SOD1-Knockout Mice Are Resistant to Lethal Effects of Thioacetamide-Induced Hepatotoxicity

We investigated the responses of mice that are defective for superoxide dismutase 1 (SOD1) to thioacetamide (TAA)-induced hepatotoxicity. When a lethal dose of TAA (500 mg/kg) was intraperitoneally injected, the wild-type (WT) mice all died within 36h, but all of the SOD1-knockout (KO) mice survived. To elucidate the mechanism responsible for this, we examined the acute effects of a sublethal dose of TAA (200 mg/kg) on the livers of WT and KO mice. The extent of TAA-induced liver damage was less in the KO mice. The levels of proteins modified with acetyl-lysine, a marker for TAA metabolism, were lower in the KO mice than the WT mice upon the TAA treatment. The KO mice, which were under oxidative stress per se, exhibited a lower CYP2E1 activity. Thus, we conclude that elevated TAA metabolites and ROS that are produced by CYP-mediated drug metabolism trigger lipogenesis as well as liver damage and determine the fate of the mice.