Several hypolipidemic drugs and industrial plasticizers induce hepatic peroxisome proliferation and hepatocellular carcinomas when fed to rodents. Since plasticizers are used extensively in plastics which contact food and since plasticizers can diffuse from plastics into food, the general population as well as people taking hypolipidemic drugs are exposed to significant amounts of these chemicals. Neither the mechanisms by which these agents, termed peroxisome proliferators, induce hepatocellular carcinomas nor the way in which diet may inhibit peroxisome proliferator-induced carcinogenesis have been determined. Peroxisome proliferators have been shown to act as promoters in liver carcinogenesis, but their initiating activity has never been conclusively demonstrated. Peroxisomal enzymes generate hydrogen peroxide, and increased formation of lipofuscin pigments (an indication of oxidative damage) is associated with the long-term administration of these agents. We therefore propose to test the hypotheses that 1) peroxisome proliferators act as initiators as well as promoters in hepatocarcinogenesis; 2) oxidative damage is responsible for the induction of hepatocarcinogenesis by peroxisome proliferators; and 3) essential dietary antioxidants such as selenium, vitamin E, or vitamin C will protect against oxidative damage induced by peroxisome proliferators and thus inhibit initiation or promotion by these agents. The peroxisome proliferator ciprofibrate will be fed to rats during the initiation phase of two-stage hepatocarcinogenesis and the induction of tumors and putative preneoplastic lesions will be determined. Products of cellular oxidation in hepatocytes after the administration of ciprofibrate to rats and to primary hepatocyte cultures will be measured. Finally, the effect of dietary antioxidants on ciprofibrate- induced hepatocarcinogenesis and on oxidative damage in hepatocytes will be studied. These results may make it possible to derive the benefits of these compounds without the risk of developing hepatic tumors simply by consuming higher amounts of essential dietary antioxidants, such as selenium or vitamins E or C.
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