Molecular Mechanism of PXR- and CAR-Dependent Drug Transporter Regulation

5 MOLECULAR MECHANISM OF PXR- AND CAR-DEPENDENT DRUG TRANSPORTER REGULATION 

PXR and CAR cross talk at the DR4(I) element of the -7.8-kb enhancer of MDR1. Competition of both nuclear receptors for binding to DR4(I) has to be anticipated, as they bind to this element with comparable relative affinities [149]. However, cooperative regulation of MDR1 expression by PXR and CAR is also conceivable, as CAR exhibits specific binding to the extended 5 half site of DR4(II). 

3ATT TCACCT PGTTCTCAAGGC PJ AGTTCA TITGAGMlT/ GGC AHTTCA 

In the rat Mrp2 gene, a single ER8 motif in the proximal promoter region at around —0.4 kb was identified, which mediates induction by PXR and CAR [99], Electrophoretic mobility shift assays showed that PXR and CAR bound to this element 

The PXR-mediated induction of rat Slcol a4 was shown to be dependent mainly on a distal cluster of PXR response elements at -8.0kb of the 5 upstream region of the gene [152], Four potential PXR binding sites, arranged as DR3 motifs, were identified in silico in the 5 flanking region of rat Slcol a4. The most proximal motif was found at -5.0kb, whereas the other three clustered at about -8.0 kb. Electrophoretic mobility 

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