Comparative impacts of knockouts of two antioxidant enzymes on acetaminophen-induced hepatotoxicity in mice

Jian Hong Zhu, James P. McClung, Xiaomei Zhang, Manuel Aregullin, Chi Chen, Frank J. Gonzalez, Tae Wan Kim, Xin Gen Lei

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

We have previously shown a more potent impact of knockout of Cu,Zn-superoxide dismutase (SOD1) than that of Se-dependent glutathione peroxidase-1 (GPX1) on murine hepatotoxicity induced by an intraperitoneal (ip) injection of a high dose of acetaminophen (APAP, 600 mg/kg). The objective of this experiment was to compare the temporal impacts of knockouts of GPX1 and SOD1 alone or together on mouse susceptibility to an injection of a low dose of APAP (300 mg/kg). The APAP-mediated rises in plasma alanine aminotransferase activity and nitrate/nitrite concentrations, hepatic GSH depletion, and hepatic protein nitration at 5 and (or) 24 h were nearly abolished (P < 0.05) in SOD1-/- or GPX1 and SOD1 double-knockout (DKO) mice, while GPX1-/- mice exerted only moderate or no change compared with the WT. Despite an increased (P < 0.05) APAP-N-acetylcysteine and decreased APAP-glucuronide (P < 0.05) relative to the total APAP metabolites in urine collected for 24 h after the APAP injection, the SOD1-/- mice displayed no shift in urinary APAP-cysteine compared with the WT mice. Knockout of SOD1 prevented the APAP-induced hepatic GPX inactivation (P < 0.05), whereas knockout of GPX1 aggravated the APAP-induced hepatic SOD activity loss (P < 0.05). However, the APAP-mediated activity changes of these enzymes in liver accompanied no protein alterations. In conclusion, knockout of GPX1 or SOD1 exerted differential impact on mouse susceptibility to this low dose of APAP, but neither shifted urinary APAP-cysteine formation.

Original languageEnglish (US)
Pages (from-to)1477-1483
Number of pages7
JournalExperimental Biology and Medicine
Volume234
Issue number12
DOIs
StatePublished - Dec 2009

Bibliographical note

Funding Information:
This study was supported by the National Institute of Health grant DK53108 to XGL.

Copyright:
Copyright 2010 Elsevier B.V., All rights reserved.

Keywords

  • Acetaminophen
  • Cu,Zn-superoxide dismutase
  • Glutathione peroxidase
  • Oxidative stress
  • Protein nitration
  • Toxicity

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