Effects of high doses of vitamin E on dimethylnitrosamine hepatotoxicity and drug metabolism in the rat

Abstract

The administration of relatively high doses of vitamin E [55 mg/kg/day, intramuscular (i.m.)] to rats for 3 days resulted in a significant decrease in the acute hepatotoxieity of dimethynitrosamine (DMN). This decrease in toxicity was associated with a decrease in the hepatic metabolism of DMN. Since the metabolism of DMN is mediated by the liver microsomal mixed function oxidase (MFO), the effect of high doses of vitamin E on hepatic MFO was investigated. Rats were treated daily for 3 days with 10, 21, 45 or 100 mg/kg of vitamin E (i.m.), and various parameters of MFO activity were studied in liver cell fractions. DMN demethylase and ethylmorphine demethylase activities and cytochrome P-450 concentration were decreased in animals pretreated with 45 or 100 mg/kg of vitamin E (i.m.). Benzo(a)pyrene hydroxylase activity and cytochrome b 5, concentration were decreased only by pretreatment with the highest dose of vitamin E. NADPH cytochrome c reductase activity was unaffected by vitamin E pretreatment. Inhibition of drug metabolism in the rat was also demonstrated in vivo. Pretreatment of rats with vitamin E (100 mg/kg/day, i.m., 3 days) resulted in a significant prolongation of hexobarbital sleeping time. The effect of pretreatment of rats with vitamin E (100 mg/kg/day, i.m., for 3 days) on ethylmorphine demethylase was shown to be reversible after cessation of vitamin E administration. It is concluded that large doses of vitamin E inhibit hepatic microsomal MFO, and thus decrease the hepatoxicity of DMN by inhibiting its metabolism to a presumed active metabolite.