Novel mechanisms of protection against acetaminophen hepatotoxicity in mice by glutathione and N-acetylcysteine.
Novel mechanisms of protection against acetaminophen hepatotoxicity in mice by glutathione and N-acetylcysteine.
复制标题
DOI：
10.1002/hep.23267
复制
发表时间：
2010-01
期刊：
影响因子：
13.5
通讯作者：
Jaeschke, Hartmut
中科院分区：
文献类型：
--
作者：
Saito, Chieko;Zwingmann, Claudia;Jaeschke, Hartmut
对乙酰氨基酚（APAP）过量是急性肝衰竭的主要原因。谷胱甘肽 (GSH) 前体 N-乙酰半胱氨酸 (NAC) 用于治疗 APAP 过量患者长达 48 小时。尽管早期使用 NAC 治疗可以改善反应性代谢物 N-乙酰基对苯醌亚胺 (NAPQI) 的清除，但后期的保护机制仍不清楚。为了解决这个问题，禁食的 C3Heb/FeJ 小鼠接受 300 mg/kg APAP 治疗，然后在 APAP 后 1.5 小时静脉注射 0.65 mmol/kg GSH 或 NAC。 6小时处死动物。单独使用 APAP 会导致严重的肝损伤，并导致过氧亚硝酸盐形成和 DNA 断裂，所有这些都被两种治疗方法所减弱。然而，GSH (-82%) 在预防肝损伤方面比 NAC (-46%) 更有效。使用核磁共振波谱测量组织 ATP 水平和线粒体克雷布斯循环的底物通量，观察到与单独 APAP 相比，肝损伤的减少与线粒体 GSH 含量的加速恢复、ATP 水平的维持和线粒体克雷布斯循环的底物供应增加相关。与 GSH 相比，NAC 处理在恢复 ATP 和线粒体 GSH 水平方面效果较差，并且显示通过克雷布斯循环的底物通量减少。然而，增加 NAC 的剂量可以改善与 GSH 类似的保护作用，表明未用于 GSH 合成的氨基酸被用作线粒体能量底物。延迟使用 GSH 和 NAC 治疗可通过双重机制防止 APAP 过量，即通过提高肝脏和线粒体 GSH 水平（清除活性氧和过氧亚硝酸盐）以及支持线粒体能量代谢。
Acetaminophen (APAP) overdose is a major cause of acute liver failure. The glutathione (GSH) precursor N-acetylcysteine (NAC) is used to treat patients with APAP overdose for up to 48 h. Although it is well established that early treatment with NAC can improve the scavenging of the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI), protective mechanisms at later times remain unclear. To address this issue, fasted C3Heb/FeJ mice were treated with 300 mg/kg APAP and then received intravenously 0.65 mmol/kg GSH or NAC at 1.5 h after APAP. The animals were sacrificed at 6 h. APAP alone caused severe liver injury with peroxynitrite formation and DNA fragmentation, all of which was attenuated by both treatments. However, GSH (−82%) was more effective than NAC (−46%) in preventing liver injury. Using nuclear magnetic resonance spectroscopy to measure tissue ATP levels and the substrate flux through the mitochondrial Krebs cycle, it was observed that the reduced liver injury correlated with accelerated recovery of mitochondrial GSH content, maintenance of ATP levels and an increased substrate supply for the mitochondrial Krebs cycle compared to APAP alone. NAC treatment was less effective in recovering ATP and mitochondrial GSH levels and showed reduced substrate flux through the Krebs cycle compared to GSH. However, increasing the dose of NAC improved the protective effect similar to GSH suggesting that the amino acids not used for GSH synthesis were used as mitochondrial energy substrates. Delayed treatment with GSH and NAC protect against APAP overdose by dual mechanisms, i.e. by enhancing hepatic and mitochondrial GSH levels (scavenging of reactive oxygen and peroxynitrite) and by supporting the mitochondrial energy metabolism.
登录
查看更多内容
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：
5.1
作者：
Lash, Lawrence H.
通讯作者：
Lash, Lawrence H.
影响因子：
3.8
作者：
Knight, TR;Kurtz, A;Jaeschke, H
通讯作者：
Jaeschke, H
影响因子：
158.5
作者：
SMILKSTEIN, MJ;KNAPP, GL;RUMACK, BH
通讯作者：
RUMACK, BH