PT - JOURNAL ARTICLE AU - Tadeja Rezen AU - Mateja Hafner AU - Sandhya Kortagere AU - Sean Ekins AU - Vesna Hodnik AU - Damjana Rozman TI - Rosuvastatin and Atorvastatin are Ligands of the Human CAR/RXRα Complex AID - 10.1124/dmd.117.075523 DP - 2017 Jan 01 TA - Drug Metabolism and Disposition PG - dmd.117.075523 4099 - http://dmd.aspetjournals.org/content/early/2017/05/23/dmd.117.075523.short 4100 - http://dmd.aspetjournals.org/content/early/2017/05/23/dmd.117.075523.full AB - Statins are well known lipid lowering agents that inhibit the enzyme HMG-CoA reductase. They also activate drug metabolism but their exact receptor-mediated action has not been proven so far. The aim of this study was to test if atorvastatin and rosuvastatin are direct ligands of human CAR. We measured binding activities of atorvastatin and rosuvastatin to the human 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 modelling. 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. In conclusion, 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.