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Updated: Aug 18, 2026
Advanced 3D Liver Models for In vitro Genotoxicity Testing Following Long-Term Nanomaterial Exposure
Published on: June 5, 2020
New technologies and screening strategies for hepatotoxicity: use of in vitro models
Donna M Dambach1, Barbara A Andrews, Frederic Moulin
1Discovery Toxicology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543, USA. donna.dambach@bms.com
Abstract:
Hepatotoxicity remains a significant cause for drug failures during clinical trials. This is due, in part, to the idiosyncratic nature of toxicity in humans and inherent physiological differences between humans and preclinical species leading to limited correct prediction of adverse responses in humans. To address this issue, robust screening assays are being developed, which have heightened predictive capacity for human hepatotoxicity, and may be utilized throughout the discovery and development phases in conjunction with traditional in vivo methods, for decision making during drug selection and risk assessment. This manuscript describes an example application of in vitro-based strategies using human hepatocyte cultures in lead optimization screening in conjunction with ADME profiling, for evaluation of compound-associated CYP450 induction potential, and the identification of potentially useful biomarkers as predictors of hepatotoxicity for use in vitro, and in preclinical species and humans.
Insights
Predicting drug-induced liver injury (hepatotoxicity) is challenging. This study uses human liver cells in vitro to improve early detection of potential drug toxicity and identify predictive biomarkers.
Area of Science:
- Drug discovery and development
- Toxicology
- Hepatology
Background:
- Drug-induced liver injury (hepatotoxicity) is a major cause of clinical trial failures.
- Predicting human hepatotoxicity is difficult due to species differences and idiosyncratic reactions.
- Current preclinical models have limited predictive capacity for human adverse responses.
Purpose of the Study:
- To describe in vitro strategies for predicting human hepatotoxicity during drug development.
- To evaluate compound-associated cytochrome P450 (CYP450) induction potential.
- To identify biomarkers for predicting hepatotoxicity in vitro, preclinical species, and humans.
Main Methods:
- Utilized in vitro human hepatocyte cultures for lead optimization screening.
- Integrated ADME (Absorption, Distribution, Metabolism, and Excretion) profiling.
- Evaluated CYP450 induction potential and identified potential toxicity biomarkers.
Main Results:
- Demonstrated the application of in vitro assays in lead optimization.
- Provided a framework for evaluating compound-associated CYP450 induction.
- Identified potential biomarkers for predicting hepatotoxicity.
Conclusions:
- In vitro hepatocyte-based strategies enhance predictive capacity for human hepatotoxicity.
- These assays aid decision-making in drug selection and risk assessment.
- Biomarker identification supports earlier and more accurate toxicity prediction across species.
