ArticleScientific reports2016
Hepatic 3D spheroid models for the detection and study of compounds with cholestatic liability.
Article in Scientific reports, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 64 papers.
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Who cites it
64 citing papers in PubMed, 151 citations in OpenAlex.
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- A collagen hydrogel-based 3D Heparg model for enhanced hepatocyte function and assessment of cholestatic drug-induced liver injury.Archives of toxicology · 2026Article
- A Long-Term Human Liver Spheroid Model for Assessing Silencing and Durability of GalNAc-Conjugated siRNAs.Clinical and translational science · 2026Article
- Exploring the potential of liver microphysiological systems of varied configurations to model cholestatic chemical effects.Archives of toxicology · 2026Article
- Evaluation of a human 3D multicellular hepatic spheroid model as a platform for studying hepatic transporters.Cellular and molecular life sciences : CMLS · 2025Article
- Evaluating cannabidiol-induced liver injury with and without valproate using a three-dimensional human hepatocyte spheroid model.Toxicology in vitro : an international journal published in association with BIBRA · 2025Article
- Comparative Analysis of Species-Specific Hepatocyte Function and Drug Effects in a Liver Microphysiological System PhysioMimix LC12 and 96-Well Plates.ACS pharmacology & translational science · 2025Article
- Autologous Organoid-T Cell Co-Culture Platform for Modeling of Immune-Mediated Drug-Induced Liver Injury.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Cell-based approaches for the mechanistic understanding of drug-induced cholestatic liver injury.Archives of toxicology · 2025Review
- In vitro liver models for toxicological research.Drug metabolism and pharmacokinetics · 2025Review
- In vitro-in silico analysis reveals that loss of tankyrase1/2 improves bile acid handling in genetically engineered HepG2 cultures.Archives of toxicology · 2025Article
- Liver-on-chips for drug discovery and development.Materials today. Bio · 2024Review
- Advancing Toxicity Predictions: A Review onEnvironment & health (Washington, D.C.) · 2024Review
- Hepatic spheroid-on-a-chip: Fabrication and characterization of a spheroid-basedBiomicrofluidics · 2024Article
- Cholangiocyte organoids to study drug-induced injury.Stem cell research & therapy · 2024Article
- Impact of perfluoroalkyl substances (PFAS) and PFAS mixtures on lipid metabolism in differentiated HepaRG cells as a model for human hepatocytes.Archives of toxicology · 2024Article
- Culture methods focusing on bile canalicular formation using primary human hepatocytes in a short time.In vitro cellular & developmental biology. Animal · 2023Article
- Review
- The evolving role of investigative toxicology in the pharmaceutical industry.Nature reviews. Drug discovery · 2023Review
- Review
4 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Drug-induced cholestasis (DIC) is poorly understood and its preclinical prediction is mainly limited to assessing the compound's potential to inhibit the bile salt export pump (BSEP). Here, we evaluated two 3D spheroid models, one from primary human hepatocytes (PHH) and one from HepaRG cells, for the detection of compounds with cholestatic liability. By repeatedly co-exposing both models to a set of compounds with different mechanisms of hepatotoxicity and a non-toxic concentrated bile acid (BA) mixture for 8 days we observed a selective synergistic toxicity of compounds known to cause cholestatic or mixed cholestatic/hepatocellular toxicity and the BA mixture compared to exposure to the compounds alone, a phenomenon that was more pronounced after extending the exposure time to 14 days. In contrast, no such synergism was observed after both 8 and 14 days of exposure to the BA mixture for compounds that cause non-cholestatic hepatotoxicity. Mechanisms behind the toxicity of the cholestatic compound chlorpromazine were accurately detected in both spheroid models, including intracellular BA accumulation, inhibition of ABCB11 expression and disruption of the F-actin cytoskeleton. Furthermore, the observed synergistic toxicity of chlorpromazine and BA was associated with increased oxidative stress and modulation of death receptor signalling. Combined, our results demonstrate that the hepatic spheroid models presented here can be used to detect and study compounds with cholestatic liability.
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