The effects of BM 15.766, an inhibitor of 7-dehydrocholesterol delta 7-reductase, on cholesterol biosynthesis in primary rat hepatocytes.
The effect of the piperazine derivative BM 15.766 (4-(2-[1-(4-chlorocinnamyl)piperazin-4-yl]ethyl]-benzoic acid) on the biosynthesis of sterols was investigated in adult rat hepatocytes in primary monolayer culture. The substance led to a dose-dependent reduction of cholesterol in the serum of various species of animals such as rat, dog and marmoset. BM 15.766 showed a dose-dependent action on the incorporation of 14C-acetate in neutral, nonsaponifiable lipids. The inhibition of the overall incorporation was 10-12% (10(-5) M). No inhibition was observed in the hepatocytes over the entire dose range of 10(-8) M to 2 X 10(-5) M, while the release of the neutral lipids from the hepatocytes into the culture medium was reduced by up to 40%. The biosynthesis of cholesterol could be reduced by more than 90%. Simultaneously, 7-dehydrocholesterol levels rose in the cells and, to a less marked extent, in the medium. This can be interpreted as an indication that 7-dehydrocholesterol is incorporated into the cell membrane, which results in a lower release of 7-dehydrocholesterol into the medium in comparison with controls. The site of attack is the inhibition of the delta 5.7-sterol delta 7-reductase. The formation of desmosterol and cholestatrienol as well as other 7-dehydrocholesterol precursors could also be demonstrated. After longer incubation, there was an additional accumulation of squalene and lanosterol with simultaneous reduction of 7-dehydrocholesterol by BM 15.766, whereas the total 14C-acetate incorporation in neutral lipids was increased.
D000085:Acetates / Q000378:metabolism; D019342:Acetic Acid; D000818:Animals; D002250:Carbon Radioisotopes; D002478:Cells, Cultured; D002775:Cholestadienols / Q000378:metabolism*; D002784:Cholesterol / Q000096:biosynthesis*; D003684:Dehydrocholesterols / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D044925:Oxidoreductases Acting on CH-CH Group Donors; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats
D000085:Acetates; D002250:Carbon Radioisotopes; D002775:Cholestadienols; D003684:Dehydrocholesterols; D010879:Piperazines; C047457:BM 15766; D002784:Cholesterol; C016705:7-dehydrocholesterol; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019995:7-dehydrocholesterol reductase; D019342:Acetic Acid