Reduction of BM 15.766-induced 7-dehydrocholesterol accumulation by bezafibrate and mevinolin in rats. A non-isotopic in vivo test system for compounds reducing cholesterol synthesis.
The effects of mevinolin, a 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitor and bezafibrate, a modulator of lipoprotein metabolism, were measured on BM 15.766-induced 7-dehydrocholesterol (7-DHC) accumulation in liver and serum of rats. BM 15.766, an inhibitor of delta 7 sterol reductase, leads to an accumulation of 7-DHC, which can be used as a measure of cholesterol (CH) synthesis de novo. The investigations were carried out to evaluate the usefulness of this new non-isotopic in vivo method for testing compounds that affect directly and indirectly the CH-biosynthetic pathway. Mevinolin showed a dose-dependent reduction of BM 15.766-induced 7-DHC accumulation after a single oral dose. The dose range for reduction of 7-DHC in the liver of rats was comparable with that for serum CH-lowering in humans. Bezafibrate reduced the BM 15.766-induced 7-DHC accumulation in liver in a dose- and time-dependent manner. These findings agree with the reported reduced activity of HMG-CoA reductase and support the view, that bezafibrate reduces CH biosynthesis by modulation of lipoprotein metabolism. The 7-DHC levels in serum do not reflect those in the liver and cannot be used as a measure of CH biosynthesis. The investigations show that BM 15.766-induced 7-DHC accumulation in liver of rats is an appropriate measure for CH de novo synthesis and can be used for testing compounds that interfere directly and indirectly with the CH-biosynthetic pathway. In contrast to previously described methods, no radiolabelled precursors are necessary.(ABSTRACT TRUNCATED AT 250 WORDS)
Pill
J
J
Medizinische und Chemische Forschung, Boehringer Mannheim GmbH, Mannheim, Federal Republic of Germany.
Witte
E C
EC
Schmidt
F H
FH
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001629:Bezafibrate / Q000494:pharmacology*; D002775:Cholestadienols / Q000378:metabolism*; D002784:Cholesterol / Q000096:biosynthesis*; D003684:Dehydrocholesterols / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008148:Lovastatin / Q000494:pharmacology*; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D000924:Anticholesteremic Agents; D002775:Cholestadienols; D003684:Dehydrocholesterols; D010879:Piperazines; C047457:BM 15766; D002784:Cholesterol; D008148:Lovastatin; C016705:7-dehydrocholesterol; D001629:Bezafibrate