The cyclopeptide -amatoxin induced hepatic injury via the mitochondrial apoptotic pathway associated with oxidative stress

[Display omitted] •Alpha-amatoxin (α-AMA) has been considered the primary toxin from amatoxin-containing mushrooms, which is responsible for hepatotoxicity and death.•α-amatoxin can damage mice liver and human normal liver cells in a dose- and time-dependent manner.•α-amatoxin -induced apoptosis may occur primarily through the mitochondrial apoptotic pathway.•α-amatoxin affects the expression of p53, Bax and Bcl-2, which, in turn, activates subsequent caspase cascades.•ROS is as an upstream signaling molecule involved in α-AMA-induced apoptosis in mouse liver and L-02 cells. In order to explore the role of apoptosis in alpha-amatoxin (α-AMA) induced liver injury and probable upstream activation signals, we established animal and cellular models, respectively, for this pathophysiological condition. To this end, we evaluated the survival rate and serum biochemical parameters in BALB/c mice exposed to α-AMA at different time periods, along with the levels of oxidative and antioxidant enzymes in the liver tissue of these mice and proteins involved in apoptosis-related pathways. Our results reveal that α-AMA-induced apoptosis occurs primarily through the mitochondrial apoptotic pathway and is associated with oxidative damage. Further, in order to verify the key nodes and important upstream activators in this apoptotic pathway, we estimated the levels of p53 protein and downstream mitochondrial apoptotic pathway-related proteins in L-02 cells, all of which were found to change significantly. We also found that the levels of total and mitochondrial reactive oxygen species (ROS) in L-02 cells increased with time. Collectively, our findings suggest that α-AMA affects many cellular processes, including the expression of p53 independent of transcription and the expression of Bax and Bcl-2, thereby activating the subsequent caspase cascade pathways. In addition, we identified ROS to be an upstream signaling molecule involved in the α-AMA-induced apoptosis of mouse liver cells and L-02 cells.