Detoxification of Reactive Oxygen Species by A Nonpeptidyl Mimic of Superoxide Dismutase Cures Acetaminophen–Induced Acute Liver Failure in the Mouse

Abstract

Drug-induced acute liver failure (ALF) is a devastating and often fatal disease mainly caused by poisoning by acetaminophen (APAP). The toxic metabolite, N-acetyl-p-benzoquinone-imine (NAPQI), that leads to gluthatione depletion has been suspected to be the main effector of hepatocyte apoptosis during APAP-induced ALF. We have investigated whether reactive oxygen species (ROS) also play a role in APAP-induced ALF, and whether manganese III tetrakis (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 of MnTBAP were tested on APAP-intoxicated mice and on isolated hepatocytes incubated with APAP. MnTBAP preventively and curatively administered significantly 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-dependent manner, the molecule was ineffective when curatively administered. The significant increase in glutathione peroxidase (Gpx) activity following APAP administration, and the beneficial effects of MnTBAP suggested that ROS were produced during APAP-induced ALF. A direct evidence of ROS generation was provided by flow cytometry of isolated hepatocytes incubated with APAP. In vitro, ROS production was associated with mitochondrial damage characterized by the collapse of transmembrane potential and the loss of cardiolipin content. 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 MnTBAP to abrogate all those alterations suggests that ROS play a role in APAP-induced apoptosis of hepatocytes, and explains the beneficial effects of MnTBAP, which could be of interest in APAP-induced ALF in humans.

Antimitochondrial antibodies in acute liver failure: Implications for primary biliary cirrhosis

“…10,11 Furthermore, the generation of reactive oxygen species is associated with mitochondrial damage in murine hepatocytes incubated with APAP. 29 Our data indicate that AMAs are found in sera in almost 35% of APAP poisoning subjects, suggesting that the 2-OADC E2 lipoyl domain is a likely target of APAP-induced reactive oxygen and nitrogen species. It is known that a decrease in glutathione and CYP2E1 are risk factors in toxic liver injury, and both CYP2E1 and glutathione play important roles in APAP metabolism.…”

Pivotal role of superoxide anion and beneficial effect of antioxidant molecules in murine steatohepatitis

“…However, as already observed in 8-week-old ob/ob mice after LPS administration, 24 cytochrome c release was not followed by a strong caspase-3 activation as observed, for instance, in animal models of acute liver failure. 29,30 Our observation that lipoperoxidation was increased in whole liver and in isolated mitochondria from ob/ob mice along with cytochrome c release in the absence of strong engagement of the caspase cascade suggests that liver damage preferentially occurred through a necrotic process.…”

“…Because overproduction of ROS can lead to apoptosis and necrosis of hepatocytes, 29,30 we investigated whether the administration of SOD mimics altered the cascade of events leading to ROS-induced liver damages in NASH. We first focused on the release of cytochrome c into the cytosol, an early event caused by damage inflicted to the mitochondrial membranes by ROS.…”

Mitochondrial permeability transition in acetaminophen-induced necrosis and apoptosis of cultured mouse hepatocytes

“…Such sharing of these pathways represents and likely explains observations of both apoptosis and necrosis in acetaminophen hepatotoxicity. 21,49,50 …”