Inhibitory Effects on Lipid Metabolismn in Cultured Cells of ML‐236B, a Potent Inhibitor of 3‐Hydroxt‐3‐methylglutaryl‐Cornzyme‐A Reductase

Abstract

Effects of ML‐236B, a potent competiove inhibitor 3‐hydrocy‐3‐methyglutaryl‐CoA reductase, on the lipiod metabolism were studied using mouse L cells and human smin fibrobalsts. ML‐236B completely inhibited sterol sythesis from both [14 C]acetate and [14 C]octanoate in these cells at a tconcentration of 0.5 μg/ml (11.117 μM). withour affecting thqat form [14 C]mevalonate. Syntheses of other lipids adn macromolecules like DNA, RNA and protein were not affected at concentrations up to 5 μg/ml. Concentrations of ML‐236B giving 50% inhibitionof sterol synthesis for [14 C]acetate were as low homozygote with familial hypercholesteroloemia. The ML‐236B‐mediated inhibition of sterol syunthesis was readitly reversivle. The complkete inhibition of endogenous sterol synthesis at a higher concentration (5μg/ml) of ML‐236‐B caused a marked inhibition of cell growth even in the presence of exogenous cholesterol contained in while gfatel calf serum as lipoproteins. This inhivition of growth was prevented by teh presence in the culture medium of mevalonate, but not by acetate, thus indficating that ML‐236B inhibit cell growth by specifically interferring with mevalonate wynthesis. It is further concluded thjat slight activity of endogenous sterol synthesis, which provides enfogenous copounds generated from meavalonate, may be essential to the growth of cells even when sufficeient amounts of cholesterol are availavel to the cells.