Effect of prolonged administration of clofibric acid and di-(2-ethylhexyl)phthalate on hepatic enzyme activities and lipid peroxidation in the rat.

Male Sprague-Dawley rats were fed diets containing either 0.5% clofibric acid (CA) or 2% di-(2-ethylhexyl)phthalate (DEHP) for 2 years. Both compounds produced liver enlargement which was accompanied by the formation of liver nodules. Hepatic peroxisomal and microsomal fatty acid oxidising enzyme activities were induced in both large nodules and host tissue (i.e. tissue remaining after removal of large nodules) preparations from CA and DEHP treated rats. In contrast, little change in catalase activity was observed and the activities of cytosolic GSH peroxidase and GSH S-transferases were markedly reduced. Increased lipid peroxidation was observed by measurement of conjugated dienes in host tissue homogenates from CA and DEHP treated rats. Microsomal NADPH-dependent lipid peroxidation was also stimulated. Histological examination revealed extensive lipofuscin deposition in non-nodular, but not in nodular, tissue sections from treated rats. These results demonstrate that prolonged peroxisome proliferation can result in lipid peroxidation and that certain enzymes which metabolise hydrogen peroxide and organic hydroperoxides are either little affected or markedly inhibited.