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Apigenin Attenuates Acetaminophen-Induced Hepatotoxicity by Activating AMP-Activated Protein Kinase/Carnitine Palmitoyltransferase I Pathway.

ABSTRACT: Overuse of acetaminophen (APAP) is a major cause of drug-induced liver failure at the clinics. Apigenin (API) is a natural flavonoid derived from Matricaria chamomilla. The aim of the present study was to investigate the amelioration function of API in APAP-induced hepatotoxicity both in vitro and in vivo and investigate its potential mechanisms. Analysis results of the activities of serum alanine and aspartate aminotransferases (ALT and AST), malondialdehyde, myeloperoxidase (MPO), and reactive oxygen species (ROS) demonstrated therapeutic effects of API. MTT assay results revealed that API attenuated APAP and its metabolic product, N-acetyl-p-benzoquinone imine (NAPQI) induced cytotoxicity in a dose-dependent manner in human liver cells, L-02 cells. Subsequently, metabolomic results of cells and serum analyses demonstrated an aberrant level of carnitine palmitoyltransferase I (CPT1A). We established that API stimulated CPT1A activity in mice liver tissues and L-02 cells. Molecular docking analyses revealed potential interaction of API with CPT1A. Further investigation of the role of CPT1A in L0-2 cells revealed that API reversed cytotoxicity via the AMP-activated protein kinase (AMPK)/GSK-3? signaling pathway and compound C, which is a selective AMPK inhibitor, inhibited activation of CPT1A induced by API. API was bound to the catalytic region of AMPK as indicated by molecular docking results. In addition, compound C suppressed nuclear translocation of nuclear factor erythroid 2-related factor 2 (NRF2) that is enhanced by API and inhibited the antioxidative function of API. In summary, the study demonstrates that API attenuates APAP-induced hepatotoxicity by activating the AMPK/GSK-3? signaling pathway, which subsequently promotes CPT1A activity and activates the NRF2 antioxidant pathway.

SUBMITTER: Zhang J

PROVIDER: S-EPMC7919381 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Apigenin Attenuates Acetaminophen-Induced Hepatotoxicity by Activating AMP-Activated Protein Kinase/Carnitine Palmitoyltransferase I Pathway.

Zhang Jiaqi J Liang Xiaoqiang X Li Jiacheng J Yin Hao H Liu Fangchen F Hu Cheng C Li Ling L

Frontiers in pharmacology 20201120

Overuse of acetaminophen (APAP) is a major cause of drug-induced liver failure at the clinics. Apigenin (API) is a natural flavonoid derived from Matricaria chamomilla. The aim of the present study was to investigate the amelioration function of API in APAP-induced hepatotoxicity both in vitro and in vivo and investigate its potential mechanisms. Analysis results of the activities of serum alanine and aspartate aminotransferases (ALT and AST), malondialdehyde, myeloperoxidas ...[more]

PMID: 33658919

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Project description:Acetaminophen (APAP) is one of the most popular and safe pain medications worldwide. However, due to its wide availability, it is frequently implicated in intentional or unintentional overdoses where it can cause severe liver injury and even acute liver failure (ALF). In fact, APAP toxicity is responsible for 46% of all ALF cases in the United States. Early mechanistic studies in mice demonstrated the formation of a reactive metabolite, which is responsible for hepatic glutathione depletion and initiation of the toxicity. This insight led to the rapid introduction of N-acetylcysteine as a clinical antidote. However, more recently, substantial progress was made in further elucidating the detailed mechanisms of APAP-induced cell death. Mitochondrial protein adducts trigger a mitochondrial oxidant stress, which requires amplification through a MAPK cascade that ultimately results in activation of c-jun N-terminal kinase (JNK) in the cytosol and translocation of phospho-JNK to the mitochondria. The enhanced oxidant stress is responsible for the membrane permeability transition pore opening and the membrane potential breakdown. The ensuing matrix swelling causes the release of intermembrane proteins such as endonuclease G, which translocate to the nucleus and induce DNA fragmentation. These pathophysiological signaling mechanisms can be additionally modulated by removing damaged mitochondria by autophagy and replacing them by mitochondrial biogenesis. Importantly, most of the mechanisms have been confirmed in human hepatocytes and indirectly through biomarkers in plasma of APAP overdose patients. The extensive necrosis caused by APAP overdose leads to a sterile inflammatory response. Although recruitment of inflammatory cells is necessary for removal of cell debris in preparation for regeneration, these cells have the potential to aggravate the injury. This review touches on the newest insight into the intracellular mechanisms of APAP-induced cells death and the resulting inflammatory response. Furthermore, it discusses the translation of these findings to humans and the emergence of new therapeutic interventions.

Dataset Information

Apigenin Attenuates Acetaminophen-Induced Hepatotoxicity by Activating AMP-Activated Protein Kinase/Carnitine Palmitoyltransferase I Pathway.

Publications

Apigenin Attenuates Acetaminophen-Induced Hepatotoxicity by Activating AMP-Activated Protein Kinase/Carnitine Palmitoyltransferase I Pathway.

Similar Datasets

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