Complex Approach to Xenobiotics Hepatotoxicity Testing using a Microfluidic System

Area of Science:

• Hepatotoxicity and Drug Safety
• Cellular Toxicology
• Biomarker Discovery

Background:

• Drug-induced liver injury (DILI) poses a significant clinical challenge.
• Accurate preclinical assessment of hepatotoxicity is crucial for drug development.
• Existing models may not fully capture complex toxicological responses.

Purpose of the Study:

• To evaluate the hepatotoxicity of acetaminophen, metformin, and isoniazid.
• To establish and validate an integrated in vitro model for assessing drug-induced liver injury.
• To identify reliable biomarkers for both acute and chronic drug toxicity.

Main Methods:

• Utilized differentiated HepaRG cell spheroids cultured under microfluidic conditions.
• Assessed acute toxicity via cell viability assays.
• Measured lactate concentration, mitochondrial activity, and DNA fragmentation for chronic/non-lethal effects.

Main Results:

• Demonstrated the utility of HepaRG cell spheroids in a microfluidic system for hepatotoxicity testing.
• Lactate concentration emerged as a promising marker for chronic drug exposure and non-lethal effects.
• Integrated analysis of multiple endpoints provided a comprehensive assessment of drug-induced liver injury.

Conclusions:

• The integrated approach using HepaRG cell spheroids is efficient and applicable for assessing drug hepatotoxicity.
• This model offers a more holistic evaluation of drug safety compared to single-endpoint assays.
• Further validation can enhance its role in preclinical drug safety screening.