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Oxidative-stress and long-term hepatotoxicity: comparative study in Upcyte human hepatocytes and hepaRG cells
M Teresa Donato1,2,3, Nuria Jiménez4, María Pelechá4
1Unidad de Hepatología Experimental, Torre A. Instituto Investigación Sanitaria La Fe, Av Fernando Abril Martorell 106, 46026, Valencia, Spain. m.teresa.donato@uv.es.
Abstract:
Drug-induced liver injury (DILI) is one of the most common and serious adverse drug reactions and a major cause of drug development failure and withdrawal. Although different molecular mechanisms are implicated in DILI, enhanced ROS levels have been described as a major mechanism. Human-derived cell models are increasingly used in preclinical safety assessment because they provide quick and relatively inexpensive information in early stages of drug development. We have analyzed and compared the phenotype and functionality of two liver cell models (Upcyte human hepatocytes and HepaRG cells) to demonstrate their suitability for long-term hepatotoxicity assessments and mechanistic studies. The transcriptomic and functional analysis revealed the maintenance of phase I and phase II enzymes, and antioxidant enzymes along time in culture, although the differences found between both test systems underlie the differential sensitivity to hepatotoxins. The evaluation of several mechanisms of cell toxicity, including oxidative stress, by high-content screening, demonstrated that, by combining the stable phenotype of liver cells and repeated-dose exposure regimes to 12 test compounds at clinically relevant concentrations, both Upcyte hepatocytes and HepaRG offer suitable properties to be used in routine screening assays for toxicological assessments during drug preclinical testing.
Insights
Drug-induced liver injury (DILI) is a serious adverse drug reaction. This study shows that Upcyte human hepatocytes and HepaRG cells are suitable for long-term toxicity testing in drug development, assessing mechanisms like oxidative stress.
Area of Science:
- Hepatology
- Toxicology
- Drug Development
Background:
- Drug-induced liver injury (DILI) is a significant challenge in drug development, often linked to oxidative stress.
- Human-derived liver cell models are crucial for early-stage preclinical safety assessment.
Purpose of the Study:
- To compare the suitability of Upcyte human hepatocytes and HepaRG cells for long-term hepatotoxicity and mechanistic studies.
- To evaluate these models for routine toxicological screening in drug preclinical testing.
Main Methods:
- Comparative analysis of phenotype and functionality of Upcyte hepatocytes and HepaRG cells.
- Transcriptomic and functional analysis, including phase I, II, and antioxidant enzymes.
- High-content screening to evaluate toxicity mechanisms like oxidative stress with 12 test compounds.
Main Results:
- Both cell models maintained key liver enzyme functions over time in culture.
- Differences in sensitivity to hepatotoxins were observed between the two models.
- Both models demonstrated suitability for repeated-dose exposure assays at clinically relevant concentrations.
Conclusions:
- Upcyte hepatocytes and HepaRG cells exhibit stable phenotypes and functionality for long-term hepatotoxicity assessments.
- These models are well-suited for routine screening assays in drug preclinical toxicology.
- The models aid in understanding DILI mechanisms, including oxidative stress, during drug development.
