酶诱导和/或谷胱甘肽耗竭对小鼠甲巯咪唑诱导的肝毒性的影响及N-乙酰半胱氨酸的保护作用。
Effects of Enzyme Induction and/or Glutathione Depletion on Methimazole-Induced Hepatotoxicity in Mice and the Protective Role of N-Acetylcysteine.
作者信息
Heidari Reza, Babaei Hossein, Roshangar Leila, Eghbal Mohammad Ali
机构信息
Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. ; Pharmacology and Toxicology Department, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
Anatomical Sciences Department, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
出版信息
Adv Pharm Bull. 2014;4(1):21-8. doi: 10.5681/apb.2014.004. Epub 2013 Dec 23.
PURPOSE
Methimazole is the most convenient drug used in the management of hyperthyroid patients. However, associated with its clinical use is hepatotoxicity as a life threatening adverse effect. The exact mechanism of methimazole-induced hepatotoxicity is still far from clear and no protective agent has been developed for this toxicity.
METHODS
This study attempts to evaluate the hepatotoxicity induced by methimazole at different experimental conditions in a mice model. Methimazole-induced hepatotoxicity was investigated in different situations such as enzyme induced and/or glutathione depleted animals.
RESULTS
Methimazole (100 mg/kg, i.p) administration caused hepatotoxicity as revealed by increase in serum alanine aminotransferase (ALT) activity as well as pathological changes of the liver. Furthermore, a significant reduction in hepatic glutathione content and an elevation in lipid peroxidation were observed in methimazole-treated mice. Combined administration of L-buthionine sulfoximine (BSO), as a glutathione depletory agent, caused a dramatic change in methimazole-induced hepatotoxicity characterized by hepatic necrosis and a severe elevation of serum ALT activity. Enzyme induction using phenobarbital and/or β-naphtoflavone beforehand, deteriorated methimazole-induced hepatotoxicity in mice. N-acetyl cysteine (300 mg/kg, i.p) administration effectively alleviated hepatotoxic effects of methimazole in both glutathione-depleted and/or enzyme induced animals.
CONCLUSION
The severe hepatotoxic effects of methimazole in glutathione-depleted animals, reveals the crucial role of glutathione as a cellular defense mechanism against methimazole-induced hepatotoxicity. Furthermore, the more hepatotoxic properties of methimazole in enzyme-induced mice, indicates the role of reactive intermediates in the hepatotoxicity induced by this drug. The protective effects of N-acetylcysteine could be attributed to its radical/reactive metabolite scavenging, and/or antioxidant properties as well as glutathione replenishment activities.
目的
甲巯咪唑是治疗甲状腺功能亢进患者最常用的药物。然而，其临床应用会导致肝毒性，这是一种危及生命的不良反应。甲巯咪唑诱发肝毒性的确切机制仍不清楚，且尚未开发出针对这种毒性的保护剂。
方法
本研究试图在小鼠模型中评估不同实验条件下甲巯咪唑诱发的肝毒性。在诸如酶诱导和/或谷胱甘肽耗竭的动物等不同情况下，研究甲巯咪唑诱发的肝毒性。
结果
腹腔注射甲巯咪唑（100mg/kg）可导致肝毒性，表现为血清丙氨酸氨基转移酶（ALT）活性升高以及肝脏病理变化。此外，在接受甲巯咪唑治疗的小鼠中，观察到肝脏谷胱甘肽含量显著降低以及脂质过氧化增加。联合使用作为谷胱甘肽耗竭剂的L-丁硫氨酸亚砜胺（BSO），会导致甲巯咪唑诱发的肝毒性发生显著变化，其特征为肝坏死和血清ALT活性严重升高。预先使用苯巴比妥和/或β-萘黄酮进行酶诱导，会使小鼠中甲巯咪唑诱发的肝毒性恶化。腹腔注射N-乙酰半胱氨酸（300mg/kg）可有效减轻谷胱甘肽耗竭和/或酶诱导动物中甲巯咪唑的肝毒性作用。
结论
甲巯咪唑在谷胱甘肽耗竭的动物中具有严重的肝毒性作用，这揭示了谷胱甘肽作为细胞防御机制对抗甲巯咪唑诱发肝毒性的关键作用。此外，甲巯咪唑在酶诱导小鼠中具有更强肝毒性的特性，表明活性中间体在该药物诱发肝毒性中的作用。N-乙酰半胱氨酸的保护作用可能归因于其清除自由基/活性代谢物的能力、抗氧化特性以及谷胱甘肽补充活性。
Zotero 插件