To minimise unexpected toxicities in early phase clinical studies of new drugs, it is vital to understand fundamental similarities and differences between preclinical test species and humans. We have used physiologically-based pharmacokinetic modelling to identify doses of the model hepatotoxin acetaminophen yielding similar hepatic burdens of the reactive metabolite N-acetyl-p-benzoquinoneimine in mice and rats, to enable comparison of tissue adaptive responses under conditions of equivalent chemical insult. Mice exhibited a greater degree of liver injury than rats, despite the equivalent hepatic NAPQI burden. Transcriptomic and proteomic analyses highlighted the stronger activation of stress response pathways (including the Nrf2 oxidative stress response and autophagy) in the livers of rats. Components of these pathways were also found to be expressed at a higher basal level in the livers of rats compared with both mice and humans. Our findings exemplify a systems approach to understanding differential species sensitivity to hepatotoxicity, and have important implications for species selection and human translation in the safety testing of new drug candidates.

中文翻译：

---

一种系统方法揭示了肝脏应激反应能力的物种差异

为了最大限度地减少新药早期临床研究中的意外毒性，了解临床前试验物种与人类之间的基本相似之处和差异至关重要。我们已经使用基于生理学的药代动力学模型来确定模型肝毒素对乙酰氨基酚的剂量，从而在小鼠和大鼠中产生类似的反应性代谢物 N-乙酰基-对苯醌亚胺的肝脏负担，从而能够比较等效化学损伤条件下的组织适应性反应。尽管肝脏 NAPQI 负担相同，但小鼠的肝损伤程度高于大鼠。转录组学和蛋白质组学分析强调了大鼠肝脏中应激反应通​​路（包括 Nrf2 氧化应激反应和自噬）的更强激活。与小鼠和人类相比，还发现这些途径的成分在大鼠肝脏中以更高的基础水平表达。我们的研究结果举例说明了一种系统方法来理解不同物种对肝毒性的敏感性，并对新候选药物的安全性测试中的物种选择和人类翻译具有重要意义。