The proposal incorporates studies on the mechanism responsible for peroxisome proliferation by hypolipidemic compounds and phthalate ester plasticizers. A number of structurally similar and dissimilar hypolipidemic compounds, specifically designed to lower the lipid levels in hyperlipidemic patients, and a group of phthalate ester plasticizer compounds of industrial importance are known to induce peroxisomes and peroxisomal enzymes in livers of rodent species. The persistence of peroxisome proliferation and peroxisomal long chain fatty acid-oxidation system in liver leads to the development of hepatocellular carcinoma. The present proposal is based on the hypothesis that administration of a peroxisome proliferator leads to the induction in the liver cell of peroxisomal proteins by interacting with a stereospecific binding receptor pool in the cytoplasm. The peroxisome proliferator-receptor complex, in turn, regulates the synthesis of peroxisome specific proteins, a model similar to hormone-receptor complex suggested for estradiol and progesterone in rats and chick oviduct. The proposal describes in detail the physico-chemical characterization of a peroxisome proliferator binding protein, its ligand specificity, organ and tissue specificity, interaction of peroxisome proliferator or metabolite(s) with the receptor. The induction of peroxisomes in liver cells of selected species transplanted at extrahepatic sites will be correlated with the receptor to determine the species differences in the biological response to peroxisome proliferators.
| Lalwani, N D; Alvares, K; Reddy, M K et al. (1987) Peroxisome proliferator-binding protein: identification and partial characterization of nafenopin-, clofibric acid-, and ciprofibrate-binding proteins from rat liver. Proc Natl Acad Sci U S A 84:5242-6 |
| Reddy, J K; Reddy, M K; Usman, M I et al. (1986) Comparison of hepatic peroxisome proliferative effect and its implication for hepatocarcinogenicity of phthalate esters, di(2-ethylhexyl) phthalate, and di(2-ethylhexyl) adipate with a hypolipidemic drug. Environ Health Perspect 65:317-27 |
