MECHANISM OF DI(2-ETHYLHEXYL)PHTHALATE HEPATOTOXICITY

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In a two-year toxicology/carcinogenicity study conducted by the National Toxicology Program, di(2-ethylhexyl)phthalate (DEHP) was found to be hepatocarcinogenic in B6C3F1 mice and F334 rats. Since DEHP also causes peroxisome proliferation, it has been suggsted that the carcinogenicity of this chemical may be related to excessive peroxisomal production of H202. It is the objective of this project to examine the changes in H2O2 concentrations resulting from peroxisomal fatty acyl-CoA oxidation and catalase activity in livers of rats and mice treated with DEHP. Further assessment of an involvement of ractive intermediates of oxygen reduction in DEHP induced hepatotoxicity will be made from measurements of (a) activities of enzymes that eliminate toxic oxygen products (catalase, superoxide dismutase, glutathione peroxidase), (b) lipid peroxidation, and (c) superoxide anion radical production. New studies have begun to characterize the chemical requirements for induction of peroxisome proliferation in isolated rat hepatocytes.