Biochem. J. (2006) 399
(455–461) (Printed in Great Britain)
Mice deficient in Cu,Zn-superoxide dismutase are resistant to acetaminophen toxicity
Xin Gen LEI*1, Jian-Hong ZHU*, James P. McCLUNG*, Manuel AREGULLIN† and Carol A. RONEKER*
*Department of Animal Science, Cornell University, Ithaca, NY 14853, U.S.A., and †Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, U.S.A.
Key words: acetaminophen (APAP), antioxidant enzyme, cytochrome P450 2E1, glutathione peroxidase, protein nitration, superoxide dismutase (SOD).
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.
Abbreviations used: ALT, alanine aminotransferase; APAP, acetaminophen; CYP2E1, cytochrome P450 2E1; DKO, double knockout; GPX1, glutathione peroxidase-1; GST, glutathione S-transferase; i.p., intraperitoneal; NAPQI, N-acetyl p-benzoquinoneimine; RNS, reactive nitrogen species; SOD, superoxide dismutase; SOD1, Cu,Zn-SOD; SOD2, Mn-SOD; UGT1A6, UDPglucuronyl transferase 1A6; WT, wild-type.
1To whom correspondence should be addressed (email XL20@Cornell.edu).
Received 26 May 2006/7 July 2006; accepted 10 July 2006
Published as BJ Immediate Publication 10 July 2006, doi:10.1042/BJ20060784
The Biochemical Society, London ©2006
Editorial Advisory Panel
RSS feeds
Table of contents by email
My BJ toolbox
