The Aggravation of Clozapine-Induced Hepatotoxicity by Glycyrrhetinic Acid in Rats
The Aggravation of Clozapine-Induced Hepatotoxicity by Glycyrrhetinic Acid in Rats
复制标题
甘草次酸加重氯氮平引起的大鼠肝毒性
DOI：
10.1254/jphs.13257fp
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发表时间：
2014-04-01
影响因子：
3.5
通讯作者：
Liu, Xiao-dong
中科院分区：
文献类型：
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作者：
Jia, Ling-ling;Zhong, Ze-yu;Liu, Xiao-dong
据报道氯氮平（CLZ）与肝毒性有关。甘草次酸（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而不是减轻clz诱导的肝毒性。本研究旨在探讨GA对clz诱导的体内外肝毒性的增强作用。原代培养大鼠肝细胞的数据显示代谢物去甲基氯氮平（non -CLZ）和氯氮平n -氧化物（CLZ n -氧化物）的形成减少。体内实验结果显示，CLZ治疗7天后，大鼠体内甘油三酯（TG）明显积累，γ -谷氨酰转肽酶（γ - gt）活性、肝脏重量和血清AST均明显升高。同时给药GA增强了CLZ诱导的肝脏TG、γ - gt、肝脏重量和血清总胆固醇的升高。GA降低了血浆中非CLZ和CLZ n -氧化物的浓度。与对照组相比，GA大鼠肝微粒体中no -CLZ和CLZ n -氧化物的形成减少，CYP2C11和CYP2C19活性降低，CYP1A2活性升高。QT-PCR分析表明，GA增强了CYP1A2的表达，抑制了CYP2C11和CYP2C13的表达。以上结果均支持GA加重clz肝毒性的结论，其机制可能部分通过抑制CYP2C11和CYP2C13或诱导CYP1A2来实现。
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 gamma-glutamyl transpeptidase (gamma-GT) activity, liver weight, and serum AST in rats. Co-administration of GA enhanced the increases in hepatic TG, gamma-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.