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Updated: Jun 21, 2026
Human Liver Microphysiological System for Assessing Drug-Induced Liver Toxicity In Vitro
Published on: January 31, 2022
Cell based approaches for evaluation of drug-induced liver injury
Mhairi L Greer1, Jane Barber, Julie Eakins
1Molecular Toxicology, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, United Kingdom.
Abstract:
An improved understanding of mechanisms that underlie drug-induced liver injury (DILI) is required to enable design of drugs that have minimal potential to cause this adverse reaction in man. Available evidence suggests DILI arises in susceptible patients because of an imbalance between chemical insults (which are an inherent property of certain drugs and/or their metabolites) and the ability of the liver to mount compensatory/adaptive responses. In vivo safety testing in pre-clinical species ensures that drugs which enter clinical trials do not cause reproducible and dose-dependent liver injury in man, but is of limited value for exploration of underlying mechanisms and does not assess potential to cause rare idiosyncratic DILI. This review highlights the value that can be gained from in vitro studies using cultured hepatocytes and also hepatocyte-derived cell lines transfected with individual human cytochrome P450 (CYP450) isoforms. We have evaluated a range of mechanisms and endpoints (cell necrosis, mitochondrial injury, inhibition of biliary transporters and metabolite-mediated toxicity) using these model systems. Our data indicate that multiple mechanisms are likely to be involved in development of idiosyncratic DILI in man caused by numerous drugs, e.g. the anticonvulsant chlorpromazine.
Insights
Understanding drug-induced liver injury (DILI) mechanisms is crucial for safer drug design. In vitro studies using cultured hepatocytes and cytochrome P450 (CYP450) models offer valuable insights into DILI development.
Area of Science:
- Hepatology
- Toxicology
- Drug Development
Background:
- Drug-induced liver injury (DILI) is a significant safety concern.
- Current in vivo preclinical testing has limitations in predicting idiosyncratic DILI and elucidating mechanisms.
- DILI likely results from an imbalance between drug insults and the liver's adaptive responses.
Purpose of the Study:
- To review and highlight the value of in vitro models for understanding DILI mechanisms.
- To explore various mechanisms and endpoints contributing to DILI.
- To emphasize the need for improved DILI prediction in drug development.
Main Methods:
- Utilizing cultured hepatocytes as a model system.
- Employing hepatocyte-derived cell lines transfected with specific human cytochrome P450 (CYP450) isoforms.
- Evaluating endpoints such as cell necrosis, mitochondrial injury, biliary transporter inhibition, and metabolite-mediated toxicity.
Main Results:
- In vitro models provide valuable mechanistic insights into DILI.
- Multiple mechanisms contribute to idiosyncratic DILI.
- Specific drugs, like the anticonvulsant chlorpromazine, can trigger DILI through various pathways.
Conclusions:
- In vitro studies are essential for dissecting complex DILI mechanisms.
- A combination of mechanisms likely underlies idiosyncratic DILI.
- Improved understanding of DILI mechanisms can guide the design of safer drugs.
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