Deleterious effects of lovastatin in rats fed diets deficient or supplemented with vitamin E

MONSERRAT, A.J.; COLL, C.; CUTRÍN, J.C.; RUBIO, M.; LORES ARNAIZ, S.; BOVERIS, A.; PORTA, E.A.

Biochemical Archives

M.B.R. Press

Lugar: Kenyon, Minn; Año: 1995 vol. 11 p. 261 - 276

0749-5331

We have previously reported in this journal that prolonged dietary administration of lovastatin to vitamin E-deficient rats resulted in a dose-dependent mortality due to massive hepatic necrosis, and that vitamin E supplementation totally prevented mortality and reduced the liver damage. Since the results suggested that the lethal hepatic effects of 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 regimens were offered for six weeks alone (controls) or supplemented with 200 or 400 mg of lovastatin/kg of dieto 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 mglkg, while contrary to our expectations, in the vit. E-suppl. rats the mortality was 10% at the lovastatin dosage of 200 mg/ kg, and still 50% at the dosage of 400 mg/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 mglkg lovastatin significantly reduced plasma contents of a-tocopherol, and significantly increased the serum levels of ALT and AST in the surviving vito Edef. rats, but not in those supplemented with this vitamin. On the other hand, at the dosage of 400 mg/kg lovastatin decreased the plasma contents of a-tocopherol and ~-carotene, but increased plasma ubiquinol-9 and did not affect serum ALT 01´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 a-tocopherol. In none of the surviving rats lovastatin treatment increased the liver spontaneous and hydroxyperoxyde-induced chemiluminescence or the production of thiobarbituric acid reactive substances. Although the present results in surviving rats do not apparentIy support our "oxidative stress" hypothesis of lovastatin toxicity, they strongly suggest that rats may have adapted to the untoward effects of this drug.