title: Aggravation of clozapine-induced hepatotoxicity by glycyrrhetinic acid in rats.
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.
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, China.
authors.forename: Ling-ling
authors.initials: LL
authors.lastname: Jia
authors.forename: Ze-yu
authors.initials: ZY
authors.lastname: Zhong
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: Zhao-li
authors.initials: ZL
authors.lastname: Ling
authors.forename: Yang
authors.initials: Y
authors.lastname: Chen
authors.forename: Wei-man
authors.initials: WM
authors.lastname: Zhao
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.forename: Shu-wen
authors.initials: SW
authors.lastname: Jiang
authors.forename: Ping
authors.initials: P
authors.lastname: Xu
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Meng-yue
authors.initials: MY
authors.lastname: Hu
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Xiao-dong
authors.initials: XD
authors.lastname: Liu
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000633:toxicity*; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D003024:Clozapine / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity*; D019388:Cytochrome P-450 CYP1A2; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D003580:Cytochromes / Q000378:metabolism; D004357:Drug Synergism; D006034:Glycyrrhetinic Acid / Q000633:toxicity*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D039181:Steroid 16-alpha-Hydroxylase / Q000037:antagonists & inhibitors / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D005723:gamma-Glutamyltransferase / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D003580:Cytochromes; D014280:Triglycerides; C411706:demethylclozapine; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; C017170:Cyp1a2 protein, rat; C113764:Cyp2c13 protein, rat; D019388:Cytochrome P-450 CYP1A2; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; D005723:gamma-Glutamyltransferase; D003024:Clozapine; C079149:clozapine N-oxide; D006034:Glycyrrhetinic Acid