Calmodulin antagonists suppress cholesterol synthesis by inhibiting sterol Δ²⁴ reductasereductase

Abstract

Preincubation of hepatoma cells and human skin fibroblasts in the presence of the calmodulin antagonists trifluoperazine and N-(6-aminohexyl)-5-chloro-1-naphthalene sulfonamide resulted in a dose-dependent suppression of [¹⁴C] mevalonolactone incorporation into cholesterol. At a calmodulin antagonist concentration of 25 μmol, the incorporation of [¹⁴C] mevalonolactone into cellular cholesterol was suppressed to about 30% (hepatoma cells) and 10% (human skin fibroblasts) of control values. When the total nonsaponifiable [¹⁴C] lipids were separated and analyzed by two-dimensional thin layer chromatography, an accumulation of [¹⁴C] desmosterol was observed along with reduced formation of [¹⁴C] cholesterol. However, when cells were preincubated in the presence of [¹⁴C] dihydrolanosterol, [¹⁴C] cholesterol formation was not inhibited by the calmodulin antagonists. About 25% of the cell-associated dihydrolanosterol radioactivity was converted to cholesterol in both control and calmodulin antagonist-pretreated cells. The data suggest that calmodulin antagonists prevent the conversion of desmosterol into cholesterol by inhibiting sterol Δ²⁴ reductase and that the enzymes catalyzing sterol ring modifications are not affected by the inhibitors.