Add time:08/08/2019         Source:sciencedirect.com

The effect of 2-aza-2,3-dihydosqualene, a new compound designed to inhibit the 2,3-oxidosqualene-lanosterol cyclase [A. Duriatti et al., Biochem. Pharmac.34, 3765 (1985)] was studied as inhibitor of cholesterol biosynthesis in Swiss 3T3 fibroblasts. Treatment with the drug of cells which were grown for 2 days in a delipidated medium resulted in a marked decrease of [14C]acetate incorporation into the C27-sterol fraction. An IC50 = 0.3 μM was calculated when the cells were pre-incubated for a period of 4 hr with 2-aza-2,3-dhydrosqualene. This inhibition was correlated with an intracellular 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 precursor-product relationship of the accumulated [14C]squalene oxide(s) and the [14C]sterols was demonstrated in chase experiments in the absence of drug. Sterols more polar than cholesterol were also detected in treated fibroblasts and in the cells which underwent chase experiments; they were mainly composed of 24,25-epoxycholesterol. The C27-[14C]sterols of [14C]acetate pulse labeled cells consisted in a mixture of demosterol and cholesterol; treatment of the cells with 2-aza-2,3-dihydrosqualene resulted in a decreased conversion of desmosterol into cholesterol indicating that the Δ24-sterol reductase might be another target of the drug. 2-Aza-2,3-dihydrosqualene at 1 μM affected normal growth of 3T3 fibroblasts, this effect could be prevented by addition of exogeneous cholesterol (50 μM). Growth arrest of the treated cells was correlated with a decrease in cellular sterol content to less than 40% of controls. About 30% of the C27-sterol fraction, of the treated cells, was desmosterol. Our work demonstrates that 2-aza-2,3-dihydrosqualene is a valuable new inhibitor of cholesterol biosynthesis in mammalian cells.

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