A number of structurally diverse compounds cause peroxisome and endoplasmic reticulum proliferation in rodent liver. Accompanying this hypertrophy are changes in protein concentrations and enzymatic activities including: the microsomal fatty acid omega-hydroxylase; catalase; the peroxisomal fatty acid beta-oxidation system; the fatty acid binding protein; glutathione peroxidase; and glutathione transferase. Chemicals that induce these organelles are classified as peroxisome proliferators and include clofibrate, a hypolipidemic agent, and diethylhexyl phthalate (DEHP), a common additive of plastics which gives it flexibility. The study of the health hazards of peroxisome proliferators is important for, besides the liver hypertrophy and enzyme changes, they produce hepatocellular carcinomas. There are marked differences in the response of animal species to peroxisome proliferators with rodents the most responsive. It has been difficult to ascertain whether humans also respond to peroxisome proliferators. Since peroxisome proliferators are comprised of structurally divergent compounds, it has been difficult to account for their common induction properties. The concept of a common receptor protein or common endogenous product that may act as the immediate inducer has been proposed. Since phthalate esters may readily migrate from the plastic materials and contaminate the samples that they are in contact with, it is important to understand their biological effects, as plasticizers are used in food containers, health care products, toys, and household goods. In this grant proposal, enzymatic reactions in rat liver that are altered by DEHP-treatment will be studied. The effect of the fatty acid binding protein on enzymatic reactions will be investigated as this protein is increased by DEHP-treatment. The identity of the protein that binds DEHP will be studied for this receptor may account for the different responses in animal species. DEHP-treatment inhibits two important liver enzymes, the glutathione peroxidase and transferase, that metabolize hydrogen peroxide and reactive chemical compounds and their inhibition may account for the hepatotoxicity. The inhibitory effects of DEHP on these enzymes will be studied. Changes in fatty acid composition of liver microsomes have been detected after DEHP administration and the fatty acid composition of other organelles will be determined. The induction of the cytochrome P-450 that omega-hydrolates fatty acids is unique to peroxisome proliferators and the P-450s that catalyze various omega-hydroxylation reactions will be characterized.
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