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Updated: Jul 4, 2026
Human Liver Microphysiological System for Assessing Drug-Induced Liver Toxicity In Vitro
Published on: January 31, 2022
Cellular imaging predictions of clinical drug-induced liver injury
Jinghai J Xu1, Peter V Henstock, Margaret C Dunn
1Predictive Toxicology, Pfizer Research Technology Center, Pfizer Global Research and Development, Cambridge, Massachussetts 01239, USA.
Abstract:
Drug-induced liver injury (DILI) is the most common adverse event causing drug nonapprovals and drug withdrawals. Using drugs as test agents and measuring a panel of cellular phenotypes that are directly linked to key mechanisms of hepatotoxicity, we have developed an in vitro testing strategy that is predictive of many clinical outcomes of DILI. Mitochondrial damage, oxidative stress, and intracellular glutathione, all measured by high content cellular imaging in primary human hepatocyte cultures, are the three most important features contributing to the hepatotoxicity prediction. When applied to over 300 drugs and chemicals including many that caused rare and idiosyncratic liver toxicity in humans, our testing strategy has a true-positive rate of 50-60% and an exceptionally low false-positive rate of 0-5%. These in vitro predictions can augment the performance of the combined traditional preclinical animal tests by identifying idiosyncratic human hepatotoxicants such as nimesulide, telithromycin, nefazodone, troglitazone, tetracycline, sulindac, zileuton, labetalol, diclofenac, chlorzoxazone, dantrolene, and many others. Our findings provide insight to key DILI mechanisms, and suggest a new approach in hepatotoxicity testing of pharmaceuticals.
Insights
A new in vitro testing strategy accurately predicts drug-induced liver injury (DILI) by measuring mitochondrial damage, oxidative stress, and glutathione levels. This approach enhances pharmaceutical safety testing by identifying potential hepatotoxicants.
Area of Science:
- Hepatology
- Toxicology
- Drug Development
Background:
- Drug-induced liver injury (DILI) is a primary reason for drug nonapprovals and withdrawals.
- Current preclinical testing methods have limitations in predicting human DILI, especially idiosyncratic cases.
Purpose of the Study:
- To develop and validate an in vitro testing strategy predictive of clinical DILI outcomes.
- To identify key cellular mechanisms and biomarkers for hepatotoxicity prediction.
Main Methods:
- Utilized high-content cellular imaging to measure mitochondrial damage, oxidative stress, and intracellular glutathione in primary human hepatocytes.
- Applied the testing strategy to over 300 drugs and chemicals, including known human hepatotoxicants.
Main Results:
- The in vitro testing strategy demonstrated a 50-60% true-positive rate for predicting DILI.
- Achieved an exceptionally low false-positive rate of 0-5% for hepatotoxicity prediction.
- Successfully identified numerous idiosyncratic human hepatotoxicants.
Conclusions:
- Mitochondrial damage, oxidative stress, and glutathione levels are critical indicators of hepatotoxicity.
- This in vitro approach offers a valuable supplement to traditional preclinical animal testing for pharmaceutical safety.
- The findings suggest a novel paradigm for assessing the hepatotoxicity of drug candidates.
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