Regulation of multidrug resistance-associated protein 2 (ABCC2) by the nuclear receptors pregnane X receptor, farnesoid X-activated receptor, and constitutive androstane receptor

摘要: The multidrug resistance-associated protein 2 (MRP2, ABCC2), mediates the efflux of several conjugated compounds across apical membrane hepatocyte into bile canaliculi. We identified MRP2 in a screen designed to isolate genes that are regulated by farnesoid X-activated receptor (FXR, NR1H4). mRNA levels were induced following treatment human or rat hepatocytes with either naturally occurring (chenodeoxycholic acid) synthetic (GW4064) FXR ligands. In addition, we have shown expression is pregnane X (PXR, NR1I2) and constitutive androstane (CAR, NR1I3). Thus, rodent PXR CAR agonists results robust induction levels. dexamethasone- pregnenolone 16alpha-carbonitrile-dependent was not evident derived from null mice. contrast, phenobarbital, an activator CAR, comparable wild-type An unusual 26-bp sequence 440 bp upstream transcription initiation site contains everted repeat AGTTCA hexad separated 8 nucleotides (ER-8). PXR, bound high affinity this element as heterodimers retinoid alpha (RXRalpha, NR2B1). Luciferase reporter gene constructs containing 1 kb promoter prepared transiently transfected HepG2 cells. activity PXR-, CAR-, FXR-dependent manner. Furthermore, isolated ER-8 capable conferring responsiveness on heterologous thymidine kinase promoter. Mutation abolished nuclear response. These studies demonstrate three distinct signaling pathways converge common response 5'-flanking region gene.