Glycyrrhizin protects against acetaminophen-induced acute liver injury via alleviating tumor necrosis factor α-mediated apoptosis

Tingting Yan, Hong Wang, Min Zhao, Tomoki Yagai, Yingying Chai, Kristopher W. Krausz, Cen Xie, Xuefang Cheng, Jun Zhang, Yuan Che, Feiyan Li, Yuzheng Wu, Chad N. Brocker, Frank J. Gonzalez, Guangji Wang, Haiping Hao

Research output: Contribution to journalArticlepeer-review

27 Citations (Scopus)

Abstract

Acetaminophen (APAP) overdose is the leading cause of druginduced 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-pharmaco dynamics 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 factor a (TNFa)/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 TNFa-induced apoptotic hepatocyte death. These results demonstrate that GL rapidly attenuates APAPinduced liver injury by directly inhibiting TNFa-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.

Original languageEnglish
Pages (from-to)720-731
Number of pages12
JournalDrug Metabolism and Disposition
Volume44
Issue number5
DOIs
Publication statusPublished - 2016 May
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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