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Liquorice Extract and 18 beta-Glycyrrhetinic Acid Protect Against Experimental Pyrrolizidine Alkaloid-Induced Hepatotoxicity in Rats Through Inhibiting Cytochrome P450-Mediated Metabolic Activation

文献类型：期刊论文

作者Wang, Zhangting2; Ma, Jiang2; Yao, Sheng1,3; He, Yisheng2; Miu, Kai-Kei2; Xia, Qingsu4; Fu, Peter P.4; Ye, Yang1,3; Lin, Ge2
刊名FRONTIERS IN PHARMACOLOGY
出版日期2022-03-16
卷号13页码:14
关键词18 beta-glycyrrhetinic acid pyrrolizidine alkaloid cytochrome P450 metabolic activation competitive inhibition
DOI10.3389/fphar.2022.850859
通讯作者Lin, Ge(linge@cuhk.edu.hk)
英文摘要Misuse of pyrrolizidine alkaloid (PA)-containing plants or consumption of PA-contaminated foodstuffs causes numerous poisoning cases in humans yearly, while effective therapeutic strategies are still limited. PA-induced liver injury was initiated by cytochrome P450 (CYP)-mediated metabolic activation and subsequent formation of adducts with cellular proteins. Liquorice, a hepato-protective herbal medicine, is commonly used concurrently with PA-containing herbs in many compound traditional Chinese medicine formulas, and no PA-poisoning cases have been reported with this combination. The present study aimed to investigate hepato-protective effects of liquorice aqueous extract (EX) and 18 beta-glycyrrhetinic acid (GA, the primary bioactive constituent of liquorice) against PA-induced hepatotoxicity and the underlying mechanism. Histopathological and biochemical analysis demonstrated that both single- and multiple-treatment of EX (500 mg/kg) or GA (50 mg/kg) significantly attenuated liver damage caused by retrorsine (RTS, a representative hepatotoxic PA). The formation of pyrrole-protein adducts was significantly reduced by single- (30.3% reduction in liver; 50.8% reduction in plasma) and multiple- (32.5% reduction in liver; 56.5% reduction in plasma) treatment of GA in rats. Single- and multiple-treatment of EX also decreased the formation of pyrrole-protein adducts, with 30.2 and 31.1% reduction in rat liver and 51.8 and 53.1% reduction in rat plasma, respectively. In addition, in vitro metabolism assay with rat liver microsomes demonstrated that GA reduced the formation of metabolic activation-derived pyrrole-glutathione conjugate in a dose-dependent manner with the estimated IC50 value of 5.07 mu M. Further mechanism study showed that GA inhibited activities of CYPs, especially CYP3A1, the major CYP isoform responsible for the metabolic activation of RTS in rats. Enzymatic kinetic study revealed a competitive inhibition of rat CYP3A1 by GA. In conclusion, our findings demonstrated that both EX and GA exhibited significant hepato-protective effects against RTS-induced hepatotoxicity, mainly through the competitive inhibition of CYP-mediated metabolic activation of RTS.
WOS关键词SINUSOIDAL OBSTRUCTION SYNDROME ; HEPATIC VENOOCCLUSIVE DISEASE ; ACUTE LIVER-INJURY ; GLYCYRRHETIC ACID ; CYP3A4 ; BLOOD ; RISK
资助项目Research Grant Council of Hong Kong SAR[14106120] ; Chinese University of Hong Kong Direct Grant[4054577]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者FRONTIERS MEDIA SA
WOS记录号WOS:000784443900001
源URL[http://119.78.100.183/handle/2S10ELR8/299767]  
专题新药研究国家重点实验室
通讯作者Lin, Ge
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Nat Prod Chem Dept, Shanghai, Peoples R China
2.Chinese Univ Hong Kong, Fac Med, Sch Biomed Sci, Hong Kong, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China
4.US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA
推荐引用方式
GB/T 7714		 Wang, Zhangting,Ma, Jiang,Yao, Sheng,et al. Liquorice Extract and 18 beta-Glycyrrhetinic Acid Protect Against Experimental Pyrrolizidine Alkaloid-Induced Hepatotoxicity in Rats Through Inhibiting Cytochrome P450-Mediated Metabolic Activation[J]. FRONTIERS IN PHARMACOLOGY,2022,13:14.
APA Wang, Zhangting.,Ma, Jiang.,Yao, Sheng.,He, Yisheng.,Miu, Kai-Kei.,...&Lin, Ge.(2022).Liquorice Extract and 18 beta-Glycyrrhetinic Acid Protect Against Experimental Pyrrolizidine Alkaloid-Induced Hepatotoxicity in Rats Through Inhibiting Cytochrome P450-Mediated Metabolic Activation.FRONTIERS IN PHARMACOLOGY,13,14.
MLA Wang, Zhangting,et al."Liquorice Extract and 18 beta-Glycyrrhetinic Acid Protect Against Experimental Pyrrolizidine Alkaloid-Induced Hepatotoxicity in Rats Through Inhibiting Cytochrome P450-Mediated Metabolic Activation".FRONTIERS IN PHARMACOLOGY 13(2022):14.

入库方式： OAI收割

来源：上海药物研究所

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