PATHOBIOLOGY OF HIGH DOSE SUCROSE

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We have recently developed a new model of hepatocarcinogenesis in the rat based on initiation by diethylnitrosamine (DEN) and promotion by high levels of sucrose. This model is of interest in studies on mechanism of promotion since, at variance with those using phenobarbital, DDT, PCBs, etc., it does not require the administration of chemicals or drugs during the promoting phase. To determine if the promotion effect of sucrose is related to the disaccharide molecule per se, the combination of glucose and fructose, or the fructose moiety alone, short-term induction- promoting experiments will be conducted. In addition, long-term experiments will be carried out to corroborate that the results of the short-term studies are definitely related to promotion activity. Since high levels of sucrose can result in increased levels of cholesterol and phospholipids, morphologic perturbations in properties of the cell membrane of hepatocytes obtained from preneoplastic nodules will be studied by the use of freeze-fracture electron microscopy. Among the membrane phospholipids whose function could change are those phosphoinositides which activate Protein Kinase C. To examine whether the complex of phosphoinositides-Proteins Kinase C is changed in enzyme-altered foci, the enzyme compartmentalization and down regulation will be studied. An effect commonly observed in promoted cells is the inhibition of intercellular communication. Its existence in high- sucrose promoted cells will be determined by freeze-fracture electron microscopy and by measuring the inhibition of metabolic cooperation in tissues cultured from preneoplastic cells. Freeze- fracture will be utilized in the study of qualitative and quantitative changes of gap-junctions. Metabolic cooperation will be analyzed by the long term and also by a recently developed technique with short term exposure time after loading the test mixture. These studies should help to clarify the nature of the promotion by sucrose and the role of the possible alterations in the membrane lipids.