PMID:16831125

Citation	Lei, XG, Zhu, JH, McClung, JP, Aregullin, M and Roneker, CA (2006) Mice deficient in Cu,Zn-superoxide dismutase are resistant to acetaminophen toxicity. Biochem. J. 399:455-61
Abstract	Although antioxidants are used to treat an overdose of the analgaesic/antipyretic drug APAP (acetaminophen), roles of antioxidant enzymes in APAP-induced hepatotoxicity remain controversial. Our objective was to determine impacts of knockout of SOD1 (superoxide dismutase; Cu,Zn-SOD) alone or in combination with selenium-dependent GPX1 (glutathione peroxidase-1) on APAP-induced hepatotoxicity. All SOD1-null (SOD1-/-) and SOD1- and GPX1-double-knockout mice survived an intraperitoneal injection of 600 mg of APAP per kg of body mass, whereas 75% of WT (wild-type) and GPX1-null mice died within 20 h. Survival time of SOD1-/- mice injected with 1200 mg of APAP per kg of body mass was longer than that of the WT mice (934 compared with 315 min, P<0.05). The APAP-treated SOD1-/- mice had less (P<0.05) plasma ALT (alanine aminotransferase) activity increase and attenuated (P<0.05) hepatic glutathione depletion than the WT mice. The protection conferred by SOD1 deletion was associated with a block of the APAP-mediated hepatic protein nitration and a 50% reduction (P<0.05) in activity of a key APAP metabolism enzyme CYP2E1 (cytochrome P450 2E1) in liver. The SOD1 deletion also caused moderate shifts in the APAP metabolism profiles. In conclusion, deletion of SOD1 alone or in combination with GPX1 greatly enhanced mouse resistance to APAP overdose. Our results suggest a possible pro-oxidant role for the physiological level of SOD1 activity in APAP-mediated hepatotoxicity.
Links	PubMed PMC1615904 Online version:10.1042/BJ20060784
Keywords	Acetaminophen/pharmacokinetics; Acetaminophen/toxicity; Alanine Transaminase/biosynthesis; Animals; Benzoquinones/metabolism; Benzoquinones/toxicity; Biotransformation; Body Weight; Cytochrome P-450 CYP2E1/antagonists & inhibitors; Cytochrome P-450 CYP2E1/physiology; Drug Resistance; Enzyme Induction/drug effects; Glutathione/metabolism; Glutathione Peroxidase/deficiency; Glutathione Peroxidase/genetics; Glutathione Peroxidase/physiology; Imines/metabolism; Imines/toxicity; Liver Failure/chemically induced; Liver Failure/enzymology; Liver Failure/etiology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Oxidation-Reduction; Oxidative Stress; Peroxynitrous Acid/metabolism; Superoxide Dismutase/deficiency; Superoxide Dismutase/genetics; Superoxide Dismutase/physiology; Tyrosine/analogs & derivatives; Tyrosine/biosynthesis
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