Detoxification of reactive oxygen species by a nonpeptidyl mimic of superoxide dismutase cures acetaminophen-induced acute liver failure in the mouse

Drug-induced acute liver failure (ALF) is a devastating and often fatal dis ease mainly caused by poisoning by acetaminophen (APAP), The toxic metaboli te, N-acetyl-p-benzoquinone-imine (NAPQI), that leads to gluthatione deplet ion has been suspected to be the main effector of hepatocyte apoptosis duri ng APAP-induced ALF. We have investigated whether reactive oxygen species ( ROS) also play a role in APAP-induced ALF, and whether manganese Iii tetrak is (5,10,15,20 benzoic acid) (MnTBAP), a mimic of superoxide dismutase (SOD ) with catalase-like activity, can treat the disease in mice. The effects o f MnTBAP were tested on APAP-intoxicated mice and on isolated hepatocytes i ncubated with APAP. MnTBAP preventively and curatively administered signifi cantly improved survival times, and dramatically reduced serum transaminase activity levels and parenchymal lesions in APAP-intoxicated mice. Whereas pretreatment with N-acetyl-L-cysteine (NAC) prevented ALF in a dose-depende nt manner, the molecule was ineffective when curatively administered. The s ignificant increase in glutathione peroxidase (Gpx) activity following APAP administration, and the beneficial effects of MnTBAP suggested that ROS we re produced during APAP-induced ALF. A direct evidence of ROS generation wa s provided by how cytometry of isolated hepatocytes incubated with APAP, In vitro, ROS production was associated with mitochondrial damage characteriz ed by the collapse of transmembrane potential and the loss of cardiolipin c ontent. In livers of intoxicated mice, ALF was associated with cytochrome c release that led to the activation of caspases-9 and -3. The capacity of M nTBAP to abrogate all those alterations suggests that ROS play a role in AP AP-induced apoptosis of hepatocytes, and explains the beneficial effects of MnTBAP, which could be of interest in APAP-induced ALF in humans.