The superoxide dismutase mimetic MnTBAP prevents Fas-induced acute liver failure in the mouse

Background & Aims: Acute liver failure (ALF) of viral origin results from m assive hepatocyte apoptosis induced by the interaction between Fas expresse d on hepatocytes and Fas ligand on activated T lymphocytes. Because Fas-ind uced apoptosis of hepatocytes involves mitochondrial damages and potential reactive oxygen species (ROS) overproduction, we investigated whether manga nese III tetrakis (5,10,15,20 benzoic acid) (MnTBAP), a nonpeptidyl mimic o f superoxide dismutase (SOD), can inhibit Fas-induced ALF. Methods: An agon ist anti-Fas monoclonal antibody was used to induce hepatocyte apoptosis in vitro and ALF in vivo. Results: Preventive and curative treatments by MnTB AP significantly increased survival rates and significantly reduced asparta te aminotransferase levels and parenchymal lesions. ROS generation was sugg ested by those beneficial effects and significant increases in SOD and Gpx activities after anti-Fas injection. Flow cytometry of isolated hepatocytes incubated with anti-Fas monoclonal antibody showed that ROS production was associated with the collapse of transmembrane potential and loss of cardio lipin content. After injection of anti-Fas monoclonal antibody, mitochondri al Bcl-2 was decreased, cytochrome c released, and caspase-3 activated. Mit ochondrial alterations and their consequences were abrogated by MnTBAP. Con clusions: ROS are key executioners in Fas-induced hepatocyte apoptosis. Thi s finding explains why a nonpeptidyl mimic of SOD can cure ALF in a model o f viral hepatitis, pointing out the potential interest of this molecule in humans.