The overall objective of the proposed research on the modification of peroxisome proliferator-induced hepatocarcinogenesis is to enhance our present understanding of the mechanism(s) of carcinogenesis by di-(2-ethylhexyl) phthalate (DEHP), a widely used industrial phthalate ester plasticizer, and certain hypolipidemic agents such as ciprofibrate, which constitute two very important classes of peroxisome proliferators. Peroxisome proliferators exert unique biological and biochemical alterations in liver. These include profound proliferation of the cytoplasmic organelle peroxisome and increase in H202 generating peroxisomal long-chain fatty acid Beta-oxidation enzyme system. Since these chemicals are non-mutagenic, non-DNA damaging, and do not form adducts with DNA, it is suggested that their carcinogenicity is due to sustained proliferation of peroxisomes leading to excess generation of H202 and other active oxygen species. The proposed studies of modification of peroxisome proliferator carcinogenesis with antioxidants (vitamin E, and ethoxyquin) and with high-dietary fat should generate new information regarding the role of lipid peroxidation and antioxidants in liver carcinogenesis. This proposal includes studies on: 1) the effect of antioxidant ethoxyquin on carcinogenesis by DEHP; 2) the role of dietary vitamin E on inhibiting peroxisome proliferator carcinogenesis; 3) the role of dietary fat on enhancing peroxisome proliferator carcinogenesis; 4) the effect of ethoxyquin on cell proliferation and growth of putative preneoplastic lesions in liver induced by a peroxisome proliferator; and 5) the effect of ethoxyquin on DNA repair and alterations in protein synthesis and certain enzymes in liver induced by a peroxisome proliferator. It is anticipated that antioxidants may prove useful for individuals who are exposed to phthalate ester plasticizers and those requiring continued use of anti-hyperlipidemic drugs.
