Laboratory of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Chiba Institute of Science, Choshi, Chiba 288–0025, Japan.
Biol Pharm Bull. 2011;34(3):366-70. doi: 10.1248/bpb.34.366.
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.
对乙酰氨基酚（APAP）过量会导致实验动物和人类的肝损伤。N-乙酰半胱氨酸（NAC）临床上被用作 APAP 中毒的解毒剂，据认为它通过提供半胱氨酸作为谷胱甘肽的前体而起作用，谷胱甘肽可以捕获 APAP 的一种活性代谢物。还提出了 NAC 的其他肝保护机制。在这里，我们研究了具有不同能力恢复肝谷胱甘肽的巯基化合物对 APAP 和呋塞米在小鼠中的肝毒性的影响。 overnight-fasted 雄性 CD-1 小鼠经腹腔内给予 APAP 或呋塞米。同时给予 NAC、半胱氨酸、谷胱甘肽或谷胱甘肽单乙酯与 APAP 或呋塞米。本研究中使用的所有巯基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阻止了 APAP 诱导的早期肝谷胱甘肽耗竭。半胱氨酸也显著恢复了肝谷胱甘肽水平。NAC 部分恢复了谷胱甘肽水平。外源性谷胱甘肽对肝谷胱甘肽丢失没有影响。NAC 和谷胱甘肽高度刺激肝细胞因子的表达，特别是白细胞介素 6，这可能参与了 APAP 肝毒性的缓解。不伴有肝谷胱甘肽耗竭的呋塞米诱导的肝损伤也被 NAC 和外源性谷胱甘肽减轻，支持了它们除了补充谷胱甘肽之外的保护机制。总之，外源性巯基化合物可以减轻药物引起的肝损伤。NAC 和谷胱甘肽可能至少部分通过不增加肝谷胱甘肽的机制发挥作用，但可能通过细胞因子介导和抗炎机制发挥作用。
