title: Glycyrrhizin Protects against Acetaminophen-Induced Acute Liver Injury via Alleviating Tumor Necrosis Factor α-Mediated Apoptosis.
abstract: 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.
authors.affiliation: 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.).
authors.forename: Tingting
authors.initials: T
authors.lastname: Yan
authors.affiliation: 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.).
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: 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.).
authors.forename: Min
authors.initials: M
authors.lastname: Zhao
authors.affiliation: 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.).
authors.forename: Tomoki
authors.initials: T
authors.lastname: Yagai
authors.affiliation: 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.).
authors.forename: Yingying
authors.initials: Y
authors.lastname: Chai
authors.affiliation: 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.).
authors.forename: Kristopher W
authors.initials: KW
authors.lastname: Krausz
authors.affiliation: 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.).
authors.forename: Cen
authors.initials: C
authors.lastname: Xie
authors.affiliation: 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.).
authors.forename: Xuefang
authors.initials: X
authors.lastname: Cheng
authors.affiliation: 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.).
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: 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.).
authors.forename: Yuan
authors.initials: Y
authors.lastname: Che
authors.affiliation: 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.).
authors.forename: Feiyan
authors.initials: F
authors.lastname: Li
authors.affiliation: 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.).
authors.forename: Yuzheng
authors.initials: Y
authors.lastname: Wu
authors.affiliation: 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.).
authors.forename: Chad N
authors.initials: CN
authors.lastname: Brocker
authors.affiliation: 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.).
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.affiliation: 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.) guangjiwang@hotmail.com haipinghao@cpu.edu.cn.
authors.forename: Guangji
authors.initials: G
authors.lastname: Wang
authors.affiliation: 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.) guangjiwang@hotmail.com haipinghao@cpu.edu.cn.
authors.forename: Haiping
authors.initials: H
authors.lastname: Hao
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects*; D065767:Activation, Metabolic / Q000187:drug effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy*; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D019695:Glycyrrhizic Acid / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D020011:Protective Agents; D014409:Tumor Necrosis Factor-alpha; D000082:Acetaminophen; D019695:Glycyrrhizic Acid; D019392:Cytochrome P-450 CYP2E1; D053422:Receptor-Interacting Protein Serine-Threonine Kinases