Acetaminophen‐Induced Alterations in Hepatic Mitochondrial Manganese Superoxide Dismutase (MnSOD; SOD2) Activity in Mice

In overdose the analgesic/antipyretic acetaminophen (APAP) is hepatotoxic. Toxicity is mediated by hepatic metabolism to a reactive metabolite (NAPQI). Following low doses NAPQI is detoxified by glutathione (GSH); however, in overdose GSH is depleted, NAPQI covalently binds to proteins, and oxygen/nitrogen stress occurs. Toxicity is believed to occur by mitochondrial dysfunction. MnSOD inactivation occurs during many oxidant stress mediated diseases; thus, we examined MnSOD in APAP toxicity. MnSOD is a critical mitochondrial antioxidant enzyme in preventing oxygen/nitrogen stress within the mitochondria. Mice were treated with 300 mg/kg APAP. GSH was significantly reduced by 65% at 0.5 h and remained reduced from 1–4 h returning to control levels by 6 h. Serum ALT (hepatotoxicity) did not significantly increase until 4 h and was 2290 IU/L at 6 h. MnSOD activity was significantly reduced by 25% at 0.5 h and was 50% at 1 h and 2 h. In a dose‐response study performed at 1 h, GSH was significantly depleted by 62% and 80% with nonhepatotoxic doses of 50 and 100 mg/kg APAP, respectively. No further GSH depletion occurred with 200 and 300 mg/kg APAP. MnSOD activity was reduced by 28, 32 and 57% with 50, 100 and 300 mg/kg APAP respectively. Thus, MnSOD activity is dramatically decreased following toxic and nontoxic doses of APAP, and MnSOD inactivation precedes induction of hepatic toxicity. Supported by NIH grant 1 R01 DK079008.