The metabolism and hepatotoxicity of ginkgolic acid(17:1) in vitro  

作　　者：YAO Qing-Qing LI Li XU Ming-Cheng HU Hai-Hong ZHOU Hui YU Lu-Shan ZENG Su YAO Qing-Qing;LI Li;XU Ming-Cheng;HU Hai-Hong;ZHOU Hui;YU Lu-Shan;ZENG Su(Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences;Department of Pharmacy & Geriatrics Institute of Zhejiang Province, Zhejiang Hospital)

机构地区：[1]Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences [2]Department of Pharmacy & Geriatrics Institute of Zhejiang Province, Zhejiang Hospital

出　　处：《Chinese Journal of Natural Medicines》2018年第11期829-837,共9页中国天然药物（英文版）

基　　金：supported by the National Key Project of China(No.2017YFC0908600);the National Natural Science Foundation of China(No.81173120);the National Natural Science Foundation of Zhejiang Province(No.LQ15H310003)

摘　　要：Pharmacological activities and adverse side effects of ginkgolic acids(GAs), major components in extracts from the leaves and seed coats of Ginkgo biloba L, have been intensively studied. However, there are few reports on their hepatotoxicity. In the present study, the metabolism and hepatotoxicity of GA(17:1), one of the most abundant components of GAs, were investigated. Kinetic analysis indicated that human and rat liver microsomes shared similar metabolic characteristics of GA(17:1) in phase I and II metabolisms. The drug-metabolizing enzymes involved in GA(17:1) metabolism were human CYP1 A2, CYP3 A4, UGT1 A6, UGT1 A9, and UGT2 B15, which were confirmed with an inhibition study of human liver microsomes and recombinant enzymes. The MTT assays indicated that the cytotoxicity of GA(17:1) in HepG2 cells occurred in a time-and dose-dependent manner. Further investigation showed that GA(17:1) had less cytotoxicity in primary rat hepatocytes than in HepG2 cells and that the toxicity was enhanced through CYP1 A-and CYP3 A-mediated metabolism.Pharmacological activities and adverse side effects of ginkgolic acids（GAs）, major components in extracts from the leaves and seed coats of Ginkgo biloba L, have been intensively studied. However, there are few reports on their hepatotoxicity. In the present study, the metabolism and hepatotoxicity of GA（17：1）, one of the most abundant components of GAs, were investigated. Kinetic analysis indicated that human and rat liver microsomes shared similar metabolic characteristics of GA（17：1） in phase I and II metabolisms. The drug-metabolizing enzymes involved in GA（17：1） metabolism were human CYP1 A2, CYP3 A4, UGT1 A6, UGT1 A9, and UGT2 B15, which were confirmed with an inhibition study of human liver microsomes and recombinant enzymes. The MTT assays indicated that the cytotoxicity of GA（17：1） in HepG2 cells occurred in a time-and dose-dependent manner. Further investigation showed that GA（17：1） had less cytotoxicity in primary rat hepatocytes than in HepG2 cells and that the toxicity was enhanced through CYP1 A-and CYP3 A-mediated metabolism.

关 键 词：Ginkgolic acid （17 ： 1） CYTOTOXICITY Liver microsomes Recombinant enzyme HEPATOTOXICITY 

分 类 号：R95[医药卫生—药学] R917