DRUG TRANSPORT IN THE BRAIN - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 419

localization and expression within the CNS, these observations suggest that MRP/Mrp
isoforms play a critical role in regulating the brain accumulation and distribution of
therapeutic compounds.
Several lines of evidence indicate that all of the functionally characterized MRP
isoforms (1 to 8) are expressed in at least one CNS compartment and that they prob-
ably play a role in transport of drugs and metabolites. In addition, gene and protein
expression in brain tissue has been reported for MRP9; however, functional charac-
terization of this transporter in brain cellular compartments has yet to be examined.
It should be noted that there is substantial controversy about the localization and
function of certain family members in the CNS. In the following section we provide a
summary of current knowledge with respect to MRP substrate profile and expression
at the brain barriers and in the cellular components of the brain parenchyma. Our
group has recently published a comprehensive review on MRP/Mrp expression and
function in the CNS. 83
At the BBB, many studies have reported the cellular localization and molecular
(i.e., gene and protein) expression of MRP/Mrp isoforms. Using RT-PCR analy-
sis, Zhang and colleagues identified the presence of Mrp1 mRNA in both cultured
bovine brain microvessel endothelial cells and in capillary-enriched fractions of brain
homogenates. 84 More recently, confocal laser scanning microscopy studies have lo-
calized MRP1 to the luminal side of the human BBB. 85 At the mammalian BBB, there
is also evidence for the expression of Mrp2 (in rat but not detected in cow or human),
MRP4/Mrp4 (human, cow, mouse), Mrp5 (cow, mouse), and Mrp6 (cow). 84 , 86 - 90
The presence of several different MRP homologs at the BBB may be important in
controlling the uptake of organic anions into the brain.
Immunocytochemical studies in rodents have provided evidence for abluminal
Mrp1 expression in choroid plexus epithelial cells of the blood-CSF barrier. 56 Stud-
ies in triple-knockout mice [e.g., mdr1a ( )] showed

increased accumulation of etoposide in the CSF compared to double-knockout mice
[e.g., mdr1a (

− / − ), mdr1b ( − / − ), Mrp1 ( − / −

)], which suggests that Mrp1 may act to mediate or-
ganic anion efflux into the blood. 56 MRP4/Mrp4 expression has been detected at both
luminal and abluminal plasma membranes of choroid plexus epithelial cells, imply-
ing that this transporter may be involved in limiting organic anion influx from blood
and driving organic anion efflux from brain to blood. 91 High levels of Mrp5 mRNA
transcripts have also been observed in rat choroid plexus 92 ; however, high-resolution
immunofluorescence staining studies were unable to detect Mrp5 expression in murine
choroid plexus. 93

− / − ), mdr1b ( − / −

Several studies have shown that expression of MRP2/Mrp2. 92

and

MRP3/Mrp3. 85 , 92 at the blood-CSF barrier is negligible.
In the brain parenchyma, MRP/Mrp mRNA expression has been reported in as-
trocytes, microglia, oligodendrocytes, and neurons. The expression of MRP1/Mrp1,
Mrp3, Mrp4, and Mrp5 has been reported in all of these cell types. 85 , 94 - 96 Stud-
ies in our laboratory have shown Mrp1, Mrp4, and Mrp5 functional expression in a
continuous rat microglia cell line (MLS-9). 82 , 97 Using immunogold cytochemistry at
the electron microscope level, Mrp1 was found to localize primarily to the plasma
membrane in MLS-9 cells. 76 Although Mrp6 gene and protein expression has not
been observed in astrocytes, microglia, and oligodendrocytes, 96 , 98 a recent study