As inhibitors of
3-hydroxy-3-methylglutaryl-CoA reductase,
statins are an important first-line treatment for
hypercholesterolemia. However, a recognized side-effect of
statin therapy is
myopathy, which in severe cases can present as potentially fatal
rhabdomyolysis. This represents an important impediment to successful
statin therapy, and despite decades of research the molecular mechanisms underlying this side-effect remain unclear. Current evidence supports a role for reduced levels of
mevalonate pathway intermediates, with the most accepted hypothesis being a reduction in
isoprenoids formation, leading to faulty post-translational modifications of
membrane-associated proteins. We have undertaken a comprehensive analysis of the impact of nine
statins on two human cell lines; Huh7
hepatoma and RD
rhabdomyosarcoma. In both cell lines, concentration-dependent inhibition of prenylation was observed for
cerivastatin and
simvastatin, which could be rescued with the pathway intermediate
mevalonate; in general, muscle cells were more sensitive to this effect, as measured by the levels of unprenylated Rap1A, a marker for prenylation by geranylgeranyl
transferase I. Concentration-dependent toxicity was observed in both cell lines, with muscle cells again being more sensitive. Importantly, there was no correlation between inhibition of prenylation and cell toxicity, suggesting they are not causally linked. The lack of a causal relationship was confirmed by the absence of cytotoxicity in all cell lines following exposure to specific inhibitors of geranylgeranyl
transferases I and II, and farnesyl
transferase. As such, we provide strong evidence against the commonly accepted hypothesis linking inhibition of prenylation and
statin-mediated toxicity, with the two processes likely to be simultaneous but independent.