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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA043719-06
Application #
2091238
Study Section
Metabolic Pathology Study Section (MEP)
Project Start
1987-09-01
Project End
1995-03-31
Budget Start
1993-04-01
Budget End
1995-03-31
Support Year
6
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Nutrition
Type
Other Domestic Higher Education
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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