SUMOylation of pregnane X receptor suppresses rifampicin-induced CYP3A4 and P-gp expression and activity in LS174T cells

The pregnane x receptor (pxr) has been well-established as a critical mediator in regulating important drug metabolizing enzymes and transporter proteins,including cytochrome p450 3a4 (cyp3a4) and p-glycoprotein (p-gp). previous studies identified that pxr served as a molecular target of sumoylation. however,the impact of sumoylation of pxr on its transcriptional activity in regulating the expression/activity of the target genes is poorly investigated. in the current study,we established cell-based models of sumoylated pxr in ls174t cells to investigate the impact of sumoylation of pxr on regulating the expression/activity of cyp3a4 and p-gp. our results revealed that rifampicin-induced pxr transactivation of the cyp3a4 and p-gp promoter was suppressed by sumoylation of pxr in reporter gene assay. the mrna and protein expression of cyp3a4 and p-gp was also suppressed. moreover,cyp3a4 enzymatic assay and rho123 intracellular assay revealed that rifampicin-induced cyp3a4 and p-gp activity was also suppressed by sumoylated pxr. our data collectively indicated for the first time that sumoylation of pxr exerts suppressive effect on rifampicin-induced expression and activity of cyp3a4 and p-gp,which suggest that alteration in the sumoylation status of pxr will be expected to affect the cyp3a4 mediated drug metabolism and p-gp mediated drug transport. © 2015 japanese pharmacological society.