Antcin H Protects Against Acute Liver Injury Through Disruption of the Interaction of c-Jun-N-Terminal Kinase with Mitochondria.
Antrodia Camphorate (AC) is a mushroom that is widely used in Asian countries to prevent and treat various diseases, including liver diseases. However, the active ingredients that contribute to the biological functions remain elusive. The purpose of the present study is to test the hepatoprotective effect of Antcin H, a major triterpenoid chemical isolated from AC, in murine models of acute liver injury.



We found that Antcin H pretreatment protected against liver injury in both acetaminophen (APAP) and galactosamine/tumor necrosis factor (TNF)α models. More importantly, Antcin H also offered a significant protection against acetaminophen-induced liver injury when it was given 1 h after acetaminophen. The protection was verified in primary mouse hepatocytes. Antcin H prevented sustained c-Jun-N-terminal kinase (JNK) activation in both models. We excluded an effect of Antcin H on acetaminophen metabolism and TNF receptor signaling and excluded a direct effect as a free radical scavenger or JNK inhibitor. Since the sustained JNK activation through its interaction with mitochondrial Sab, leading to increased mitochondrial reactive oxygen species (ROS), is pivotal in both models, we examined the effect of Antcin H on p-JNK binding to mitochondria and impairment of mitochondrial respiration. Antcin H inhibited the direct effect of p-JNK on isolated mitochondrial function and binding to isolated mitochondria. Innovation and Conclusion: Our study has identified Antcin H as a novel active ingredient that contributes to the hepatoprotective effect of AC, and Antcin H protects against liver injury through disruption of the binding of p-JNK to Sab, which interferes with the ROS-dependent self-sustaining activation of MAPK cascade. Antioxid. Redox Signal. 26, 207-220.
1 Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University , Beijing, China .|2 USC Research Center for Liver Disease, Keck School of Medicine, University of Southern California , Los Angeles, California.
Yazhen
Y
Huo
2 USC Research Center for Liver Disease, Keck School of Medicine, University of Southern California , Los Angeles, California.
Sanda
S
Win
2 USC Research Center for Liver Disease, Keck School of Medicine, University of Southern California , Los Angeles, California.
Tin Aung
TA
Than
1 Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University , Beijing, China .
Shutao
S
Yin
3 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University , Beijing, China .
Min
M
Ye
1 Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University , Beijing, China .
Hongbo
H
Hu
2 USC Research Center for Liver Disease, Keck School of Medicine, University of Southern California , Los Angeles, California.
Neil
N
Kaplowitz
D000082:Acetaminophen / Q000633:toxicity; D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D002782:Cholestenes / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism*; D008954:Models, Biological; D010936:Plant Extracts / Q000494:pharmacology; D020011:Protective Agents / Q000494:pharmacology; D011485:Protein Binding; D017382:Reactive Oxygen Species / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects
D000975:Antioxidants; D002782:Cholestenes; D010936:Plant Extracts; D020011:Protective Agents; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D000082:Acetaminophen; D048031:JNK Mitogen-Activated Protein Kinases
Antcin H; Antrodia Camphorate; ROS; c-Jun-N-terminal kinase; liver injury; mitochondria