The studies proposed in this application are designed to further characterize the nutritional model of hepatocarcinogenesis in rats fed a choline-devoid diet. When fed to male rats, the diet induces liver cell death and regeneration, and liver cancer. on the other hand, female rats are resistant to the hepatonecrogenic action of the diet, and do not develop liver cancer. This sex difference will be exploited to better define the role played by liver cell death and regeneration in hepatocarcinogenesis, and to probe into the mechanisms of female's resistance to both. Liver cancer that develops in male rats carry mutation(s) of the p53 gene, and studies will be performed to characterize the mutation(s), whether single or multiple, its site(s), and the nucleotides involved; and, to determine whether it occur (s) early in the treatment of the rats, and may thus be a genomic alteration contributing to the neoplastic transformation of liver cells in this model of carcinogenesis. Beside being hepatocarcinogenic per se, a choline-devoid diet acts as a strong co-carcinogen. Other studies will address the question of whether the sex of the rats influences that action too, and the occurrence or expression of p53 mutations. Rat liver is known to contain """"""""spontaneously"""""""" initiated cells. Interest in these cells is growing, since they could be involved in the genesis of carcinomas induced by chemical, as well as non-chemical models of hepatocarcinogenesis. At the present time, though, very little is known about the properties of these cells. We are therefore proposing to explore the feasibility of obtaining isolated and purified preparations of these cells for direct study. In humans, the incidence of liver carcinoma is higher in males than in females, and a high association exists between hapatic cancer and chronic conditions of liver damage and repair. The proposed studies are therefore relevant also in the context of the human disease entities.
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