Paradoxical effects of perturbation of intracellular levels of glutathione on halothane-induced hepatotoxicity in hyperthyroid rats

Fundam Appl Toxicol. 1984 Apr;4(2 Pt 1):221-30. doi: 10.1016/0272-0590(84)90123-4.


Exposure of hyperthyroid rats to halothane results in a centrilobular necrosis of the liver and an 11-fold increase in serum glutamate-pyruvate transaminase (SGPT) levels. These effects are not seen in euthyroid animals. Paradoxically, administration of diethylmaleate to hyperthyroid rats significantly decreased the levels of hepatic glutathione and blocked the halothane-induced hepatic necrosis as well as decreased the elevation of SGPT. In contrast, pretreatment of animals with N-acetylcysteine, an intracellular sulfhydryl repletor , significantly increased the severity of the halothane-induced hepatic necrosis and increased the elevation of SGPT. Similarly, cysteamine, another intracellular sulfhydryl repletor , also exacerbated halothane-induced liver injury. Halothane-induced hepatotoxicity is at least in part apparently regulated by cellular glutathione levels. Paradoxically, glutathione seems to be involved in the bioactivation rather than the detoxification of halothane.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetylcysteine / toxicity
  • Alanine Transaminase / blood
  • Animals
  • Chemical and Drug Induced Liver Injury / metabolism*
  • Chemical and Drug Induced Liver Injury / pathology
  • Glutathione / metabolism*
  • Halothane / toxicity*
  • Hyperthyroidism / metabolism*
  • Liver / pathology
  • Male
  • Maleates / toxicity
  • Rats
  • Sulfhydryl Compounds / metabolism
  • Time Factors
  • Triiodothyronine / pharmacology


  • Maleates
  • Sulfhydryl Compounds
  • Triiodothyronine
  • Alanine Transaminase
  • diethyl maleate
  • Glutathione
  • Halothane
  • Acetylcysteine