The research proposed in this application is designed to study two aspects of chemical hepatocarcinogenesis: 1) the influence of a dietary deficiency of a single nutritive factor, choline, on tumor induction; and, 2) the nature and functional properties of so-called oval cells. Feeding a diet devoid of choline to rats has been shown to promote the induction of preneoplastic lesions, as well as of hepatocellular carcinomas, by several known chemical carcinogens. Studies are proposed aimed at investigating possible mechanism(s) whereby the diet acts as a promoter of liver carcinogenesis. Mechanisms to be considered are: 1) stimulation of hepatocyte replication; 2) diet and carcinogen-induced changes in the properties of hepatocyte membranes; and, 3) transmethylation reactions involving methylation of hepatocyte macromolecules. The influence of the diet on initiation of liver carcinogenesis will also be investigated. In recent years, a renewed interest has developed about the possibility that bile duct(ular) cells, beside hepatocytes, may also be target cells of chemical hepatocarcinogens, and progenitors, in certain instances, of hepatocellular carcinomas as well as of cholangiocarcinomas. Proliferation of bile duct(ular) cells, with emergence of so-called oval cells, is a common, early event occurring in the liver of rats exposed to chemial carcinogens. Studies are proposed aimed at achieving the isolation of homogeneous preparations of oval cells from the liver of carcinogen-treated rats; at investigating some of the metabolic and biologic properties of these cells; and, at probing whether these cells do indeed play any role in the genesis of epithelial liver tumors.
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