Molecular basis of differences among statins and a comparison with antioxidant vitamins

Although all statin drugs lower levels of circulating low-density lipoprotein cholesterol by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A, molecular differences among statins affect their metabolism, solubility, and intramembrane localization, which in turn is likely to influence their efficacy and safety. In addition, these properties may have a differential impact on the pleiotropic effects of statins, including their ability to improve endothelial function and to affect proliferation and apoptosis in vascular tissues. Many pleiotropic effects of statins appear to be due to inhibition of small guanosine triphosphate-binding proteins and/or restoration of nitric oxide bioavailability, and atorvastatin metabolites may also directly protect vascular tissues from oxidative damage. The possibility of cardiovascular benefits from antioxidant effects of atorvastatin metabolites contrasts with the lack of benefits seen in most studies of antioxidant vitamins. This article reviews some of the differences in pleiotropic effects of statins and assesses the contribution of their solubility and membrane localization as the possible basis for these differences. In addition, the possibility that statin benefits on stroke reflect pleiotropic effects is reviewed. Finally, possible reasons for differences between the effects of atorvastatin metabolites and antioxidant vitamins are considered.