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: 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
• Journal: Drug metabolism and disposition: the biological fate of chemicals (Drug Metab Dispos) Vol. 44 Issue 5 Pg. 720-31 (May 2016) ISSN: 1521-009X [Electronic] United States
• PMID: 26965985 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: U.S. Government work not protected by U.S. copyright.

Chemical References

• Protective Agents
• Tumor Necrosis Factor-alpha
• Acetaminophen
• Glycyrrhizic Acid
• Cytochrome P-450 CYP2E1
• Receptor-Interacting Protein Serine-Threonine Kinases

Topics

• Acetaminophen (adverse effects)
• Activation, Metabolic (drug effects)
• Animals
• Apoptosis (drug effects)
• Cell Line
• Chemical and Drug Induced Liver Injury (drug therapy)
• Cytochrome P-450 CYP2E1 (metabolism)
• Glycyrrhizic Acid (pharmacology)
• Hepatocytes (drug effects, metabolism)
• Humans
• Liver (drug effects, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mitochondria, Liver (drug effects, metabolism)
• Protective Agents (pharmacology)
• Receptor-Interacting Protein Serine-Threonine Kinases (metabolism)
• Tumor Necrosis Factor-alpha (metabolism)