Potent inhibition of cholesterol biosynthesis in 3T3 fibroblasts by N-[(1,5,9)-trimethyldecyl]-4 alpha,10-dimethyl-8-aza-trans-decal-3 beta-ol, a new 2,3-oxidosqualene cyclase inhibitor.
N-[(1,5,9)-trimethyldecyl]-4 alpha,10-dimethyl-8-aza-trans-decal-3 beta-ol, a new compound rationally designed to inhibit the 2,3-oxidosqualene cyclase (M. Taton et al., Biochem. biophys. Res. Commun. 138, 764, 1986) was studied as an inhibitor of cholesterol biosynthesis in Swiss 3T3 fibroblasts. Treatment of cells, which were grown for 2 days in a delipidated medium, resulted in a dramatic decrease of [14C]acetate incorporation into the C27-sterol fraction. An IC50 of 20 nM was calculated, which classes this drug amongst the most powerful cholesterol biosynthesis inhibitors acting at the 2,3-oxidosqualene-lanosterol cyclase tested so far on mammalian cells. The inhibition of the C27-sterols synthesis was correlated with the accumulation of 2,3-[14C]oxidosqualene and of 2,3:22,23-[14C]dioxidosqualene indicating that the cyclase was indeed an intracellular target of the drug. A minor secondary target was identified as the sterol-8-ene isomerase. Cells treated with the inhibitor also accumulated sterols more polar than cholesterol which could originate, for example, from the metabolization of 2,3:22,23-dioxidosqualene. Treatment of the cells with increasing concentrations of the drug resulted in a progressive reduction of the HMG-CoA reductase activity (up to 50% of control). The drug affected normal growth of the fibroblasts and growth arrest was correlated with a decrease in cellular cholesterol content to less than 50% of control. This work indicates that N-[(1,5,9)-trimethyldecyl]-4 alpha,10-dimethyl-8-aza-trans-decal-3 beta-ol is a potent and promising new tool in the inhibition of cholesterol biosynthesis in mammalian cells.
Gerst
N
N
Laboratoire de Biochimie Végétale, Institut de Botanique, Strasbourg, France.
Duriatti
A
A
Schuber
F
F
Taton
M
M
Benveniste
P
P
Rahier
A
A
D000924:Anticholesteremic Agents / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002784:Cholesterol / Q000096:biosynthesis*; D005347:Fibroblasts / Q000378:metabolism; D006903:Hydroxymethylglutaryl CoA Reductases / Q000032:analysis; D019751:Intramolecular Transferases; D007535:Isomerases / Q000037:antagonists & inhibitors*; D007546:Isoquinolines / Q000494:pharmacology*; D013261:Sterols / Q000032:analysis / Q000096:biosynthesis; D013329:Structure-Activity Relationship
D000924:Anticholesteremic Agents; D007546:Isoquinolines; D013261:Sterols; C049832:MDL 28815; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D007535:Isomerases; D019751:Intramolecular Transferases; C021924:lanosterol synthase