Several structurally diverse hypolipidemic drugs and some widely used industrial phthalate-ester plasticiers constitute two valuable classes of xenobiotics, capable of inducing peroxisome proliferation in the hepatocytes of rodents and some non-rodent species including primates. Prolonged induction of peroxisome proliferation with these non-mutagenic and non-DNA chemicals, referred to as peroxisome proliferators, leads to the development of hepatocellular carcinomas in rats and mice. PPs are used as valuable tools to investigate the cellular, biochemical, and molecular aspects of hepatic peroxisome proliferation and hepatocarcinogenesis. The proposed hypothesis that PPs exert their pleiotropic effect by interacting with a specific binding protein(s)-(the postulated PP-receptors(s)), and that continued ligand-receptor interaction and activation of a specific set of genes leads to increased synthesis of H202-generating peroxisomal beta-oxidation enzymes, is highly attractive. The resultant PP- receptor interaction and oxidative stress caused by H202- generating beta-oxidation system are postulated to play a role in the initiation and promotion of hepatocarcinogenesis.
The specific aims of the proposed research include: 1) Synthesis of the structural analogs of clofibrate and ciprofibrate and investigation of the structure-biological activity relationship; 2) Establishing the existence of the PP-receptor(s): purification, characterization and preparation of antibodies and synthesis of ligands; 3) Further characterization of the biological, biochemical, and molecular aspects of PP-induced pleiotropic response; 4) Expression of peroxisomal catalase and beta- oxidation genes, and the selected genes of phase I activating and phase II detoxifying enzymes during the development of PP- induced hepatocellular carcinoma in the rat and to compare the biological properties of PP-induced liver tumors with those induced by classical carcinogens; and 5) The in vivo generation of free radicals and formation of hydroxyl free radical adduct of DNA in the livers of rats maintained on PPs.
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