Abstract Title:

Prooxidative Toxicity and Selenoprotein Suppression by Cerivastatin in Muscle Cells.

Abstract Source:

Toxicol Lett. 2012 Oct 20. Epub 2012 Oct 20. PMID: 23092657

Abstract Author(s):

Jessica Fuhrmeister, Martha Tews, Andrea Kromer, Bernd Moosmann

Article Affiliation:

Evolutionary Pathobiochemistry Group, Institute for Pathobiochemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.

Abstract:

Statins are the most widely used drugs for the treatment of hypercholesterolemia. In spite of their overall favourable safety profile, they do possess serious myotoxic potential, whose molecular origin has remained equivocal. Here, we demonstrate in cultivated myoblasts and skeletal muscle cells that cerivastatin at nanomolar concentrations interferes with selenoprotein synthesis and evokes a heightened vulnerability of the cells towards oxidative stressors. A correspondingly increased vulnerability was found with atorvastatin, albeit at higher concentrations than with cerivastatin. In selenium-saturated cells, cerivastatin caused a largely indiscriminate suppression of selenoprotein biosynthesis and reduced the steady state-levels of glutathione peroxidase 1 (GPx1) and selenoprotein N (SelN). Selenite, ebselen, and ubiquinone were unable to prevent the devitalizing effect of statin treatment, despite the fact that the cellular baseline resistance against tert-butyl hydroperoxide was significantly increased by picomolar sodium selenite. Mevalonic acid, in contrast, entirely prevented the statin-induced decrease in peroxide resistance. These results indicate that muscle cells may be particularly susceptible to a statin-induced suppression of essential antioxidant selenoproteins, which provides an explanation for the disposition of these drugs to evoke adverse muscular side-effects.

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