Effects of lovastatin (mevinolin) on sterol levels and on activity of azoles in Saccharomyces cerevisiae

Abstract

The hypocholesterolemic drug lovastatin (mevinolin) was found to be very effective in lowering the sterol levels of the wild-type yeast Saccharomyces cerevisiae. Lovastatin dramatically decreased the steryl ester content from 2.62 to 0.8 micrograms/mg (dry weight), whereas the free sterol content decreased only from 2.79 to 2.24 micrograms/mg (dry weight) when lovastatin was present in the medium at 10 micrograms/ml. At higher concentrations (100 micrograms/ml), lovastatin nearly abolished the accumulation of steryl esters and decreased the free sterol concentration to less than 1.3 micrograms/mg (dry weight). As a result of the lowered sterol levels, proportional amounts of exogenous sterol were taken up from the medium during aerobic, respiratory conditions. Nearly all of the exogenous sterol taken up was partitioned into the free sterol fraction. The inhibition of sterol esterification in the presence of lovastatin was dependent on heme synthesis. The result of these combined effects caused the MICs of three azole antifungal drugs (ketoconazole, clotrimazole, and miconazole) to be lowered from 6- to 32-fold when lovastatin was present in the medium at 10 micrograms/ml.