Yan Tingting, Wang Hong, Zhao Min, Yagai Tomoki, Chai Yingying, Krausz Kristopher W, Xie Cen, Cheng Xuefang, Zhang Jun, Che Yuan, Li Feiyan, Wu Yuzheng, Brocker Chad N, Gonzalez Frank J, Wang Guangji, Hao Haiping
State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu, People's Republic of China (Ti.Y., H.W., M.Z., Yi.C., X.C., J.Z., Yu.C., F.L., Y.W., G.W., H.H.); Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (Ti.Y., To.Y., K.W.K., C.X., C.N.B., F.J.G.).
State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu, People's Republic of China (Ti.Y., H.W., M.Z., Yi.C., X.C., J.Z., Yu.C., F.L., Y.W., G.W., H.H.); Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (Ti.Y., To.Y., K.W.K., C.X., C.N.B., F.J.G.)
Drug Metab Dispos. 2016 May;44(5):720-31. doi: 10.1124/dmd.116.069419. Epub 2016 Mar 10.
Acetaminophen (APAP) overdose is the leading cause of drug-induced acute liver failure in Western countries. Glycyrrhizin (GL), a potent hepatoprotective constituent extracted from the traditional Chinese medicine liquorice, has potential clinical use in treating APAP-induced liver failure. The present study determined the hepatoprotective effects and underlying mechanisms of action of GL and its active metabolite glycyrrhetinic acid (GA). Various administration routes and pharmacokinetics-pharmacodynamics analyses were used to differentiate the effects of GL and GA on APAP toxicity in mice. Mice deficient in cytochrome P450 2E1 enzyme (CYP2E1) or receptor interacting protein 3 (RIPK3) and their relative wild-type littermates were subjected to histologic and biochemical analyses to determine the potential mechanisms. Hepatocyte death mediated by tumor necrosis factorα(TNFα)/caspase was analyzed by use of human liver-derived LO2 cells. The pharmacokinetics-pharmacodynamics analysis using various administration routes revealed that GL but not GA potently attenuated APAP-induced liver injury. The protective effect of GL was found only with intraperitoneal and intravenous administration and not with gastric administration. CYP2E1-mediated metabolic activation and RIPK3-mediated necroptosis were unrelated to GL's protective effect. However, GL inhibited hepatocyte apoptosis via interference with TNFα-induced apoptotic hepatocyte death. These results demonstrate that GL rapidly attenuates APAP-induced liver injury by directly inhibiting TNFα-induced hepatocyte apoptosis. The protective effect against APAP-induced liver toxicity by GL in mice suggests the therapeutic potential of GL for the treatment of APAP overdose.
对乙酰氨基酚（APAP）过量是西方国家药物性急性肝衰竭的主要原因。甘草酸（GL）是从传统中药甘草中提取的一种强效肝保护成分，在治疗APAP诱导的肝衰竭方面具有潜在的临床应用价值。本研究确定了GL及其活性代谢产物甘草次酸（GA）的肝保护作用及其潜在作用机制。采用多种给药途径及药代动力学-药效学分析来区分GL和GA对小鼠APAP毒性的影响。对细胞色素P450 2E1酶（CYP2E1）或受体相互作用蛋白3（RIPK3）缺陷的小鼠及其相对野生型同窝小鼠进行组织学和生化分析，以确定潜在机制。利用人肝源性LO2细胞分析肿瘤坏死因子α（TNFα）/半胱天冬酶介导的肝细胞死亡。采用多种给药途径的药代动力学-药效学分析表明，GL而非GA能有效减轻APAP诱导的肝损伤。GL的保护作用仅在腹腔注射和静脉注射时发现，而胃内给药时未发现。CYP2E1介导的代谢活化和RIPK3介导的坏死性凋亡与GL的保护作用无关。然而，GL通过干扰TNFα诱导的凋亡性肝细胞死亡来抑制肝细胞凋亡。这些结果表明，GL通过直接抑制TNFα诱导的肝细胞凋亡迅速减轻APAP诱导的肝损伤。GL对小鼠APAP诱导的肝毒性的保护作用表明其在治疗APAP过量方面具有治疗潜力。
