Abstract
In recent years, several drugs have been withdrawn from use by regulatory bodies owing to hepatotoxicity; therefore, studies on drug-induced liver injury (DILI) are being actively pursued. Most studies evaluating DILI use rats or mice as animal models to determine drug toxicity; however, the toxicity of a drug can vary between rats or mice. These inconsistencies in in vivo studies among different animal models affect the extrapolation of experimental results to humans. Thus, it is particularly important to choose the most suitable animal model to determine drug hepatotoxicity owing to the genomic differences between rats and mice resulting from evolution. In this study, genome-wide transcriptome analysis was used to explore hepatotoxicity caused by differences in species. Our findings provide the preclinical basis to further study the mechanisms of drug hepatotoxicity and aid in the selection of animal models to determine drug safety. We used murine models (Sprague-Dawley and Wistar rats, ICR and Kunming mice) in this study and by using transcriptome sequencing with the differentially expressed genes in rat and mouse livers as the entry point, we explored the mechanism of oxidative stress and the difference in gene expression in the lipid-metabolism pathway between rats and mice. The clinically established hepatotoxic drugs, fructus psoraleae and acetaminophen were used to validate our study. Using pathological studies, we confirmed that oxidative stress in mice was more serious than that in rats, and that Kunming mice were more suited for the study of oxidative stress-related DILI. The validity of our findings was further verified based on gene expression. Thus, our study could serve as a valuable reference for the evaluation of potential preclinical hepatotoxicity. Moreover, it could be used in the prediction and early diagnosis of drug-induced liver injury caused by traditional Chinese medicine or synthetic drugs, thereby providing a new avenue for drug-toxicity studies.
Highlights
Drug-induced liver injury (DILI) refers to liver injury caused by a drug or its metabolites, or due to hypersensitivity of the special population or tolerance of the liver to drugs, known as druginduced liver disease
Based on the results obtained using transcriptome studies to explore the correlation between the hepatotoxicity phenotypes of two species of rats, two species of mice, and humans, we studied the biological pathways of the differences in hepatotoxicity among different species and identified the appropriate animal models that might be suitable for the study of different hepatotoxicity phenotypes
We downloaded the human gene set of oxidative stress and steatosis-related pathways from the database
Summary
Drug-induced liver injury (DILI) refers to liver injury caused by a drug or its metabolites, or due to hypersensitivity of the special population or tolerance of the liver to drugs, known as druginduced liver disease. DILI manifests clinically as various acute or chronic liver diseases. This condition is self-limiting and mild, especially when the drug is discontinued; in severe cases, Species Difference in Hepatotoxicity it may result in fatalities (Chalasani et al, 2014; Wang et al, 2018). More than 30,000 drugs and healthcare products are available, of which more than 1,000 drugs have already been identified to cause DILI (Yu et al, 2015). Evaluation of drug safety is crucial for drug developers and clinical pharmacists. Evaluating and predicting the drugs that are capable of causing DILI is often a challenge, as this parameter is an inevitable requirement for the development of translational toxicology and precision medicine
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