DELETERIOUS EFFECTS OF LOVASTATIN IN RATS FED DIETS DEFICIENT OR SUPPLEMENTED WITH VITAMIN-E

We have previously reported in this journal that prolonged dietary adm inistration of lovastatin to vitamin E-deficient rats resulted in a do se-dependent mortality due to massive hepatic necrosis, and that vitam in E supplementation totally prevented mortality and reduced the liver damage. Since the results suggested that the lethal hepatic effects o f lovastatin were due to oxidative stress, we have now reexplored this situation in more detail. Female weaning Wistar rats were fed either a diet deficient or supplemented with vitamin E, and these two regimen s were offered for six weeks alone (controls) or supplemented with 200 or 400 mg of lovastatin/kg of diet. The results showed that in vit. E -def. rats treated with lovastatin the mortality was 40% at the dosage of 200 mg/kg, and 50% at the dosage of 400 mg/kg, while contrary to o ur expectations, in the vit. E-suppl. rats the mortality was 10% at th e lovastatin dosage of 200 mg/kg, and still 50% at the dosage of 400 m g/kg. This time the lethal effects of lovastatin could not be ascribed to any histologic evidence of severe liver necrosis. At the dosage of 200 mg/kg lovastatin significantly reduced plasma contents of alpha-t ocopherol, and significantly increased the serum levels of ALT and AST in the surviving vit. E-def. rats, but not in those supplemented with this vitamin. On the other hand, at the dosage of 400 mg/kg lovastati n decreased the plasma contents of alpha-tocopherol and beta-carotene, but increased plasma ubiquinol-9 and did not affect serum ALT or AST in vit. E-def. rats. In vit. E-suppl. rats the only significant change associated with lovastatin at 400 mg/kg was a decrease in plasma alph a-tocopherol. In none of:the surviving rats lovastatin treatment incre ased the liver spontaneous and hydroxyperoxyde-induced chemiluminescen ce or the production of thiobarbituric acid reactive substances. Altho ugh the present results in surviving rats do not apparently support ou r ''oxidative stress'' hypothesis of lovastatin toxicity, they strongl y suggest that rats may have adapted to the untoward effects of this d rug.