甘草次酸加重大鼠氯氮平诱导的肝毒性。

Aggravation of clozapine-induced hepatotoxicity by glycyrrhetinic acid in rats.

机构信息

Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, China.

出版信息

J Pharmacol Sci. 2014;124(4):468-79. doi: 10.1254/jphs.13257fp.

Abstract

Clozapine (CLZ) was reported to be associated with hepatotoxicity. Glycyrrhetinic acid (GA) has a liver protective effect. Our preliminary experiments showed that GA aggravated rather than attenuated CLZ-induced hepatotoxicity in primary cultured rat hepatocytes. The study aimed to describe the enhancing effect of GA on CLZ-induced hepatotoxicity in vivo and in vitro. Data from primary cultured rat hepatocytes showed the decreased formation of metabolites demethylclozapine (nor-CLZ) and clozapine N-oxide (CLZ N-oxide). The results in vivo showed that 7-day CLZ treatment led to marked accumulation of triglyceride (TG) and increase in γ-glutamyl transpeptidase (γ-GT) activity, liver weight, and serum AST in rats. Co-administration of GA enhanced the increases in hepatic TG, γ-GT, liver weight, and serum total cholesterol induced by CLZ. GA decreased plasma concentrations of nor-CLZ and CLZ N-oxide. Compared with control rats, hepatic microsomes of GA rats exhibited the decreased formations of nor-CLZ and CLZ N-oxide, accompanied by decreases in activities of CYP2C11 and CYP2C19 and increased activity of CYP1A2. QT-PCR analysis demonstrated that GA enhanced expression of CYP1A2, but suppressed expression of CYP2C11 and CYP2C13. All these results support the conclusion that GA aggravated CLZ-induced hepatotoxicity, which was partly via inhibiting CYP2C11 and CYP2C13 or inducing CYP1A2.

摘要

氯氮平（CLZ）被报道与肝毒性有关。甘草酸（GA）具有肝脏保护作用。我们的初步实验表明，GA 在原代培养的大鼠肝细胞中加重了而非减轻了 CLZ 诱导的肝毒性。本研究旨在描述 GA 对 CLZ 诱导的体内和体外肝毒性的增强作用。原代培养的大鼠肝细胞的数据显示，去甲基氯氮平（nor-CLZ）和氯氮平 N-氧化物（CLZ N-氧化物）的代谢物形成减少。体内结果表明，7 天的 CLZ 处理导致大鼠甘油三酯（TG）大量积累，γ-谷氨酰转肽酶（γ-GT）活性、肝重和血清天冬氨酸转氨酶（AST）升高。GA 的共同给药增强了 CLZ 引起的肝 TG、γ-GT、肝重和血清总胆固醇的增加。GA 降低了 nor-CLZ 和 CLZ N-氧化物的血浆浓度。与对照大鼠相比，GA 大鼠的肝微粒体显示 nor-CLZ 和 CLZ N-氧化物的形成减少，同时 CYP2C11 和 CYP2C19 的活性降低，CYP1A2 的活性增加。QT-PCR 分析表明，GA 增强了 CYP1A2 的表达，但抑制了 CYP2C11 和 CYP2C13 的表达。所有这些结果都支持 GA 加重 CLZ 诱导的肝毒性的结论，这部分是通过抑制 CYP2C11 和 CYP2C13 或诱导 CYP1A2 实现的。