Several hypolipidemic drugs, plasticizers, perfluorinated fatty acids, and other chemicals induce hepatic peroxisome proliferation and hepatocellular carcinoma when administered to rodents. The mechanism by which these agents induce hepatocellular carcinomas is not known, but likely is related to biochemical changes induced by peroxisome proliferators, since they have never been shown to be genotoxic. Peroxisome proliferators induce cell proliferation and the increased expression of several proteins, including the enzymes of the peroxisomal beta-oxidation pathway, the carnitine acyltransferases, and cytochrome P-450IVA1. The induction of these enzymes causes metabolic changes in hepatocytes, including altered lipid metabolism and increased production of hydrogen peroxide. We therefore propose to test the hypotheses that peroxisome proliferators induce hepatic tumors by 1) the induction of increased hydrogen peroxide production, 2) the induction of long-term cell proliferation, and 3) an alteration of lipid metabolism so as to lead to altered eicosanoid levels. We have found the peroxisome proliferator perfluorodecanoic acid (PFDA) differs from other peroxisome proliferators by inhibiting peroxisomal beta-oxidation, by increasing glutathione concentrations, and by not having promoting activity. This unusual peroxisome proliferator will be examined (and compared to ciprofibrate) for 1) its mechanism of inhibiting peroxisomal beta-oxidation, and thus of inhibiting hydrogen peroxide production, 2) its ability to induce hepatocyte proliferation over a long period of time, 3) its mechanism of increasing cellular glutathione, which may play a role in hydrogen peroxide detoxification, and 4) its ability to induce genotoxicity in the form of hydroxymethyldeoxyuridine and 8-hydroxydeoxyguanosine. Selenium and vitamin I, which were found to alter ciprofibrate-induced carcinogenesis, will also be examined for their ability to influence cell proliferation by ciprofibrate. Finally, the effect of peroxisome proliferators on levels of eicosanoids in hepatocytes, and the effect of altering eicosanoid levels on the induction of peroxisomal enzyme activities, DNA synthesis, and tumor promotion by peroxisome proliferators will be studied. These studies are important for the elucidation of the mechanisms by which peroxisome proliferators induce tumors.
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