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系统方法揭示了肝脏应激反应能力的物种差异

Giusy Russomanno¹, Rowena Sison-Young¹, Lucia A Livoti¹

¹Department of Pharmacology & Therapeutics, Institute of Systems, Molecular & Integrative Biology, University of Liverpool, Liverpool, L69 3GE, UK.

Toxicological sciences : an official journal of the Society of Toxicology

|August 30, 2023

概括

由于较强的应激反应途径,老鼠比小鼠更能适应药物诱导的肝损伤. 这一发现影响了药物安全测试的临床前物种选择.

科学领域:

药理学药理学是指药理学的学科.
毒理学毒理学毒理学
系统生物学系统生物学

背景情况:

了解药物毒性的物种差异对于临床前安全测试至关重要.
乙氨基 (APAP) 诱导的肝损伤因物种而异,与反应性代谢物 (NAPQI) 形成有关.
基于生理学的药物动力学建模有助于比较物种对同等化学侮辱的反应.

研究的目的:

为了比较时间性肝脏组织的反应与小鼠和大鼠中等效的乙氨基诱导的NAPQI负担.
为了研究不同物种对药物诱导的肝损伤的敏感性背后的分子机制.
评估大鼠,小鼠和人类肝脏应激反应的基础和适应能力.

主要方法:

基于生理学的药理动力学建模,以确定相当的APAP剂量.
生物化学测定和血清生物标记分析以量化肝损伤.
组织组织病理学评估肝损伤.
转录基因和蛋白质基因分析以调查应激反应途径.

主要成果:

尽管对肝脏的NAPQI负担相当,但小鼠的肝脏损伤比大鼠更大.
老鼠表现出压力反应通路 (Nrf2,自) 作为适应机制的强烈激活.
与老鼠和人类相比,老鼠具有更高的压力反应途径组件的基底表达.

结论:

鼠对肝脏应激反应的基础和适应能力比小鼠和人类更强大.
不同物种对APAP肝毒性的敏感性受压力反应能力的影响.
这些发现对物种选择和在药物安全评估中对形成反应性代谢物化合物的人类翻译有影响.

关键词:

乙氨基的使用方法肝脏损伤肝脏损伤是什么?氧化应激是一种氧化应激.在临床前的物种.

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