Regulation Of Mrp2 Expression Research Articles

Effect of hypoxia on expression of multidrug resistance protein 2 and its regulation mechanism

Drug efflux transporters plays a key role in pharmacokinetics parameters changes. In recent years, in addition to P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), MRP2 has become an advanced research hotspot. Several signaling pathways andtranscription factors have been reported to be involved in regulation of MRP2 expression in hypoxic microenvironment of tumor, such as peroxisome proliferators-activated receptors (PPARα), nuclear factor κB (NF-κB), pregnane X receptor (PXR), farnesoid X receptor (FXR), constitutive androstane receptor (CAR) and microRNA. But it is not fully understood how MRP2 is regulated under hypoxia. MRP2 is one of the most important efflux transporter proteins. Many drugs or inhibitors have been shown to be its substrate. In the hypoxic environment, changes in expression of MRP2 can significantly affect drug's pharmacokinetics (absorption, distribution, metabolism, excretion). Simultaneously, the regulation of MRP2 expression under hypoxic might involve several signal pathways and many genes, which constitute an integral gene regulatory networks.

Glutamate-mediated upregulation of the multidrug resistance protein 2 in porcine and human brain capillaries.

As a member of the multidrug-resistance associated protein (MRP) family, MRP2 affects the brain entry of different endogenous and exogenous compounds. Considering the role of this transporter at the blood-brain barrier, the regulation is of particular interest. However, there is limited knowledge regarding the factors that regulate MRP2 in neurologic disease states. Thus, we addressed the hypothesis that MRP2 might be affected by a glutamate-induced signaling pathway that we previously identified as one key mechanism in the regulation of P-glycoprotein. Studies in isolated porcine brain capillaries confirmed that glutamate and N-methyl-d-aspartic acid (NMDA) exposure upregulates expression and function of MPR2. The involvement of the NMDA receptor was further suggested by the fact that the NMDA receptor antagonist MK-801 [(5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine], as well as the NMDA receptor glycine binding site antagonist L-701,324 [7-chloro-4-hydroxy-3-(3-phenoxy)phenyl-2(1H)-quinolinone], prevented the impact of glutamate. A role of cyclooxygenase-2 was indicated by coincubation with the cyclooxygenase-2 inhibitor celecoxib and the cyclooxygenase-1/-2 inhibitor indomethacin, which both efficaciously abolished a glutamate-induced upregulation of MRP2. Translational studies in human capillaries from surgical specimen demonstrated a relevant MRP2 efflux function and indicated an effect of glutamate exposure as well as its prevention by cyclooxygenase-2 inhibition. Taken together the findings provide first evidence for a role of a glutamate-induced NMDA receptor/cyclooxygenase-2 signaling pathway in the regulation of MRP2 expression and function. The response to excessive glutamate concentrations might contribute to overexpression of MRP2, which has been reported in neurologic diseases including epilepsy. The overexpression might have implications for brain access of various compounds including therapeutic drugs.

466 Post-transcriptional regulation of MRP2 expression

466 Post-transcriptional regulation of MRP2 expression