Selenoprotein MsrB1 deficiency exacerbates acetaminophen-induced hepatotoxicity via increased oxidative damage

Arch Biochem Biophys. 2017 Nov 15:634:69-75. doi: 10.1016/ Epub 2017 Oct 3.


Acetaminophen (APAP) overdose induces acute liver damage and failure via reactive oxygen species production and glutathione (GSH) depletion. Methionine sulfoxide reductase B1 (MsrB1) is an antioxidant selenoenzyme that specifically catalyzes the reduction of methionine R-sulfoxide residues. In this study, we used MsrB1 gene-knockout mice and primary hepatocytes to investigate the effect of MsrB1 on APAP-induced hepatotoxicity. Analyses of histological alterations and serum indicators of liver damage showed that MsrB1-/- mice were more susceptible to APAP-induced acute liver injury than wild-type (MsrB1+/+) mice. Consistent with the in vivo results, primary MsrB1-/- hepatocytes displayed higher susceptibility to APAP-induced cytotoxicity than MsrB1+/+ cells. MsrB1 deficiency increased hepatic oxidative stress after APAP challenge such as hydrogen peroxide production, lipid peroxidation, and protein oxidation levels. Additionally, basal and APAP-induced ratios of reduced-to-oxidized GSH (GSH/GSSG) were significantly lower in MsrB1-/- than in MsrB1+/+ livers. Nrf2 nuclear accumulation and heme oxygenase-1 expression levels after APAP challenge were lower in MsrB1-/- than in MsrB1+/+ livers, suggesting that MsrB1 deficiency attenuates the APAP-induced activation of Nrf2. Collectively, the results of this study suggest that selenoprotein MsrB1 plays a protective role against APAP-induced hepatotoxicity via its antioxidative function.

Keywords: Acetaminophen; Hepatic damage; Methionine sulfoxide; Oxidative stress; Selenoenzyme MsrB1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetaminophen / adverse effects
  • Acetaminophen / toxicity*
  • Animals
  • Antioxidants / metabolism
  • Chemical and Drug Induced Liver Injury / metabolism*
  • Chemical and Drug Induced Liver Injury / pathology*
  • Male
  • Methionine Sulfoxide Reductases / deficiency*
  • Methionine Sulfoxide Reductases / genetics
  • Methionine Sulfoxide Reductases / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oxidative Stress / drug effects*
  • Reactive Oxygen Species / metabolism*


  • Antioxidants
  • Reactive Oxygen Species
  • Acetaminophen
  • Methionine Sulfoxide Reductases
  • MsrB1 protein, mouse