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Published on: November 27, 2019
Interspecies differences in acetaminophen sensitivity of human, rat, and mouse primary hepatocytes
Katalin Jemnitz1, Zsuzsa Veres, Katalin Monostory
1Department of Biochemical Pharmacology, Institute of Biomolecular Chemistry, Chemical Research Center, Hungarian Academy of Sciences, PO Box. 17, H-1525 Budapest, Hungary. jemnitz@chemres.hu <jemnitz@chemres.hu>
Abstract:
Most of the experiments studying acetaminophen (APAP) induced hepatotoxicity were performed using moue as model specie, right because its high sensitivity. While the toxic responses can be called forth easily in mice, the human relevancy of these results is questionable. In this study human, rat, and mouse primary hepatocytes were treated with increasing concentrations of APAP, and cell viability was measured by MTT cytotoxicity assay. Pronounced interspecies differences were obtained in cell viability following 24h of APAP treatment starting at 24h after seeding (EC50: 3.8mM, 7.6mM, and 28.2mM, in mouse, rat, and human hepatocyte culture, respectively). The longer time of culturing highly increased the resistance of hepatocytes of all species investigated. In rat hepatocyte culture EC50 values were 6.0mM, 12.5mM, and 18.8mM, when starting APAP treatment after 24, 48, and 72 h of seeding. Although N-acetylbenzoquinoneimine, a minor metabolite of APAP, which is mainly formed by CYP2E1 at high APAP concentration in every species studied, is thought to initiate the toxic processes, no correlation was found between CYP2E1 activities and hepatocyte sensitivity of different species. We conclude that the toxicity induced by APAP overdose highly depends on the animal model applied.
Insights
Acetaminophen (APAP) overdose toxicity varies significantly between animal models. Mouse models show high sensitivity, but human relevance is questionable due to interspecies differences in hepatotoxicity.
Area of Science:
- Toxicology
- Pharmacology
- Cell Biology
Background:
- Acetaminophen (APAP) induced hepatotoxicity studies often use mice due to sensitivity.
- However, the human relevance of mouse models for APAP toxicity is uncertain.
- Understanding interspecies differences is crucial for accurate toxicity assessments.
Purpose of the Study:
- To investigate and compare acetaminophen (APAP) induced hepatotoxicity across human, rat, and mouse primary hepatocytes.
- To evaluate the impact of culture duration on hepatocyte sensitivity to APAP.
- To explore the role of CYP2E1 in APAP-induced hepatotoxicity across species.
Main Methods:
- Primary hepatocytes from human, rat, and mouse were cultured.
- Cells were treated with varying concentrations of APAP at different time points post-seeding.
- Cell viability was assessed using the MTT cytotoxicity assay.
Main Results:
- Significant interspecies differences in APAP EC50 values were observed: mouse (3.8mM), rat (7.6mM), and human (28.2mM) after 24h treatment.
- Hepatocyte resistance to APAP increased with longer culture times across all species.
- No direct correlation was found between CYP2E1 activity and species-specific APAP sensitivity.
Conclusions:
- Acetaminophen (APAP) overdose hepatotoxicity is highly dependent on the animal model used.
- Mouse models overestimate APAP toxicity compared to human and rat models.
- Results highlight the need for careful consideration of animal models in APAP toxicity research.
