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Rats were fed a 5 or 20% casein diet that causes liver necrosis unless supplemented with vitamin E or selenite. The following activities were studied in liver subcellular fractions: enzymic formation of lipid peroxides, NADPH-cytochrome creductase, oxidative demethylation of aminopyrine, and incorporation of [14C]leucine into protein (with microsomes); xanthine oxidase (with soluble supernatant); and RNA polymerases I and II (with nuclei). Formation of lipid peroxides was higher in rats fed diets without vitamin E and was not reduced significantly by dietary selenite. The activity of xanthine oxidase was higher in animals fed the 20% casein than in those fed the 5% casein diet; however, a higher activity was observed in the rats fed the latter diet without vitamin E or selenite than in those receiving these supplements. The activity of RNA polymerase I was higher in rats fed the low casein diet. Other activities examined were not affected significantly by the level of dietary casein or by vitamin E or selenite.

The effect of feeding a protein-free diet on DNA synthesis in vivo in normal and regenerating liver, and on the activity of two enzymes, DNA polymerase and thymidine kinase, which are supposed to be involved in this process was investigated. Regenerating liver from rats fed a protein-free diet for 7 days incorporated 2H-thymidine into DNA at about the same rate as controls, whereas in resting liver the DNA synthesis in vivo was markedly reduced by protein deprivation. In regenerating liver the supernatant DNA polymerase and the thymidine kinase activities increased in protein-depleted rats at about the same level as in controls. In resting liver, the protein-free diet led to a marked increase of thymidine kinase activity; the DNA polymerase activity was also increased when assayed with heat-denatured DNA as primer, but remained unchanged with native DNA. The effect on the DNA polymerase activity was not due to reduced food intake because the same results were obtained with pair-fed animals. The hepatic DNA synthesis in vivo was markedly reduced by 3 days of starvation; at this time, the supernatant DNA polymerase activity was not significantly modified, and became higher than controls only after 4 days of fasting.

The capacity to oxidize succinate was studied with liver mitochondria, homogenates or slices from rats maintained with commercial diets or with semipurified diets with or without addition of vitamin E or sodium selenite. A decline in the oxidation rate was observed with all systems in vitamin E-deficient, selenium-deficient animals, and in some instances in rats fed commercial diets. The decline was prevented by administration of large amounts of vitamin E. Dietary selenite prevented decline in mitochondria, but not in homogenates or slices. The significance of respiratory decline as a possible specific lesion of the latent phase of dietary liver necrosis is discussed.

1Rats were fed diets with 20 and 5% of crude or fat-extracted casein as protein source, with or without added methionine, cystine, vitamin E and Factor 3-active sodium selenite. The growth, mortality from hepatic necrosis and liver regeneration after partial hepatectomy were studied.2The adequate dietary protein level given by the 20% of casein, as well as dietary addition of sulfur amino acids did not afford complete protection against liver necrosis. Vitamin E or selenite protected completely when added in sufficient amount to either rations. It may be concluded that the mortality observed in rats fed the 20% casein diet is due to lack of Factor 3-active selenium in the casein used.3The mortality from liver necrosis was higher in male than in female rats. Seasonal variations in the incidence of necrosis were noted.4The regeneration of the liver was slightly impaired in rats fed the 5% casein diets as compared with those fed the 20% casein ones; it was not affected by dietary addition of methionine, cystine or vitamin E.