Lipophilic beta-adrenoceptor antagonists stimulate cholesterol biosynthesis in human skin fibroblasts.
The effect of a series of beta-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 beta-blocking potency, selectivity for beta 1 or beta 2 adrenoceptors and partial agonistic activity of the drugs, thus ruling out a beta-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 beta-adrenoceptor antagonists with HMHCoA-reductase, the feed-back regulated rate limiting step of cholesterol biosynthesis.
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D002784:Cholesterol / Q000096:biosynthesis*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D007741:Labetalol / Q000494:pharmacology; D008790:Metoprolol / Q000494:pharmacology; D010869:Pindolol / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D012867:Skin / Q000187:drug effects / Q000378:metabolism*; D013237:Stereoisomerism
D000319:Adrenergic beta-Antagonists; D011412:Propanolamines; C026777:ICI 118551; D002784:Cholesterol; D011433:Propranolol; D010869:Pindolol; D006903:Hydroxymethylglutaryl CoA Reductases; D008790:Metoprolol; D007741:Labetalol