Protective effects of exogenous glutathione and related thiol compounds against drug-induced liver injury.
Protective effects of exogenous glutathione and related thiol compounds against drug-induced liver injury.
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DOI：
10.1248/bpb.34.366
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发表时间：
2011-03
影响因子：
2
通讯作者：
Y. Masubuchi;J. Nakayama;Y. Sadakata
中科院分区：
文献类型：
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作者：
Y. Masubuchi;J. Nakayama;Y. Sadakata
过量服用对乙酰氨基酚（APAP）会导致实验动物和人类的肝脏损伤。N-乙酰半胱氨酸（NAC）在临床上被用作APAP中毒的解毒剂，它被认为是通过提供半胱氨酸作为谷胱甘肽的前体来起作用，谷胱甘肽捕获APAP的反应性代谢物。NAC的其他肝保护机制也被提出。在这里，我们研究了具有不同能力的巯基化合物，以恢复肝脏谷胱甘肽，对APAP和呋塞米在小鼠中的肝毒性的影响。过夜禁食的雄性CD-1小鼠腹腔内给予APAP或呋塞米。NAC、半胱氨酸、谷胱甘肽或谷胱甘肽单乙酯与APAP或呋塞米同时给药。本研究中使用的所有硫醇化合物均有效保护小鼠免受APAP诱导的肝损伤。只有谷胱甘肽单乙酯完全防止APAP诱导的早期肝脏谷胱甘肽耗竭。半胱氨酸也显着恢复肝脏谷胱甘肽水平。NAC部分恢复谷胱甘肽水平。外源性谷胱甘肽对肝脏谷胱甘肽损失无影响。NAC和谷胱甘肽可显著刺激肝脏细胞因子尤其是白细胞介素-6的表达，这可能与减轻APAP肝毒性有关。呋塞米诱导的肝损伤，这并不伴随肝脏谷胱甘肽耗竭，也减弱了NAC和外源性谷胱甘肽，支持他们的保护机制，而不是补充谷胱甘肽。结论：外源性巯基物质可减轻药物性肝损伤。NAC和谷胱甘肽可能发挥其作用，至少部分地，通过机制，是独立的增加肝脏谷胱甘肽，但可能通过精氨酸介导的抗炎机制。
An overdose of acetaminophen (APAP) causes liver injury both in experimental animals and humans. N-acetylcysteine (NAC) is clinically used as an antidote for APAP intoxication, and it is thought to act by providing cysteine as a precursor of glutathione, which traps a reactive metabolite of APAP. Other hepatoprotective mechanisms of NAC have also been suggested. Here, we examined the effects of thiol compounds with different abilities to restore hepatic glutathione, on hepatotoxicity of APAP and furosemide in mice. Overnight-fasted male CD-1 mice were given APAP or furosemide intraperitoneally. NAC, cysteine, glutathione, or glutathione-monoethyl ester was administered concomitantly with APAP or furosemide. All thiol compounds used in this study effectively protected mice against APAP-induced liver injury. Only glutathione-monoethyl ester completely prevented APAP-induced early hepatic glutathione depletion. Cysteine also significantly restored hepatic glutathione levels. NAC partially restored glutathione levels. Exogenous glutathione had no effect on hepatic glutathione loss. NAC and glutathione highly stimulated the hepatic expression of cytokines, particularly interleukin-6, which might be involved in the alleviation of APAP hepatotoxicity. Furosemide-induced liver injury, which does not accompany hepatic glutathione depletion, was also attenuated by NAC and exogenous glutathione, supporting their protective mechanisms other than replenishment of glutathione. In conclusion, exogenous thiols could alleviate drug-induced liver injury. NAC and glutathione might exert their effects, at least partially, via mechanisms that are independent of increasing hepatic glutathione, but probably act through cytokine-mediated and anti-inflammatory mechanisms.