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The aggravation of clozapine-induced hepatotoxicity by glycyrrhetinic acid in rats
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نویسنده
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jia l.-l. ,zhong z.-y. ,li f. ,ling z.-l. ,chen y. ,zhao w.-m. ,li y. ,jiang s.-w. ,xu p. ,yang y. ,hu m.-y. ,liu l. ,liu x.-d.
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منبع
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journal of pharmacological sciences - 2014 - دوره : 124 - شماره : 4 - صفحه:468 -479
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چکیده
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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. © the japanese pharmacological society.
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کلیدواژه
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Clozapine; CYP1A2; CYP2C11; Glycyrrhetinic acid; Hepatotoxicity
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آدرس
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key laboratory of drug metabolism and pharmacokinetics,china pharmaceutical university,nanjing 210009, China, key laboratory of drug metabolism and pharmacokinetics,china pharmaceutical university,nanjing 210009, China, key laboratory of drug metabolism and pharmacokinetics,china pharmaceutical university,nanjing 210009, China, key laboratory of drug metabolism and pharmacokinetics,china pharmaceutical university,nanjing 210009, China, key laboratory of drug metabolism and pharmacokinetics,china pharmaceutical university,nanjing 210009, China, key laboratory of drug metabolism and pharmacokinetics,china pharmaceutical university,nanjing 210009, China, key laboratory of drug metabolism and pharmacokinetics,china pharmaceutical university,nanjing 210009, China, key laboratory of drug metabolism and pharmacokinetics,china pharmaceutical university,nanjing 210009, China, key laboratory of drug metabolism and pharmacokinetics,china pharmaceutical university,nanjing 210009, China, key laboratory of drug metabolism and pharmacokinetics,china pharmaceutical university,nanjing 210009, China, key laboratory of drug metabolism and pharmacokinetics,china pharmaceutical university,nanjing 210009, China, key laboratory of drug metabolism and pharmacokinetics,china pharmaceutical university,nanjing 210009, China, key laboratory of drug metabolism and pharmacokinetics,china pharmaceutical university,nanjing 210009, China
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Authors
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