Abstract

Statins are well known lipid lowering agents that inhibit the enzyme 3-hydroxy-3-methylglutaryl–CoA (HMG-CoA) reductase. They also activate drug metabolism but their exact receptor-mediated action has not been proven so far. We tested whether atorvastatin and rosuvastatin are direct ligands of human constitutive androstane receptor (CAR). We measured binding activities of atorvastatin and rosuvastatin to the human constitutive androstane receptor/retinoid X receptor α ligand-binding domain (CAR/RXRα-LBD) heterodimer with surface plasmon resonance (SPR). Additionally, three-dimensional models of CAR/RXRα-LBD were constructed by ligand-based and structure-based in silico modeling. Experiments and computational modeling show that atorvastatin and rosuvastatin bind to the human CAR/RXRα-LBD heterodimer, suggesting both can modulate the activity of CAR through direct interaction with the LBD of this receptor. We confirm that atorvastatin and rosuvastatin are direct ligands of CAR. The clinical consequences of CAR activation by statins are in their potential drug-drug interactions, and changes in glucose and energy metabolism.