Suppression of statin effectiveness by copper and zinc in yeast and human cells

Abstract

Summary Lovastatin and other statins inhibit HMG-CoA reductase, which carries out an early step in the sterol biosynthesis pathway. Statins lower cholesterol and are widely prescribed to prevent heart disease, but like many drugs, they can interact with nutritionally acquired metabolites. To probe these interactions, we explored the effect of a diverse library of metabolites on statin effectiveness using a Saccharomyces cerevisiae model. In yeast, treatment with lovastatin results in reduced growth. We combined lovastatin with the library of metabolites, and found that copper and zinc ions impaired the ability of the statin to inhibit yeast growth. Using an integrated genomic and metabolomic approach, we found that lovastatin plus metal synergistically upregulated some sterol biosynthesis genes. This altered pattern of gene expression resulted in greater flux through the sterol biosynthesis pathway and an increase in ergosterol levels. Each sterol intermediate level was correlated with expression of the upstream gene. Thus, the ergosterol biosynthetic response induced by statin is enhanced by copper and zinc. In cultured mammalian cells, these metals also rescued statin growth inhibition. Because copper and zinc impair the ability of statin to reduce sterol biosynthesis, dietary intake of these metals could have clinical relevance for statin treatment in humans.

The effects of statins on the mevalonic acid pathway in recombinant yeast strains expressing human HMG-CoA reductase

“…Here, statins substantially lowered the level of ergosterol and (in most instances) much more strongly the levels of all its triterpene precursors (Table 1). This is in accordance with the results of Fowler et al [27] showing a profound decrease of ergosterol level and an even deeper depletion of its precursors in lovastatin-treated yeast cells. Both these results indicate that following HMGR inhibition the yeast cell, whether it expresses the native enzyme [27] or the human one (this work), increases the rate of precursor conversion into ergosterol in an attempt to maintain the supply of this vital sterol.…”

Topical Simvastatin as Host-Directed Therapy against Severity of Cutaneous Leishmaniasis in Mice

“…Perhaps more interesting is that the observed reduction in parasite growth might be a direct effect of statins on the L. major HMG-CoA reductase 26 . Several other studies have reported a direct anti-fungal role for statins in extracellular culture 27 28 29 . In contrast, we observed no effect on extracellular growth of L. major promastigote parasites in presence of simvastatin at various concentrations tested (data not shown).…”

Integrative phenomics reveals insight into the structure of phenotypic diversity in budding yeast

“…We extracted metabolites (Supplemental Note) and performed derivatizations as previously described (Fowler et al 2011). All metabolite analysis was done on a Leco Pegasus 4D system (GC3GC-TOFMS).…”