Protective effects of thiopronin against isoniazid-induced hepatotoxicity in rats
Protective effects of thiopronin against isoniazid-induced hepatotoxicity in rats
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硫普宁对异烟肼所致大鼠肝毒性的保护作用
DOI：
10.1016/j.tox.2009.08.006
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发表时间：
2009-10-29
期刊：
影响因子：
4.5
通讯作者：
Peng, Renxiu
中科院分区：
文献类型：
--
作者：
Yue, Jiang;Dong, Guicheng;Peng, Renxiu
异烟肼是一种广泛用于治疗结核病的药物，但肝毒性是治疗过程中的一个主要问题。硫普罗宁含有SH基团，通常被认为是一种抗氧化剂。本研究的目的是探讨硫普宁在异烟肼引起的肝损伤和 DNA 损伤中的作用。从第 11 天到第 21 天，每天给大鼠注射异烟肼（100 mg/kg，腹腔注射），持续 21 天，并与或不与硫普罗宁共同给药（60 mg/kg，腹腔注射）。通过 HPLC-MS/MS 在精密切割的大鼠肝切片中分析硫普罗宁对异烟肼诱导的 DNA 氧化损伤的影响。肝损伤的诊断指标（丙氨酸转氨酶和天冬氨酸转氨酶）和组织病理学分析表明，硫普罗宁可预防异烟肼引起的肝毒性。在体内，根据氯唑沙宗羟化酶和苯胺羟化酶的评估，硫普罗宁显着抑制异烟肼诱导的 CYP2E1 活性 (p < 0.001)。硫普罗宁浓度依赖性地抑制 CYP2E1 依赖性苯胺羟基化，狄克逊图表明硫普罗宁是 CYP2E1 的竞争性抑制剂。硫普罗宁通过胞质谷胱甘肽 S-转移酶 (GST)（包括 mu GST 和 alpha GST）显着减弱异烟肼诱导的解毒系统抑制。在精确切割的肝脏切片中，硫普罗宁的自由基清除活性减少了异烟肼诱导的 DNA 加合物的产生 (p < 0.05)。总而言之，这些结果表明，硫普宁除了作为清除剂的作用外，还通过抑制自由基的产生来发挥其针对异烟肼诱导的肝毒性的保肝活性。硫普罗宁可通过抑制肝脏 CYP2E1 减少自由基的产生，并直接或通过诱导胞质 GST 增加自由基的清除。 (c) 2009 Elsevier Ireland Ltd. 保留所有权利。
Isoniazid is a widely used drug for the treatment of tuberculosis, but hepatotoxicity is a major concern during treatment. Thiopronin contains an SH-group and is generally considered an antioxidant. The aim of the present study was to investigate the effects of thiopronin during liver injury and DNA damage induced by isoniazid. Rats were injected daily with isoniazid (100 mg/kg, i.p.) for 21 days with or without thiopronin co-administration (60 mg/kg, i.p.) from day 11 to day 21. The influence of thiopronin on isoniazid-induced DNA oxidative damage was analyzed in precision-cut rat liver slices by HPLC-MS/MS. Thiopronin prevented isoniazid-induced hepatotoxicity, indicated by both diagnostic indicators of liver damage (alanine aminotransferase and aspartate aminotransferase) and histopathological analysis. In vivo, thiopronin significantly inhibited isoniazid-induced CYP2E1 activity as assessed by both chlorzoxazone hydroxylase and aniline hydroxylase (p < 0.001). Thiopronin concentration-dependently inhibited CYP2E1-dependent aniline hydroxylation, and the Dixon plots suggest that thiopronin is a competitive inhibitor of CYP2E1. Thiopronin markedly attenuated isoniazid-induced inhibition of the detoxification system through cytosolic glutathione S-transferases (GSTs), including mu GST and alpha GST. In precision-cut liver slices, the free radical scavenging activity of thiopronin reduced the generation of DNA adducts induced by isoniazid (p < 0.05). Altogether, these results suggest that thiopronin exerts its hepatoprotective activity against isoniazid-induced hepatotoxicity by inhibiting the production of free radicals in addition to its role as a scavenger. Thiopronin may reduce free radical generation via inhibition of hepatic CYP2E1 and increase the removal of free radicals directly or through the induction of cytosolic GSTs. (c) 2009 Elsevier Ireland Ltd. All rights reserved.