Ethane production and liver necrosis in rats after administration of drugs and other chemicals

Lipid peroxidation and liver necrosis due to a number of drugs and chemicals were studied. The agents were administered to control, vitamin E-deficient, and selenium-deficient rats. Vitamin E deficiency was documented by a low serum tocopherol level (0.34 mg/100 ml) and selenium deficiency by a specific activity of the selenoenzyme glutathione peroxidase in 105,000g liver supernatant which was approximately 1% of the control value. Glutathione S-transferase specific activity, measured with 1-chloro-2,4-dinitrobenzene as substrate, was doubled by selenium deficiency. Ethane production was measured as the index of in vivo lipid peroxidation. Hepatic necrosis was assessed histologically and by measuring serum glutamic-pyruvic transaminase. When no agents were administered, vitamin E-deficient rats produced more ethane than did control or selenium-deficient rats. Phenobarbital did not cause an increase in ethane production. CCl4 (60 μl/100 g) and BrCCl3 (5 μl/100 g) caused large ethane production and moderately severe liver necrosis. The vitamin E-deficient and selenium-deficient groups given BrCCl3 produced more ethane than the controls but had no more severe hepatic necrosis than the controls. Thioacetamide (5 mmol/kg) and acetaminophen (3 g/kg) caused moderate to severe liver necrosis but only small ethane production. Vitamin E deficiency potentiated acetaminophen hepatotoxicity and selenium deficiency inhibited it. Iodipamide (1.5 mmol/kg) caused very large ethane production and death within hours in vitamin E-deficient rats. At a dose of 2 mmol/kg it caused severe liver necrosis in control rats but only small ethane production. This dose caused no liver necrosis in selenium-deficient rats. Acetylhydrazine (30 mg/kg) caused moderate ethane production in all groups but no liver necrosis. A single dose of ethanol (0.68 ml/100 g) led to small production of ethane in all groups. This study shows that many agents are capable of causing in vivo lipid peroxidation, but that lipid peroxidation does not always correlate with liver necrosis. Selenium deficiency is not a simple glutathione peroxidase deficiency state, as hepatic glutathione S-transferase is increased by it and it protects against acetaminophen and iodipamide hepatotoxicity.