A systems approach reveals species differences in hepatic stress response capacity.
A systems approach reveals species differences in hepatic stress response capacity.
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DOI：
10.1093/toxsci/kfad085
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发表时间：
2023-10-30
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影响因子：
--
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--
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为了最大限度地减少新药早期临床前研究中意外毒性的发生，了解临床前物种和人类之间的基本相似性和差异至关重要。对乙酰氨基酚（APAP）肝损伤敏感性的种属差异与生物活化为反应性代谢物N-乙酰基-对-苯醌亚胺（NAPQI）的药物分数差异有关。我们已经使用基于生理学的药代动力学建模来确定APAP的口服剂量（在小鼠和大鼠中分别为300和1000 mg/kg），其产生类似的NAPQI的肝脏负荷，以使得能够在等效化学损伤的条件下比较时间肝组织响应。尽管等效NAPQI损伤的药代动力学和生物化学验证，血清生物标志物和组织病理学分析显示小鼠仍然表现出比大鼠更大程度的肝损伤。转录组学和蛋白质组学分析强调了大鼠肝脏中应激反应途径（包括Nrf 2氧化应激反应和自噬）的更强激活，表明对等效损伤的更稳健的转录适应。与小鼠和人类相比，这些途径的组分在大鼠肝脏中的基础水平也更高。我们的研究结果为了解不同物种对肝毒性的敏感性提供了一种系统方法。多组学分析表明，大鼠具有比小鼠和人类更大的肝脏应激反应的基础和适应能力，这对与活性代谢物形成相关的新药候选物的安全性测试中的物种选择和人类翻译具有重要意义。
To minimize the occurrence of unexpected toxicities in early phase preclinical studies of new drugs, it is vital to understand fundamental similarities and differences between preclinical species and humans. Species differences in sensitivity to acetaminophen (APAP) liver injury have been related to differences in the fraction of the drug that is bioactivated to the reactive metabolite N-acetyl-p-benzoquinoneimine (NAPQI). We have used physiologically based pharmacokinetic modeling to identify oral doses of APAP (300 and 1000 mg/kg in mice and rats, respectively) yielding similar hepatic burdens of NAPQI to enable the comparison of temporal liver tissue responses under conditions of equivalent chemical insult. Despite pharmacokinetic and biochemical verification of the equivalent NAPQI insult, serum biomarker and tissue histopathology analyses revealed that mice still exhibited a greater degree of liver injury than rats. 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, indicative of a more robust transcriptional adaptation to the equivalent insult. 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. Multiomics analysis indicated that rats possess a greater basal and adaptive capacity for hepatic stress responses than mice and humans, with important implications for species selection and human translation in the safety testing of new drug candidates associated with reactive metabolite formation.
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影响因子：
4.6
作者：
Clarke, Jessica L.;Murray, James B.;Copple, Ian M.
通讯作者：
Copple, Ian M.
影响因子：
4.8
作者：
Lee, Eun-Woo;Lai, Yurong;Unadkat, Jashvant D.
通讯作者：
Unadkat, Jashvant D.
DOI：
10.1074/jbc.m109.096545
发表时间：
2010-05-28
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Copple IM;Lister A;Obeng AD;Kitteringham NR;Jenkins RE;Layfield R;Foster BJ;Goldring CE;Park BK
通讯作者：
Park BK
影响因子：
3.8
作者：
McGill, Mitchell R.;Williams, C. David;Xie, Yuchao;Ramachandran, Anup;Jaeschke, Hartmut
通讯作者：
Jaeschke, Hartmut
影响因子：
3.6
作者：
Lau, Alexandria;Whitman, Samantha A.;Jaramillo, Melba C.;Zhang, Donna D.
通讯作者：
Zhang, Donna D.