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

Abstract

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 CLZinduced hepatotoxicity in primary cultured rat hepatocytes. The study aimed to describe the enhancing effect of GA on CLZinduced hepatotoxicity in vivo and in vitro. Data from primary cultured rat hepatocytes showed the decreased formation of metabolites demethylclozapine (norCLZ) and clozapine Noxide (CLZ Noxide) .The results in vivo showed that 7day CLZ treatment led to marked accumulation of triglyceride (TG) and increase in g glutamyl transpeptidase (gGT) activity, liver weight, and serum AST in rats. Coadministration of GA enhanced the increases in hepatic TG, gGT, liver weight, and serum total cholesterol induced by CLZ. GA decreased plasma concentrations of norCLZ and CLZ Noxide. Compared with control rats, hepatic microsomes of GA rats exhibited the decreased formations of norCLZ and CLZ Noxide, accompanied by decreases in activities of CYP2C11 and CYP2C19 and increased activity of CYP1A2. QTPCR analysis demonstrated that GA enhanced expression of CYP1A2, but suppressed expression of CYP2C11 and CYP2C13. All these results support the conclusion that GA aggravated CLZinduced hepatotoxicity, which was partly via inhibiting CYP2C11 and CYP2C13 or inducing CYP1A2.

Involvement of the histamine H4 receptor in clozapine-induced hematopoietic toxicity: Vulnerability under granulocytic differentiation of HL-60 cells

“…In the present in vitro study using HL-60 cells, exposure to clozapine (> 50 μM) decreased the survival rate in all state of the hematopoietic process. Clozapine has been demonstrated to decrease cell survival at 60 μM, but not at 40 μM for 2 days in primary cultured hepatocytes from rats (Jia et al, 2014).…”

Age-associated changes of cytochrome P450 and related phase-2 gene/proteins in livers of rats

“…Taken together, CYPs are crucial enzymes in drug metabolism and disposition. (Zanger & Schwab 2013) Induction or inhibition of CYPs have been implicated in therapeutic efficacy and toxicity, (Jia et al 2014;Mach et al 2014;Mach et al 2016) and age-associated diseases. (Bondarenko et al 2016;Velenosi et al 2012) especially in children (Kilanowicz et al 2015;Li et al 2017;McPhail et al 2016) and in elderly (McPhail et al 2016;Salmin et al 2017;Wauthier et al 2007) Thus, a better understanding of age-associated changes of CYPs is of significance for pharmacology, toxicology, and therapeutics.…”

“…(Kang et al 2008) Age also influences drug-drug interactions. (Jia et al 2014) Age-associated changes in P450 and corresponding nuclear factors are a major determinant in CYP regulation of drug metabolism, especially during development (children) and in senescence (elderly). (Durnas et al 1990;Kilanowicz et al 2015;Shi & Klotz 2011) The expression and maturation of CYPs during development is a major topic of research, (Kilanowicz et al 2015) and immature rats have been proposed as a potential model for xenobiotics risk evaluation for children.…”

Peer Review #1 of "Age-associated changes of cytochrome P450 and related phase-2 gene/proteins in livers of rats (v0.2)"

“…(Kang et al 2008) Age also influences drug-drug interactions. (Jia et al 2014) Age-associated changes in P450 and corresponding nuclear factors are a major PeerJ reviewing PDF | (2019:04:36465:1:0:NEW 13 Jun 2019)…”