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Updated: Mar 8, 2026
Human Liver Microphysiological System for Assessing Drug-Induced Liver Toxicity In Vitro
Published on: January 31, 2022
A Comparative Analysis of Drug-Induced Hepatotoxicity in Clinically Relevant Situations
Christoph Thiel1, Henrik Cordes1, Lorenzo Fabbri1
1Institute of Applied Microbiology (iAMB), Aachen Biology and Biotechnology (ABBt), RWTH Aachen University, Worringerweg 1, Aachen, Germany.
Abstract:
Drug-induced toxicity is a significant problem in clinical care. A key problem here is a general understanding of the molecular mechanisms accompanying the transition from desired drug effects to adverse events following administration of either therapeutic or toxic doses, in particular within a patient context. Here, a comparative toxicity analysis was performed for fifteen hepatotoxic drugs by evaluating toxic changes reflecting the transition from therapeutic drug responses to toxic reactions at the cellular level. By use of physiologically-based pharmacokinetic modeling, in vitro toxicity data were first contextualized to quantitatively describe time-resolved drug responses within a patient context. Comparatively studying toxic changes across the considered hepatotoxicants allowed the identification of subsets of drugs sharing similar perturbations on key cellular processes, functional classes of genes, and individual genes. The identified subsets of drugs were next analyzed with regard to drug-related characteristics and their physicochemical properties. Toxic changes were finally evaluated to predict both molecular biomarkers and potential drug-drug interactions. The results may facilitate the early diagnosis of adverse drug events in clinical application.
Insights
Understanding drug toxicity is crucial. This study identifies drug subsets with similar cellular impacts, aiding early adverse drug event diagnosis and predicting drug-drug interactions.
Area of Science:
- Pharmacology
- Toxicology
- Computational Biology
Background:
- Drug-induced toxicity poses a significant clinical challenge.
- Understanding the molecular mechanisms of the transition from therapeutic effects to adverse events is critical.
- A patient-specific context is essential for evaluating drug toxicity.
Purpose of the Study:
- To comparatively analyze toxicity of fifteen hepatotoxic drugs at the cellular level.
- To investigate the transition from therapeutic drug responses to toxic reactions.
- To identify molecular biomarkers and predict drug-drug interactions for early adverse drug event diagnosis.
Main Methods:
- Physiologically-based pharmacokinetic (PBPK) modeling to contextualize in vitro toxicity data.
- Quantitative analysis of time-resolved cellular drug responses.
- Comparative analysis of toxic changes, gene perturbations, and drug properties.
Main Results:
- Identified subsets of hepatotoxic drugs with similar effects on cellular processes, gene functions, and individual genes.
- Linked drug subsets to specific drug characteristics and physicochemical properties.
- Evaluated toxic changes to predict molecular biomarkers and potential drug-drug interactions.
Conclusions:
- The study provides a framework for understanding drug toxicity mechanisms.
- Identified drug subsets can inform early diagnosis of adverse drug events.
- Predictive biomarkers and drug-drug interaction insights can enhance clinical care and drug development.
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