EFFECTS OF DEHP ON LIVER

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Di-(2-ethylhexyl)phthalate (DEHP) is a plasticizer that is used in the manufacture of polyvinyl plastics. Since DEHP is not polymerized in the plastic, it may migrate from plastic containers and contaminate food, water, blood components, or may be ingested directly from the plastic. DEHP is a potent inducer of the microsomal fatty acid omega-hydroxylation and peroxisomal fatty acid beta-oxidation systems in rates, but other species such as hamsters, guinea pigs, and humans are reported to be less responsive to DEHP treatment. DEHP is reported to have a variety of toxic effects in the rate, but its effects on other species have not been studied. DEHP has become a controversial subject, because of its widespread use as a plasticizer and its possible toxic effects. Government regulatory bodies must decide if DEHP usage should be restricted. This proposal will determine the specific activities of hydroxylation of fatty acids and the hydrolysis product of DEHP, mono-ethylhexyl phthalate (MEHP) in rats, hamsters, guinea pigs, and human microsomes. The results of this study will determine if a species specificity exists in the metabolism of phthalates. The induction of microsomal and peroxisomal enzymes will be studied in DEHP-treated animals and in primary hepatocyte cultures treated with MEHP for 1 to 5 days. The cytochrome P-450 that catalyzes the omega-hydroxylation of fatty acids that is induced by DEHP-treatment will be isolated and characterized. Quantitation of the P-450 induced by DEHP will be performed in livers and extrahepatic organs of control and DEPH-treated rats by Western blot analysis. The microsomes will be subjected to electrophoresis and the selective identification of the P-450 that mediates omega-hydroxylation by its antibody. The antibody and antigen complex will be quantitated by comparison with standard curves. The effects of DEHP also will be studied in perfused rat livers by examining the detoxification of hydrogen peroxide as measured by the release of glutathione disulfide. the accumulation of lipid peroxidation by-products and the incorporation of omega-oxidized fatty acid derivatives into phospholipids will be measured. These studies will help characterize the acute biochemical effects of DEHP on liver cells.