table2_Research on the Species Difference of the Hepatotoxicity of Medicine Based on Transcriptome.xlsx

In recent years, several drugs have been withdrawn from use by regulatory bodies owing to hepatotoxicity; therefore, studies on drug-induced liver injury (DILI) are being actively pursued.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

近年来，已有多款药物因肝毒性被监管机构撤市，因此针对药物性肝损伤（drug-induced liver injury，DILI）的相关研究正得到广泛开展。目前多数评估DILI的研究以大鼠或小鼠作为动物模型来检测药物毒性，但药物毒性在大鼠和小鼠之间可能存在差异。不同动物模型的体内实验结果存在此类不一致性，会影响实验结果向人类的外推。因此，鉴于大鼠与小鼠因进化过程产生的基因组差异，选择最适宜的动物模型用于检测药物肝毒性尤为重要。本研究采用全基因组转录组分析技术，探究物种差异介导的肝毒性机制，研究结果可为药物肝毒性机制的深入研究以及药物安全性评价所需动物模型的筛选提供临床前依据。本研究采用啮齿类动物模型，包括Sprague-Dawley大鼠、Wistar大鼠、ICR小鼠及昆明小鼠；以转录组测序分析大鼠与小鼠肝脏的差异表达基因为切入点，探究了氧化应激机制以及大鼠与小鼠脂质代谢通路的基因表达差异。本研究选用临床已确认的肝毒性药物补骨脂（fructus psoraleae）与对乙酰氨基酚（acetaminophen）开展验证实验，通过病理学实验证实小鼠的氧化应激水平显著高于大鼠，且昆明小鼠更适用于氧化应激相关DILI的研究。本研究结果的可靠性进一步通过基因表达数据得到验证，因此可为潜在临床前肝毒性的评价提供重要参考依据。此外，本研究可用于预测与早期诊断中药或合成药物引发的药物性肝损伤，为药物毒性研究提供全新思路。