The Aggravation of Clozapine-Induced Hepatotoxicity by Glycyrrhetinic Acid in Rats

• Published in: Journal of Pharmacological Sciences 2014/04/20, Vol.124(4), pp.468-479
• Main Authors: Jia, Ling-ling, Zhong, Ze-yu, Li, Feng, Ling, Zhao-li, Chen, Yang, Zhao, Wei-man, Li, Ying, Jiang, Shu-wen, Xu, Ping, Yang, Yang, Hu, Meng-yue, Liu, Li, Liu, Xiao-dong
• Format: Article
• Language: English
• Subjects: Animals; Antipsychotic Agents - toxicity; Aryl Hydrocarbon Hydroxylases - antagonists & inhibitors; Aryl Hydrocarbon Hydroxylases - metabolism; Cells, Cultured; Cholesterol - blood; clozapine; Clozapine - analogs & derivatives; Clozapine - metabolism; Clozapine - toxicity; CYP1A2; CYP2C11; Cytochrome P-450 CYP1A2; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System - metabolism; Cytochrome P450 Family 2; Cytochromes - metabolism; Drug Synergism; gamma-Glutamyltransferase - metabolism; glycyrrhetinic acid; Glycyrrhetinic Acid - toxicity; Hepatocytes - drug effects; Hepatocytes - metabolism; hepatotoxicity; Liver - drug effects; Liver - metabolism; Male; Organ Size - drug effects; Rats; Rats, Sprague-Dawley; Steroid 16-alpha-Hydroxylase - antagonists & inhibitors; Steroid 16-alpha-Hydroxylase - metabolism; Triglycerides - metabolism
• ISSN: 1347-8613; 1347-8648
• DOI: 10.1254/jphs.13257FP

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.