The multidrug resistance protein 4 (MRP4/ABCC4) mediates excretion of a number of endogenous natural compounds (eg DHEA-S, prostaglandins and cyclic nucleotides) as well as nucleotide forms of drugs used in cancer and immunotherapy. We have shown previously that MRP4 overexpression in hematopoietic cell lines decreases the efficacy of antiretroviral drugs. However, the role of MRP4 in normal physiology remains undefined. We generated Mrp4-deficient mice through embryonic stem-cell gene targeting. Mice homozygous for the absence of Mrp4 are viable and fertile, but accumulate greater amounts of the chemotherapeutic agent topotecan in the brain after systemic administration. This is consistent with our immunohistochemical analysis (see Abstract by G.L. Scheffer) demonstrating that Mrp4 localization in the choroid plexus (CP) epithelium and in the brain capillary endothelium. To explore the transport function of Mrp4 in the CP we used intraventricular microdialysis sampling. The animals lacking Mrp4 have increased cerebrospinal fluid (CSF) topotecan concentrations after intravenous administration. We also demonstrate that MRP4 is expressed in human CP and brain capillary endothelium. Our results are compatible with Mrp4 limiting the CSF and brain penetration of topotecan due to its localization in both the CP epithelium and the brain capillary endothelium. This ability to differentially localize is unique among the Mrp family members that have been described. Finally, due to its broad substrate specificity it is likely that Mrp4 will strongly contribute to the CNS barriers that restrict the CSF and brain penetration of a number of therapeutic and non-therapeutic organic anions.
[Proc Amer Assoc Cancer Res, Volume 45, 2004]