A role for the glutathione peroxidase/reductase enzyme system in the protection from paracetamol toxicity in isolated mouse hepatocytes

Biochem Pharmacol. 1989 Oct 1;38(19):3323-30. doi: 10.1016/0006-2952(89)90630-8.


The role of the glutathione peroxidase/reductase (GSH-Px/GSSG-Rd) enzyme system in protection from paracetamol toxicity was investigated in isolated mouse hepatocytes in primary culture. The effect of inhibitors of these enzymes on the toxicity of paracetamol and on t-butylhydroperoxide (t-BOOH), used as a positive control, was determined. 1,3-Bis(chloroethyl)-1-nitrosourea (BCNU) was used to inhibit GSSG-Rd, and goldthioglucose (GTG) used to inhibit GSH-Px. Both these inhibitors increased cell membrane damage in response to oxidative stress initiated by t-BOOH. However, they also increased the susceptibility of hepatocytes to paracetamol toxicity, indicating that a component of paracetamol's toxic effect involves formation of species that are detoxified by the GSH-Px/GSSG-Rd enzymes. To further examine the role of these enzymes, age-related differences in their activity were exploited. Hepatocytes from two-week-old mice were less susceptible to both t-BOOH and paracetamol toxicity than were those from adult mice. This corresponds to higher activity of cytosolic GSH-Px/GSSG-Rd in this age group. However, after inhibition of GSSG-Rd with BCNU, hepatocytes from these postnatal mice were more susceptible to paracetamol toxicity. This suggests that the higher activity of GSH-Px/GSSG-Rd in hepatocytes from two-week-old mice is responsible for their reduced susceptibility to paracetamol toxicity. The data indicate that the GSH-Px/GSSG-Rd enzymes contribute to protection from paracetamol toxicity and suggest that formation of peroxides contributes to this drug's hepatotoxic effects.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetaminophen / toxicity*
  • Age Factors
  • Animals
  • Benzoquinones*
  • Carmustine / pharmacology
  • Glutathione / analysis
  • Glutathione Peroxidase / physiology*
  • Glutathione Reductase / physiology*
  • Imines / pharmacology
  • In Vitro Techniques
  • Liver / drug effects*
  • Mice
  • Oxidation-Reduction
  • Peroxides / pharmacology
  • tert-Butylhydroperoxide


  • Benzoquinones
  • Imines
  • Peroxides
  • Acetaminophen
  • tert-Butylhydroperoxide
  • Glutathione Peroxidase
  • Glutathione Reductase
  • N-acetyl-4-benzoquinoneimine
  • Glutathione
  • Carmustine