The orphan nuclear receptor SXR coordinately regulates drug metabolism andefflux

Cytochrome P450 3A4 is an important mediator of drug catabolism that can be regulated by the steroid and xenobiotic receptor (SXR). We show here that SXR also regulates drug efflux by activating expression of the gene MDR1, w hich encodes the protein P-glycoprotein (ABCB1). Paclitaxel (Taxol), a comm only used chemotherapeutic agent, activated SXR and enhanced P-glycoprotein -mediated drug clearance. In contrast, docetaxel (Taxotere), a closely rela ted antineoplastic agent, did not activate SXR and displayed superior pharm acokinetic properties. Docetaxel's silent properties reflect its inability to displace transcriptional corepressors from SXR. We also found that ET-74 3, a potent antineoplastic agent, suppressed MDR1 transcription by acting a s an inhibitor of SXR. These findings demonstrate how the molecular activit ies of SXR can be manipulated to control drug clearance.