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Suppression of statin effectiveness by copper and zinc in yeast and human cells
Douglas M Fowler1, Sara J Cooper, Jason J Stephany
1Department of Genome Sciences, University of Washington, Box 355065, Seattle, WA 98195, USA.
Abstract:
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.
Insights
Copper and zinc ions reduce the effectiveness of lovastatin (a cholesterol-lowering drug) by enhancing sterol biosynthesis. This interaction, observed in yeast and mammalian cells, suggests dietary metal intake may impact statin treatment efficacy in humans.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Statins, including lovastatin, are crucial for managing cholesterol and preventing heart disease by inhibiting HMG-CoA reductase in the sterol biosynthesis pathway.
- Nutritional metabolites can interact with drug efficacy, necessitating investigation into these complex biological relationships.
Purpose of the Study:
- To investigate how various metabolites affect statin effectiveness.
- To explore the specific interactions between copper, zinc, and lovastatin in biological systems.
Main Methods:
- Utilized a Saccharomyces cerevisiae model to screen a metabolite library for interactions with lovastatin.
- Employed integrated genomic and metabolomic approaches to analyze gene expression and metabolite levels.
- Validated findings in cultured mammalian cells.
Main Results:
- Copper and zinc ions were identified as significantly impairing lovastatin's ability to inhibit yeast growth.
- Lovastatin combined with metal ions synergistically upregulated sterol biosynthesis genes, increasing flux and ergosterol levels.
- These metals also rescued statin-induced growth inhibition in mammalian cells.
Conclusions:
- Copper and zinc enhance the sterol biosynthesis response to statins.
- Dietary intake of copper and zinc may have clinical implications for individuals undergoing statin therapy.
- Understanding these metal-statin interactions is crucial for optimizing cardiovascular disease prevention strategies.
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