Multidrug resistance protein 1 protects the choroid plexus epithelium and contributes to the blood-cerebrospinal fluid barrier.
@article{Wijnholds2000MultidrugRP, title={Multidrug resistance protein 1 protects the choroid plexus epithelium and contributes to the blood-cerebrospinal fluid barrier.}, author={Jan Wijnholds and Elizabeth C. M. DeLange and George L. Scheffer and D J van den Berg and C A Mol and Martin A. van der Valk and Alfred H. Schinkel and Rik J. Scheper and D. D. Breimer and Piet Borst}, journal={The Journal of clinical investigation}, year={2000}, volume={105 3}, pages={ 279-85 } }
Multidrug resistance protein 1 (MRP1) is a transporter protein that helps to protect normal cells and tumor cells against the influx of certain xenobiotics. We previously showed that Mrp1 protects against cytotoxic drugs at the testis-blood barrier, the oral epithelium, and the kidney urinary collecting duct tubules. Here, we generated Mrp1/Mdr1a/Mdr1b triple-knockout (TKO) mice, and used them together with Mdr1a/Mdr1b double-knockout (DKO) mice to study the contribution of Mrp1 to the tissue…
356 Citations
Mrp4 Confers Resistance to Topotecan and Protects the Brain from Chemotherapy
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The topotecan resistance of cells overexpressingMrp4 and the polarized expression of Mrp4 in the choroid plexus and brain capillary endothelial cells indicate that Mr p4 has a dual role in protecting the brain from cytotoxins and suggest that the therapeutic efficacy of central nervous system-directed drugs that are Mrp3 substrates may be improved by developing Mrp 4 inhibitors.
Differential, strain-specific cellular and subcellular distribution of multidrug transporters in murine choroid plexus and blood–brain barrier
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Differential expression of the multidrug resistance‐related proteins ABCb1 and ABCc1 between blood‐brain interfaces
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There are major differences in the mechanisms by which blood‐brain interfaces fulfill their neuroprotective functions, and the data highlight the significance of the neuroProtective function of the choroid plexus during brain maturation, when the microvasculature is still developing.
Functional Expression of the Multidrug Resistance Protein 1 (MRP1) in Microglia.
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Strong that the MRP1 is both and functional in also suggest that can act as a “second” barrier to drug and regulate brain distribution/accumulation of various xenobiotics including protease (SAQ), 10 µ M ritonavir (RIT), or 50 µ M indinavir (IND).
Apparent Lack of Mrp1-Mediated Efflux at the Luminal Side of Mouse Blood-Brain Barrier Endothelial Cells
- Biology, MedicinePharmaceutical Research
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Efflux mediated by mrp1 does not seem to occur across the luminal membrane of the endothelial cells forming the mouse BBB, indicating that the BBB remained intact.
Multidrug resistance protein 2 (MRP2) transports HIV protease inhibitors, and transport can be enhanced by other drugs
- Biology, MedicineAIDS
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Human MRP2 actively transports several HPI and could, based on its known and assumed tissue distribution, therefore reduce HPI oral bioavailability and may also limit brain and fetal penetration of these drugs and increase their hepatobiliary, intestinal and renal clearance.
Multidrug Resistance-Associated Proteins: Expression and Function in the Central Nervous System
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It is proposed that these primary and secondary barriers work in tandem to limit overall accumulation and distribution of xenobiotics in the central nervous system.
Expression of HNF4alpha in the human and rat choroid plexus – Implications for drug transport across the blood-cerebrospinal-fluid (CSF) barrier
- BiologyBMC Molecular Biology
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This study evidences activity of HNF4alpha in human and rat choroid plexus and targets DMEs and drug transporters and may well determine availability of drugs at the blood-CSF barrier.
References
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It is shown that the lack of mrp1 protein results in increased etoposide-induced damage to the mucosa of the oropharyngeal cavity and to the seminiferous tubules of the testis, and specific inhibitors of MRP1 used to reverse MDR might lead to drug-induced mucositis, (temporary) infertility, and diabetes insipidus.
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Together, these transporters may coordinate secretion and reabsorption of natural product substrates and therapeutic drugs, including chemotherapeutic agents, antipsychotics, and HIV protease inhibitors, into and out of the central nervous system.
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Tissue distribution of the multidrug resistance protein.
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The presence of MRP in bronchiolar epithelium, heart muscle, and macrophages would agree with the glutathione S-conjugate carrier activity previously detected in these cells, and in 46 of 119 untreated tumors from various histogenetic origins MRP staining was seen.
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The results suggest that this ubiquitous GS-X pump, which mediates the cellular excretion of many drugs, glutathione S-conjugates of lipophilic xenobiotics and endogenous cysteinyl leukotrienes, is dispensable in mice, making treatment of MDR with MRP-specific reversal agents potentially feasible.
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P-glycoprotein expression in capillary endothelium of brain and testes and not other tissues (i.e., kidney and placenta) may in part explain this phenomenon and could have important implications in cancer chemotherapy.
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Probenecid and sulfinpyrazone may be useful lead compounds for the development of clinical reversal agents specific for MRP-mediated drug resistance, as determined by immunocytochemistry and electron microscopy.
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It is demonstrated that depletion of intracellular glutathione by DL-buthionine (S,R)-sulfoximine results in a complete reversal of resistance to doxorubicin, daunorubICin, vincristine, and VP-16 in lung carcinoma cells transfected with a MRP cDNA expression vector, and this results support the hypothesis that MRP functions as a glutATHione S-conjugate carrier.