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 ,ug/mg (dry weight), whereas the free sterol content decreased only from 2.79 to 2.24 ,ug/mg (dry weight) when lovastatin was present in the medium at 10 ,ug/ml. At higher concentrations (100 ,ug/ml), lovastatin nearly abolished the accumulation of steryl esters and decreased the free sterol concentration to less than 1.3 ,ug/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 aUl 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 Fg/ml.

Simvastatin Inhibits Candida albicans Biofilm In Vitro

“…An inhibitor of squalene synthetase, an intermediate step in the cholesterol pathway, blocked staphyloxanthin production and attendant virulence in Staphylococcus aureus (43). Lovastatin-mediated growth inhibition has been reported for several pathogenic and nonpathogenic yeasts and one mold (31,39,44). For example, 100 M simvastatin or atorvastatin inhibited growth of four Candida species (C. albicans, tropicalis, glabrata, and parapsilosis) as well as Aspergillus fumigatus (36).…”

Inhibition of Sterol Biosynthesis Reduces Tombusvirus Replication in Yeast and Plants

“…To test this possibility, we also applied lovastatin, which is a potent inhibitor of hydroxymethylglutaryl-coenzyme A (HMGCoA) reductase (coded by the HMG1 and HMG2 genes in yeast), a rate-limiting enzyme in the mevalonate pathway that regulates cholesterol synthesis. Lovastatin acts as a competitive inhibitor of HMG-CoA reductase, effectively lowering sterol levels in yeast (11,27). The application of lovastatin reduced TBSV repRNA accumulation in yeast by 4-fold (Fig.…”

SUT1 is a putative Zn[II]2Cys6‐transcription factor whose upregulation enhances both sterol uptake and synthesis in aerobically growing Saccharomyces cerevisiae cells

“…The transfer reaction was performed at 30 8C with shaking and was started by the addition of the cell suspension at a final density of D 600 20 U´mL 21 into Tris/EDTA buffer containing 100 mg´mL 21 [4][5][6][7][8][9][10][11][12][13][14] C]cholesterol at a specific activity of 10 000 d.p.m.´mg 21 and dissolved in Tergitol/ ethanol. The final concentration of Tergitol/ethanol was 4%.…”

“…Samples were applied on silica gel plates (Silica Gel 60, Merck), and the plates were developed with hexane/ diethyl ether/acetic acid (70 : 30 : 2, v/v/v). The amounts of free and esterified [4][5][6][7][8][9][10][11][12][13][14] C]cholesterol were quantified by scanning the TLC plate with an Automatic TLC-linear analyser (LB2832, Berthold).…”

“…The level of endogenous sterol was shown to modulate the efficiency of sterol uptake which is inversely proportional to the endogenous sterol level [12,13]. Moreover, heme was described as a major factor negatively regulating sterol uptake [1,13,14].…”