title: Prooxidative toxicity and selenoprotein suppression by cerivastatin in muscle cells.
abstract: Statins are the most widely used drugs for the treatment of hypercholesterolemia. In spite of their overall favorable 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 toward 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.
authors.affiliation: Evolutionary Pathobiochemistry Group, Institute for Pathobiochemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Fuhrmeister
authors.forename: Martha
authors.initials: M
authors.lastname: Tews
authors.forename: Andrea
authors.initials: A
authors.lastname: Kromer
authors.forename: Bernd
authors.initials: B
authors.lastname: Moosmann
mesh_terms: D000818:Animals; D000069059:Atorvastatin; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006538:Heptanoic Acids / Q000633:toxicity; D006861:Hydrogen Peroxide; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000633:toxicity*; D008798:Mevalonic Acid / Q000031:analogs & derivatives; D051379:Mice; D032446:Myoblasts / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects*; D011725:Pyridines / Q000633:toxicity*; D011758:Pyrroles / Q000633:toxicity; D051381:Rats; D012643:Selenium / Q000378:metabolism / Q000494:pharmacology; D051140:Selenoproteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011725:Pyridines; D011758:Pyrroles; D051140:Selenoproteins; C015367:mevalonolactone; D000069059:Atorvastatin; C086276:cerivastatin; D006861:Hydrogen Peroxide; D012643:Selenium; D008798:Mevalonic Acid