Acetaminophen-induced liver injury in rats and mice: comparison of protein adducts, mitochondrial dysfunction, and oxidative stress in the mechanism of toxicity.
Acetaminophen-induced liver injury in rats and mice: comparison of protein adducts, mitochondrial dysfunction, and oxidative stress in the mechanism of toxicity.
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DOI：
10.1016/j.taap.2012.08.015
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发表时间：
2012-11-01
影响因子：
3.8
通讯作者：
Jaeschke, Hartmut
中科院分区：
文献类型：
--
作者：
McGill, Mitchell R.;Williams, C. David;Xie, Yuchao;Ramachandran, Anup;Jaeschke, Hartmut
在西方，过量服用对乙酰氨基酚(APAP)是导致急性肝功能衰竭的最常见原因。在小鼠中，单次给药可迅速诱导APAP的肝毒性。由于APAP中毒既具有临床相关性，又具有实验方便性，已成为一种流行的肝损伤模型。早期数据表明，大鼠对APAP毒性具有抵抗力。因此，小鼠是机械研究的首选物种。此外，最近的研究表明，APAP对人类的毒性机制与小鼠相似。尽管如此，一些调查人员仍然使用老鼠。来自过去四十年的新的机制信息促使人们重新评估这些物种之间的差异。比较可以提供有趣的见解，并确认或排除RAT作为APAP研究的一个选项。为此，我们用APAP治疗大鼠和小鼠，并测量了肝损伤、APAP代谢、氧化应激和c-jun氨基末端激酶(JNK)的激活参数。与早期数据一致，我们发现大鼠对APAP毒性具有高度抵抗力。尽管两个物种的APAP代谢总体相似，但大鼠的线粒体蛋白加合物显著较低。因此，大鼠的氧化应激程度也较低。最后，虽然小鼠表现出广泛的JNK激活和线粒体易位，但在大鼠肝脏中检测不到这一点。这些数据支持线粒体功能障碍是APAP治疗后发生坏死的关键因素的假说。由于线粒体损伤也发生在人类身上，因此大鼠不是APAP肝脏毒性研究的临床相关物种。
Acetaminophen (APAP) overdose is the most common cause of acute liver failure in the West. In mice, APAP hepatotoxicity can be rapidly induced with a single dose. Because it is both clinically relevant and experimentally convenient, APAP intoxication has become a popular model of liver injury. Early data demonstrated that rats are resistant to APAP toxicity. As a result, mice are the preferred species for mechanistic studies. Furthermore, recent work has shown that the mechanisms of APAP toxicity in humans are similar to mice. Nevertheless, some investigators still use rats. New mechanistic information from the last forty years invites a reevaluation of the differences between these species. Comparison may provide interesting insights and confirm or exclude the rat as an option for APAP studies. To this end, we treated rats and mice with APAP and measured parameters of liver injury, APAP metabolism, oxidative stress, and activation of the c-jun N-terminal kinase (JNK). Consistent with earlier data, we found that rats were highly resistant to APAP toxicity. Although overall APAP metabolism was similar in both species, mitochondrial protein adducts were significantly lower in rats. Accordingly, rats also had less oxidative stress. Finally, while mice showed extensive activation and mitochondrial translocation of JNK, this could not be detected in rat livers. These data support the hypothesis that mitochondrial dysfunction is critical for the development of necrosis after APAP treatment. Because mitochondrial damage also occurs in humans, rats are not a clinically relevant species for studies of APAP hepatotoxicity.
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影响因子：
25.7
作者：
Antoine, Daniel J.;Jenkins, Rosalind E.;Dear, James W.;Williams, Dominic P.;McGill, Mitchell R.;Sharpe, Matthew R.;Craig, Darren G.;Simpson, Kenneth J.;Jaeschke, Hartmut;Park, B. Kevin
通讯作者：
Park, B. Kevin
影响因子：
5.9
作者：
Jaeschke H;McGill MR;Ramachandran A
通讯作者：
Ramachandran A
醛酮还原酶 7A 保护肝细胞和组织免受对乙酰氨基酚诱导的氧化应激和肝毒性
影响因子：
13.5
作者：
Ahmed, Munzir M. E.;Wang, Tao;Yang, James Y.
通讯作者：
Yang, James Y.
影响因子：
2.1
作者：
Kelava, Tomislav;Cavar, Ivan;Culo, Filip
通讯作者：
Culo, Filip
影响因子：
13.5
作者：
Kon, K;Kim, JS;Lemasters, JJ
通讯作者：
Lemasters, JJ