Prooxidative toxicity and selenoprotein suppression by cerivastatin in muscle cells

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.

► Cerivastatin at low non-toxic doses makes muscle cells vulnerable to prooxidants.
► This effect is associated with a suppression of selenoproteins GPx1 and SelN.
► The devitalizing effect of cerivastatin occurs at all selenite concentrations.
► It is fully reversible by mevalonate, but not by ebselen or ubiquinone.
► Atorvastatin shows a similar behavior at higher concentrations.