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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA043719-01A1
Application #
3186019
Study Section
Metabolic Pathology Study Section (MEP)
Project Start
1987-09-01
Project End
1990-08-31
Budget Start
1987-09-01
Budget End
1988-08-31
Support Year
1
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Type
Sch of Home Econ/Human Ecology
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506
Hong, J T; Glauert, H P (2000) Effect of extracellular matrix on the expression of peroxisome proliferation associated genes in cultured rat hepatocytes. Toxicol In Vitro 14:177-84
Espandiari, P; Glauert, H P; Lee, E Y et al. (1999) Promoting activity of the herbicide dicamba (2-methoxy-3, 6-dichlorobenzoic acid) in two stage hepatocarcinogenesis. Int J Oncol 14:79-84
Hong, J T; Glauert, H P (1998) Stimulation of the DNA binding activity of AP-1 by the peroxisome proliferator ciprofibrate and eicosanoids in cultured rat hepatocytes. Toxicology 131:99-107
Leung, L K; Glauert, H P (1997) Lack of correlation between hepatic prostaglandin concentrations and DNA synthesis after the administration of phenobarbital and the peroxisome proliferator ciprofibrate in rats. Toxicology 123:101-9
Glauert, H P; Hong, J T; Leung, L K et al. (1996) Role of eicosanoid metabolism in carcinogenesis by peroxisome proliferators. Ann N Y Acad Sci 804:719-21
Hong, J T; Glauert, H P (1996) Comitogenicity of eicosanoids and the peroxisome proliferator ciprofibrate in cultured rat hepatocytes. J Cell Physiol 169:309-19
Leung, L K; Glauert, H P (1996) Reduction of the concentrations of prostaglandins E2 and F2alpha, and thromboxane B2 in cultured rat hepatocytes treated with the peroxisome proliferator ciprofibrate. Toxicol Lett 85:143-9
Hong, J T; Wilson, M W; Glauert, H P (1995) Effect of phenobarbital and the peroxisome proliferator ciprofibrate on gamma-Glutamyltranspeptidase activity and leukotriene C4 concentration in cultured rat hepatocytes. J Biochem Toxicol 10:239-243
Espandiari, P; Thomas, V A; Glauert, H P et al. (1995) The herbicide dicamba (2-methoxy-3,6-dichlorobenzoic acid) is a peroxisome proliferator in rats. Fundam Appl Toxicol 26:85-90
Berberian, I; Chen, L C; Robinson, F R et al. (1995) Effect of dietary retinyl palmitate on the promotion of altered hepatic foci by 3,3',4,4'-tetrachlorobiphenyl and 2,2',4,4',5,5'-hexachlorobiphenyl in rats initiated with diethylnitrosamine. Carcinogenesis 16:393-8

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