INCREASE OF 7-DEHYDROCHOLESTEROL IN SERUM AND LIVER AND PERICENTRAL PROLIFERATION OF PEROXISOMES IN THE LIVER OF RATS AFTER SEVERE INHIBITION OF CHOLESTEROL-BIOSYNTHESIS BY BM-15.766

Sprague-Dawley rats of both sexes were treated for three months with B M 15.766, an inhibitor of cholesterol biosynthesis in conjunction with standard or high-fat and high-cholesterol diets. In serum and Livers of all drug-treated rats lowered cholesterol concentration associated with an increase of 7-dehydrocholesterol (7-DHC) was found. Electron m icroscopy of the liver showed a distinct proliferation of peroxisomes and an increase of dumb-bell shaped mitochondria in the pericentral zo ne 3. Abnormal-shaped peroxisomes with DAB-negative loops attached to their membranes were found in the intermediate zone 2. These alteratio ns were more accentuated in drug-treated rats fed standard diet, then in treated rats receiving a high-fat and high-cholesterol diet. The ob servations demonstrate, that the increase of 7-DHC is due to the inhib ition of 7-DHC-delta7-reductase by BM 15.766 and emphasize the zonal h eterogeneity of hepatocytes. The relevance of these observations for t he investigation of the human Smith-Lemli-Opitz syndrome, in which als o decreased plasma-cholesterol levels and an increase of 7-DHC were re ported, is discussed.