A quantitative analysis of fine structure and drug metabolism in livers of clofibrate-treated young adult and retired breeder rats

The effects of clofibrate on the fine structure and drug-metabolizing capacity of livers of normolipidemic young adult virgin (YA) and hypercholesterolemic retired breeder (RB) male rats were measured by morphometric and biochemical procedures. The oral administration of clofibrate for 7 days significantly increased liver weight and reduced the cholesterol concentrations in the serum and liver tissue in both groups of animals. The hepatic triglyceride (TG) concentration and the volume of cytoplasmic lipid droplets, presumably TG, as well as the serum TG concentration, increased only in the drug-treated RB rats. Clofibrate treatment resulted in significant increases in the volumes of the hepatocytes and their constituent mitochondria and microbodies and caused a proliferation of the smooth-surfaced endoplasmic reticulum. Although the magnitude of the hypocholesterolemic response was considerably greater in the RB animals, the morphological changes were much more marked in the YA group. However, the surface area of the rough-surfaced endoplasmic reticulum was reduced in the livers of the drug-treated RB rats. NADPH cytochrome creductase specific activity was significantly increased in both the RB and YA animals, but the concentration of cytochrome P-450 (per mg microsomal protein) increased only in the YA rats. Neither the cytochrome b5concentration nor the rate of ethylmorphine N-demethylation was significantly affected by clofibrate administration. The results suggest that there is no positive correlation between the hypocholesterolemic response to clofibrate and the degree of subcellular changes in the hepatocytes and that this hypolipidemic drug elicits a minimal effect on the concentrations of the components of the hepatic microsomal drug-metabolizing system.