ArticleArchives of toxicology2024
Uncovering the mechanism of troglitazone-mediated idiosyncratic drug-induced liver injury with individual-centric models.
Article in Archives of toxicology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- Introduction to the 3RsC's cross-platform microphysiological systems evaluation for drug-induced liver injury in collaboration with FDA-CDER.Regulatory toxicology and pharmacology : RTP · 2026Article
- Improving hepatic metabolic function with 3D iPSC-derived human hepatocytes.Cell biology and toxicology · 2026Article
- A serum-derived 3D tumor model platform for personalized prediction and monitoring of chemotherapeutic response in pancreatic ductal adenocarcinoma.Translational oncology · 2026Article
- A newFrontiers in toxicology · 2026Article
- AI-enhanced clinical trial-in-a-dish platform for improved DILI risk classification and mechanistic insights into hepatotoxicity.Frontiers in toxicology · 2026Article
- Drug metabolizing enzymes and transporters, and their roles for the development of drug-induced liver injury.Expert opinion on drug metabolism & toxicology · 2025Review
- Modelling hepatocellular carcinoma microenvironment phenotype to evaluate drug efficacy.Scientific reports · 2025Article
- Engineering liver disease models in vitro: emerging trends and innovations.eGastroenterology · 2025Review
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Authors and funding
3 authors.
Funding
Abstract
Idiosyncratic drug-induced liver injury is a rare and unpredictable event. Deciphering its initiating-mechanism is a hard task as its occurrence is individual dependent. Thus, studies that utilize models that are not individual-centric might drive to a general mechanistic conclusion that is not necessarily true. Here, we use the individual-centric spheroid model to analyze the initiating-mechanism of troglitazone-mediated iDILI risk. Individual-centric spheroid models were generated using a proprietary cell educating technology. These educated spheroids contain hepatocytes, hepatic stellate cells, activated monocyte-derived macrophages, and dendritic cells under physiological conditions. We show that phases 1 and 2 drug-metabolizing enzymes were induced in an individual-dependent manner. However, we did not observe any association of DEMs induction and troglitazone (TGZ)-mediated iDILI risk. We analyzed TGZ-mediated iDILI and found that a 44-year-old male showed iDILI risk that is associated with TGZ-mediated suppression of IL-12 expression by autologous macrophages and dendritic cells. We performed a rescue experiment and showed that treatment of spheroids from this 44-year-old male with TGZ and recombinant IL-12 suppressed iDILI risk. We confirmed the mechanism in another 31-year-old female with iDILI risk. We demonstrate here that individual-centric spheroid are versatile models that allow to predict iDILI risk and to analyze a direct effect of the drug on activated macrophages and dendritic cells to uncover the initiating-mechanism of iDILI occurrence. This model opens perspectives for a personalized strategy to mitigate iDILI risk.
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