TY - JOUR
T1 - Glycyrrhizin protects against acetaminophen-induced acute liver injury via alleviating tumor necrosis factor α-mediated apoptosis
AU - Yan, Tingting
AU - Wang, Hong
AU - Zhao, Min
AU - Yagai, Tomoki
AU - Chai, Yingying
AU - Krausz, Kristopher W.
AU - Xie, Cen
AU - Cheng, Xuefang
AU - Zhang, Jun
AU - Che, Yuan
AU - Li, Feiyan
AU - Wu, Yuzheng
AU - Brocker, Chad N.
AU - Gonzalez, Frank J.
AU - Wang, Guangji
AU - Hao, Haiping
N1 - Funding Information:
This work was supported by the Intramural Research Program of the National Institutes of Health National Cancer Institute and China Scholarship Council [No. 201407060024] and the National Natural Science Foundation of China [No. 81430091, 81325025, and 81273586].
PY - 2016/5
Y1 - 2016/5
N2 - 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.
AB - 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.
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U2 - 10.1124/dmd.116.069419
DO - 10.1124/dmd.116.069419
M3 - Article
C2 - 26965985
AN - SCOPUS:84963853541
VL - 44
SP - 720
EP - 731
JO - Drug Metabolism and Disposition
JF - Drug Metabolism and Disposition
SN - 0090-9556
IS - 5
ER -