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Published on: August 25, 2022
Zebrafish as model organisms for studying drug-induced liver injury
A D Bastiaan Vliegenthart1, Carl S Tucker, Jorge Del Pozo
1Pharmacology, Toxicology and Therapeutics, British Heart Foundation, Centre for Cardiovascular Science, The Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, EH16 4TJ, UK.
Abstract:
Drug-induced liver injury (DILI) is a major challenge in clinical medicine and drug development. New models are needed for predicting which potential therapeutic compounds will cause DILI in humans, and new markers and mediators of DILI still need to be identified. This review highlights the strengths and weaknesses of using zebrafish as a high-throughput in vivo model for studying DILI. Although the zebrafish liver architecture is different from that of the mammalian liver, the main physiological processes remain similar. Zebrafish metabolize drugs using similar pathways to those in humans; they possess a wide range of cytochrome P450 enzymes that enable metabolic reactions including hydroxylation, conjugation, oxidation, demethylation and de-ethylation. Following exposure to a range of hepatotoxic drugs, the zebrafish liver develops histological patterns of injury comparable to those of mammalian liver, and biomarkers for liver injury can be quantified in the zebrafish circulation. The zebrafish immune system is similar to that of mammals, but the zebrafish inflammatory response to DILI is not yet defined. In order to quantify DILI in zebrafish, a wide variety of methods can be used, including visual assessment, quantification of serum enzymes and experimental serum biomarkers and scoring of histopathology. With further development, the zebrafish may be a model that complements rodents and may have value for the discovery of new disease pathways and translational biomarkers.
Insights
Zebrafish offer a promising high-throughput model for studying drug-induced liver injury (DILI). This model shows comparable liver injury patterns and allows for biomarker quantification, aiding in predicting human DILI.
Area of Science:
- Toxicology
- Genetics
- Drug Development
Background:
- Drug-induced liver injury (DILI) presents significant challenges in medicine and drug development.
- Identifying reliable models and biomarkers for predicting human DILI is crucial.
Purpose of the Study:
- To evaluate the strengths and weaknesses of zebrafish as a high-throughput in vivo model for DILI research.
- To explore the utility of zebrafish in identifying new DILI pathways and translational biomarkers.
Main Methods:
- Review of existing literature on zebrafish as a model for DILI.
- Comparison of zebrafish and mammalian liver physiology and drug metabolism pathways.
- Analysis of methods for quantifying DILI in zebrafish, including histology and biomarker analysis.
Main Results:
- Zebrafish share conserved drug-metabolizing pathways with humans, utilizing cytochrome P450 enzymes.
- Exposure to hepatotoxic drugs induces histological injury patterns in zebrafish livers similar to mammals.
- Circulating biomarkers for liver injury can be quantified in zebrafish.
Conclusions:
- Zebrafish possess key physiological similarities to mammals, making them a valuable in vivo model for DILI.
- Further development of the zebrafish model can complement rodent studies and aid in discovering new DILI pathways and biomarkers.
