title: Mice deficient in Cu,Zn-superoxide dismutase are resistant to acetaminophen toxicity.
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.
authors.affiliation: Department of Animal Science, Cornell University, Ithaca, NY 14853, USA. XL20@Cornell.edu
authors.forename: Xin Gen
authors.initials: XG
authors.lastname: Lei
authors.forename: Jian-Hong
authors.initials: JH
authors.lastname: Zhu
authors.forename: James P
authors.initials: JP
authors.lastname: McClung
authors.forename: Manuel
authors.initials: M
authors.lastname: Aregullin
authors.forename: Carol A
authors.initials: CA
authors.lastname: Roneker
mesh_terms: D000082:Acetaminophen / Q000493:pharmacokinetics / Q000633:toxicity*; D000410:Alanine Transaminase / Q000096:biosynthesis; D000818:Animals; D016227:Benzoquinones / Q000378:metabolism / Q000633:toxicity; D001711:Biotransformation; D001835:Body Weight; D019392:Cytochrome P-450 CYP2E1 / Q000502:physiology; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004351:Drug Resistance; D004790:Enzyme Induction / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007097:Imines / Q000378:metabolism / Q000633:toxicity; D017093:Liver Failure / Q000139:chemically induced* / Q000201:enzymology / Q000209:etiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D030421:Peroxynitrous Acid / Q000378:metabolism; D013482:Superoxide Dismutase / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000096:biosynthesis; D000094765:Glutathione Peroxidase GPX1
chemical_list: D016227:Benzoquinones; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D007097:Imines; D030421:Peroxynitrous Acid; C002744:3-nitrotyrosine; D000082:Acetaminophen; D014443:Tyrosine; D005979:Glutathione Peroxidase; D019392:Cytochrome P-450 CYP2E1; D013482:Superoxide Dismutase; D000410:Alanine Transaminase; C028473:N-acetyl-4-benzoquinoneimine; D005978:Glutathione; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse