The role of liver glutathione in the acute toxicity of retrorsine to rats.

(1) Two procedures have been used to change the glutathione concentration in the livers of male rats. The glutathione level is increased to about double that of the controls, 0.5 h after the administration of cysteine (200 mg/kg, i.p.) and to about 25% that of controls, 1 h after the administration of 2-chloroethanol (30 mg/kg, i.p.). (2) The acute LD50 of retrorsine to rats (42 mg/kg) is increased by pretreatment with cysteine to 83 mg/kg and decreased by pre-treatment with chloroethanol to 23 mg/kg. In all three groups, deaths are accompanied by haemorrhagic centrilobular necrosis of the liver. (3) 2 h after the administration of retrorsine to rats (60 mg/kg), the levels of pyrrolic metabolites in the livers of animals pre-dosed with cysteine or chloroethanol are respectively about 60% and 200% those of rats given no pre-treatment. (4) Neither in the normal nor in the pre-treated rats dose retrorsine (60 mg/kg) cause a detectable fall in liver glutathione concentration 0.5-4 h after dosing. By 24 h, the glutathione concentration in the livers of the retrorsine-dosed rats is higher than those of the corresponding controls. There was no significant change in the liver weights of the treated rats relative to the controls. (5) Treatment of rats with retrorsine (60 mg/kg) causes a fall in the liver concentrations of cytochrome P-450, 24 h after dosing. This loss of cytochrome P-450 is increased in rats pre-treated with chloroethanol. The concentrations of cytochrome b5 in the same animals are not significantly reduced.