Vitamin E and hepatotoxic agents

I . It has been suggested that carbon tetrachloride damages rat liver by accelerating processes of lipid peroxidation at subcellular sites and that the protective action of vitamin E is due to its functioning as an antioxidant in vivo. Direct evidence for these mechanisms in vivo has been sought and is critically examined. 2. The increased production of malondialdehyde by rat liver microsomal fractions during incubation with CCl, was shown to be a function of the vitamin E status of the rat and of an in vitro reaction, which could not be correlated with the hepatotoxic action of CCI,. 3. Evidence for the production of lipid peroxides by CCl, in the livers of vitamin E-deficient and vitamin E-supplemented rats was sought ( I ) by measurement of ultraviolet spectral changes (' diene' formation) and (2) by direct micro-iodimetric determination of the peroxide. No differences in peroxide content were found between CC1,-treated and control rats, nor were the spectrophotometric changes in the ultraviolet region related to the presence of vitamin E. 4. The effect of CCI, (2.0 ml/kg orally) on ATP levels in rat liver was studied at intervals from 3 to 68 h. The primary lesion leading to necrosis and fat accumulation after CCl, treatment occurred many hours before the eventual slight decline in ATP. Although the levels of ATP were somewhat higher in vitamin E-deficient rats, vitamin E did not prevent the slight decline in ATP that took place. Since ATP is known to be highly sensitive to peroxidation, the results suggest that lipid peroxidation is not the primary event in CCl, poisoning. 5 . The effect of CC1, on the metabolism of [14C]~-a-tocopherol in the rat was studied. A single intraperitoneal dose of CCl, (2.0 ml/kg) did not increase the destruction of a-tocopherol in the liver or carcass after 24 h. Three smaller daily doses of CC14 (025 ml/kg) also did not increase a-tocopherol catabolism ; on the contrary, significantly more a-tocopherol was found in the livers of rats treated with CCI,. These results suggest that CCl4 does not increase lipid peroxidation in vivo.