MOLECULAR DETERMINANTS OF PEROXISOME PROLIFERATOR ACTION

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Peroxisome proliferators elicit marked hepatic proliferation and hepatocellular carcinoma when administered to rodents. At least seventy chemicals have been identified as peroxisome proliferators including the industrial phthalate ester plasticizer di-(2-ethylhexyl)phthalate (DEHP), chlorphenoxyacetic acid herbicides, halogenated hydrocarbon solvents and some anti-hyperlipidemic drugs. Human exposure to the peroxisome proliferating agents and rodent carcinogen DEHP is well documented as it is used extensively in the manufacture of polyvinylchloride plastics to render these materials more flexible. Biological effects of peroxisome proliferators appear to be mediated via an interaction with a specific intracellular receptor protein, peroxisome proliferator-activated receptor alpha (PPARalpha), a member of the steroid/thyroid hormone receptor superfamily of ligand-dependent transcription factors. Preliminary data have been obtained suggesting that some peroxisome proliferating agents bind directly to and induce conformational changes within recombinant mouse PPARalpha (mPPARalpha). Toward the goal of a molecular description of peroxisome proliferator action, the object of this project is to test the following hypothesis: (1) the industrial phthalate ester plasticizer di-(2-ethylhexyl)phthalate and its primary metabolite mono-(2- ethylhexyl)phthalate interact directly with mRRAPalpha; (2) ligand binding by mPPARalpha is a two-step process involving ligand recognition and a subsequent ligand binding-induced receptor conformational change resulting in the formation of a unique protein interaction interface within the ligand binding domain of the receptor; (3) heterodimerization with retinoid X receptor alpha (RXRalpha) alters the conformation and function of the mPPARalpha ligand binding domain; (4) binding of mPPARalpha to peroxisome proliferator response elements requires prior dimerization with RXRalpha; and (5) ligand-induced mPPARalpha conformational changes promotes interaction of the receptor with distinct cellular proteins that serve to couple the receptor to the basic transcriptional machinery. The long-term goal of this project is to provide a complete understanding of the role of mPPARalpha-mediated transcriptional activation in peroxisome proliferation and hepatocellular carcinoma. Because of the potential for wide-spread human exposure, a better understanding of the mechanism(s) underlying the biological effects of peroxisome proliferators will be of critical importance in determining the hazard that these compounds pose to public health.