Lipophilic β-adrenoceptor antagonists stimulate cholesterol biosynthesis in human skin fibroblasts

The effect of a series of β-adrenoceptor antagonists on cholesterol biosynthesis was studied in vitro in normal human skin fibroblasts. Some, but not all, of the drugs studied stimulated the incorporation of [2-¹⁴C]-acetate into cell sterols in a dose-dependent manner. This effect was unrelated to β-blocking potency, selectivity for β₁ or β₂ adrenoceptors and partial agonistic activity of the drugs, thus ruling out a β-receptor mediated mechanism. A positive, statistically significant correlation was found, however, between the drug lipophilicity and the stimulation of sterol biosynthesis. Propranolol, the most effective agent in increasing [2-¹⁴C]-acetate incorporation into cellular sterols, also enhanced the conversion of 3-hydroxy-3-methylglutaryl CoA (HMGCoA) into mevalonic acid, suggesting an interference of lipophilic β-adrenoceptor antagonists with HMHCoA-reductase, the feed-back regulated rate limiting step of cholesterol biosynthesis.