4-Methylpyrazole protects against acetaminophen hepatotoxicity in mice and in primary human hepatocytes.
4-Methylpyrazole protects against acetaminophen hepatotoxicity in mice and in primary human hepatocytes.
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4-甲基吡唑可预防小鼠和原发性肝细胞中的对乙酰氨基酚肝毒性。
DOI：
10.1177/0960327118774902
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发表时间：
2018-12
影响因子：
2.8
通讯作者：
Jaeschke H
中科院分区：
文献类型：
--
作者：
Akakpo JY;Ramachandran A;Kandel SE;Ni HM;Kumer SC;Rumack BH;Jaeschke H
在美国，对乙酰氨基酚（APAP）过量导致的肝损伤是急性肝衰竭的主要原因。虽然N-乙酰半胱氨酸（NAC）治疗是APAP过量的当前标准治疗，但轶事证据表明，4-甲基吡唑（4 MP）给药在临床上可能有益。本研究的目的是检查4 MP的保护作用及其作用机制。雄性C57 BL/6 J小鼠用300 mg/kg APAP和50 mg/kg 4 MP共处理。APAP在6 h时引起的严重肝损伤（表现为血浆ALT活性升高、小叶中心坏死和核DNA片段化）几乎被4 MP完全消除。此外，4 MP在很大程度上阻止APAP诱导的c-jun N-末端激酶（JNK）的激活，磷酸化JNK和Bax的线粒体易位，以及线粒体膜间蛋白的释放。重要的是，4 MP抑制APAP-蛋白加合物的产生和APAP-GSH结合物的形成，并减弱肝脏GSH含量的消耗。这些发现与人类相关，因为4 MP也阻止了原代人肝细胞中APAP诱导的细胞死亡。总之，4 MP早期治疗可通过抑制细胞色素P450和防止反应性代谢产物的产生，完全预防APAP过量后的肝损伤。
Liver injury due to acetaminophen (APAP) overdose is the major cause of acute liver failure in the US. While treatment with N-acetylcysteine (NAC) is the current standard of care for APAP overdose, anecdotal evidence suggests that administration of 4-methylpyrazole (4MP) may be beneficial in the clinic. The objective of the current study was to examine the protective effect of 4MP and its mechanism of action. Male C57BL/6J mice were co-treated with 300mg/kg APAP and 50mg/kg 4MP. The severe liver injury induced by APAP at 6h as indicated by elevated plasma ALT activities, centrilobular necrosis and nuclear DNA fragmentation, was almost completely eliminated by 4MP. In addition, 4MP largely prevented APAP-induced activation of c-jun N-terminal kinase (JNK), mitochondrial translocation of phospho-JNK and Bax, and the release of mitochondrial inter-membrane proteins. Importantly, 4MP inhibited the generation of APAP-protein adducts and formation of APAP-GSH conjugates and attenuated the depletion of the hepatic GSH content. These findings are relevant to humans because 4MP also prevented APAP-induced cell death in primary human hepatocytes. In conclusion, early treatment with 4MP can completely prevent liver injury after APAP overdose by inhibiting cytochrome P450 and preventing generation of the reactive metabolite.
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影响因子：
3.8
作者：
Gujral, JS;Knight, TR;Jaeschke, H
通讯作者：
Jaeschke, H
影响因子：
13.5
作者：
Kon, K;Kim, JS;Lemasters, JJ
通讯作者：
Lemasters, JJ
影响因子：
6.2
作者：
BRENNAN, RJ;MANKES, RF;ZINK, BJ
通讯作者：
ZINK, BJ
DOI：
10.1111/j.1365-2125.1984.tb02495.x
发表时间：
1984-01-01
影响因子：
3.4
作者：
CLEMENTS, JA;CRITCHLEY, JAJH;PRESCOTT, LF
通讯作者：
PRESCOTT, LF
影响因子：
4.3
作者：
Du K;Xie Y;McGill MR;Jaeschke H
通讯作者：
Jaeschke H