The proposal is aimed at clarifying the seemingly contradictory effects of hypolipidemic peroxisome proliferators on the induction of liver tumors in experimental animals. While chronic administration of these agents leads to the induction of liver tumors, their short term effects are inhibitory or preventative to the induction of putative preneoplastic lesions. Even though the hypothesis that carcinogenecity of hypolipidemic peroxisome proliferators may be mediated through excess generation of potentially damaging oxygen radicals as a result of sustained elevation of peroxisomal fatty acid oxidation is attractive, our preliminary study indicates that the short term administration of these agents (BR931, DEHP) to rats does not induce peroxidative damage to liver membrane lipids. In this proposal, we will evaluate whether peroxidative damage to cellular macromolecules may be manifested after relatively long term administration of hypolipidemic peroxisome proliferators and/or when the agents are given to aged animals. We will determine the long term effects of these agents on microsomal and nuclear membrane lipid peroxidation and DNA in hepatocytes damage as well as the effects on aged rats. Balance of selected cellular enzymes responsible for the generation of H2O2 (palmitoyl CoA oxidation) and for protection against peroxidative damage (catalase, superoxide dismutases, glutathione-peroxidases, and glutathione, etc) will be evaluated to determine time or age dependent alterations of the enzyme activities. The nature of prevention and regression of carcinogen-induced preneoplastic cells to normal hepatocytes. Finally, the possibility will be scrutinized that the precursor lesions of liver tumors induced by hypolipidemic peroxisome proliferators may not be the commonly accepted lesions of enzyme altered foci. Using various enzyme markers, H3-thymidine radioautography and monoclonal antibodies against putative preneoplastic foci by hypolipidemic peroxisome proliferators will be analyzed to determine whether regression represents selective cell killing or phenotypic reversion of preneoplastic cells, we will analyze cellular changes associated with intermediate stages of chronic administration of these agents. Clarification of possible separate mechanisms (acute and chronic) with which these agents exert their effects on the liver will provide critical information regarding the control of genesis and progression of cancer in general.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA040062-01
Application #
3179507
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1985-07-01
Project End
1988-06-30
Budget Start
1985-07-01
Budget End
1986-06-30
Support Year
1
Fiscal Year
1985
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Hsieh, L L; Shinozuka, H; Weinstein, I B (1991) Changes in expression of cellular oncogenes and endogenous retrovirus-like sequences during hepatocarcinogenesis induced by a peroxisome proliferator. Br J Cancer 64:815-20
Yokota, K; Singh, U; Shinozuka, H (1990) Effects of a choline-deficient diet and a hypolipidemic agent on single glutathione S-transferase placental form-positive hepatocytes in rat liver. Jpn J Cancer Res 81:129-34
Gupta, C; Banks, M; Shinozuka, H (1989) Elevated levels of prostaglandin E2 in the liver of rats fed a choline deficient diet: possible involvement in liver tumor promotion. Cancer Lett 46:129-35
Gupta, C; Hattori, A; Shinozuka, H (1988) Suppression of EGF binding in rat liver by the hypolipidemic peroxisome proliferators, 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio-(N-beta-hydroxyethyl)ac etamide and di(2-ethylhexyl)phthalate. Carcinogenesis 9:167-9
Perera, M I; Betschart, J M; Virji, M A et al. (1987) Free radical injury and liver tumor promotion. Toxicol Pathol 15:51-9
Perera, M I; Katyal, S L; Shinozuka, H (1987) Choline deficient diet enhances the initiating and promoting effects of methapyrilene hydrochloride in rat liver as assayed by the induction of gamma-glutamyltranspeptidase-positive hepatocyte foci. Br J Cancer 56:774-8
Perera, M I; Katyal, S L; Shinozuka, H (1986) Suppression of choline-deficient diet-induced hepatocyte membrane lipid peroxidation in rats by the peroxisome proliferators 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio(N-beta-hydroxyethyl)- acetamide and di(2-ethylhexyl)phthalate. Cancer Res 46:3304-8