Research on the Species Difference of the Hepatotoxicity of Medicine Based on Transcriptome

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In recent years, several drugs have been withdrawn from use by regulatory bodies owing to hepatotoxicity; therefore, studies on drug-induced liver injury (DILI) are being actively pursued.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.

A systems approach reveals species differences in hepatic stress response capacity

“…In light of our findings, it is possible that this is due to the greater capacity of the rat liver to cope with the initial chemical insult and mitigate against the progression of downstream toxic events. Consistent with our findings, Xu et al 27 recently reported that mice better resemble humans in terms of the basal hepatic expression of oxidative stress-related genes, whilst rats better resemble humans in terms of the expression of genes associated with lipid metabolism. Transgenic Nrf2 null mice have been reported to exhibit greater susceptibility to a large number of liver toxins, including APAP 28 , whilst Kang et al 29 recently reported that the response of an Nrf2-associated gene set was typically higher in primary rat, compared with human, hepatocytes exposed to a large panel of liver toxic and safe drugs.…”

“…Our study highlights the higher basal and inducible activity of the Nrf2 antioxidant and autophagy stress responses in the livers of rats, compared with mice and humans. Consistent with our findings, Xu et al (39) reported that mice better resemble humans in terms of the basal hepatic expression of oxidative stress-related genes, whilst rats better resemble humans in terms of the expression of genes associated with lipid metabolism. Transgenic Nrf2 null mice have been reported to exhibit greater susceptibility to a large number of liver toxins, including APAP (40), whilst autophagy has been implicated in the pathogenesis of DILI (41) and shown to act as a defence mechanism in APAP hepatotoxicity by removing damaged mitochondria (42).…”

Observation of Voriconazole in the Treatment of Liver Failure Complicated With Invasive Pulmonary Fungal Infection Induced by Chinese Patent Medicine in Teenagers: 2 Case Reports

“…Case 1 developed a rash after taking an acetaminophen-containing Chinese patent medicine, developed severe liver function impairment 1 week later, and progressed to subacute liver failure 2 months later. Qubaibabuqi tablets were taken by Case 2, which contains the Chinese herb Psoralea that is known to induce oxidative stress that may cause DILI ( Xu et al, 2021 ). The patient progressed to ALF and hepatic encephalopathy after using the medicine for more than 3 months.…”

Mitochondria as the Target of Hepatotoxicity and Drug-Induced Liver Injury: Molecular Mechanisms and Detection Methods

“…There are numerous in vitro tools that are largely implemented for the assessment of the hepatotoxic potential of various compounds and that offer a valid platform to investigate mechanisms of mitochondrial toxicity. Human-based models are preferred over animal-derived systems because of their better predictive and translational value [ 186 , 187 ]. However, both are used, especially since there is a low availability of human material.…”