[Elevation of 7-dehydrocholesterol concentrations in serum and liver and pericentral peroxisome proliferation in hepatocytes of rats after inhibition of cholesterol biosynthesis by BM 15,766].
Sprague-Dawley rats of both sexes were treated for three months with BM 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 microscopy of the liver showed a distinct proliferation of peroxisomes and an increase of dumb-bell shaped mitochondria in the pericentral zone 3. Abnormal-shaped peroxisomes with DAB-negative loops attached to their membranes were found in the intermediate zone 2. These alterations were more accentuated in drug-treated rats fed standard diet, then in treated rats receiving a high-fat and high-cholesterol diet. The observations demonstrate, that the increase of 7-DHC is due to the inhibition of 7-DHC-delta 7-reductase by BM 15.766 and emphasize the zonal heterogeneity of hepatocytes. The relevance of these observations for the investigation of the human Smith-Lemli-Opitz syndrome, in which also decreased plasma-cholesterol levels and an increase of 7-DHC were reported, is discussed.
Weiss
M C
MC
Abteilung für präklinische Forschung, Boehringer Mannheim.
Baumgart
E
E
Fahimi
H D
HD
Pill
H
H
Rebel
W
W
Hartig
F
F
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D002784:Cholesterol / Q000096:biosynthesis*; D003684:Dehydrocholesterols / Q000097:blood / Q000378:metabolism*; D005260:Female; D008099:Liver / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D008830:Microbodies / Q000187:drug effects*; D008930:Mitochondria, Liver / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000924:Anticholesteremic Agents; D003684:Dehydrocholesterols; D010879:Piperazines; C047457:BM 15766; D002784:Cholesterol; C016705:7-dehydrocholesterol
Erhöhung der 7-Dehydrocholesterol-Konzentrationen in Serum und Leber und perizentrale Peroxisomenproliferation in Hepatozyten von Ratten nach Hemmung der Cholesterin-Biosynthese durch BM 15.766.