Active metabolite of atorvastatin inhibits membrane cholesterol domain formation by an antioxidant mechanism

doi:10.1074/jbc.M513000200

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Papers In Press, published online ahead of print February 7, 2006
J. Biol. Chem, 10.1074/jbc.M513000200
Submitted on December 6, 2005
Revised on January 30, 2006
Accepted on February 7, 2006

Active metabolite of atorvastatin inhibits membrane cholesterol domain formation by an antioxidant mechanism

R. Preston Mason, Mary F. Walter, Charles A. Day, and Robert F. Jacob

Elucida Research LLC, Beverly, PA 01915

Corresponding Author: rpmason{at}elucidaresearch.com

The advanced atherosclerotic lesion is characterized by the formation of microscopic cholesterol crystals which contribute to mechanisms of inflammation and apoptotic cell death. These crystals develop from membrane cholesterol domains, a process that is accelerated under conditions of hyperlipidemia and oxidative stress. In this study, the comparative effects of HMG-CoA reductase inhibitors (statins) on oxidative stress-induced cholesterol domain formation were tested in model membranes containing physiologic levels of cholesterol using small angle x-ray diffraction approaches. In the absence of HMG-CoA reductase, only the atorvastatin active o-hydroxy metabolite (ATM) blocked membrane cholesterol domain formation as a function of oxidative stress. This effect of ATM is attributed to electron donation and proton stabilization mechanisms associated with its phenoxy group located in the membrane hydrocarbon core. ATM inhibited lipid peroxidation in human low-density lipoprotein (LDL) and phospholipid vesicles in a dose-dependent manner, unlike its parent and other statins (pravastatin, rosuvastatin, simvastatin). These findings indicate an atheroprotective effect of ATM on membrane lipid organization through a potent antioxidant mechanism.

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