is acknowledged in the PubMed record.
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.
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