DRUG TRANSPORT IN THE BRAIN - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 420

has suggested that human neurons highly express MRP6. 99 In addition, MRP8 has
been shown to colocalize with microfilaments in the white matter of human brain,
suggesting that it is principally an axonal protein. 100 Although several studies have
reported that brain parenchymal cells express negligible levels of MRP2/Mrp2, 92 , 96 , 97
Hirrlinger and colleagues detected the expression of Mrp2 mRNA in astrocytes iso-
lated from embryonic rats. 96 These discrepancies may be explained by differences in
prenatal versus postnatal expression of Mrp2. 101 , 102

Breast Cancer Resistance Protein A third ABC superfamily member that may be
involved in xenobiotic efflux is breast cancer resistance protein (BCRP; also known as
ABCG2). Unlike Pgp and MRP1, ABCG2 is a “half-transporter” comprised of only
six putative transmembrane spanning domains and a single ATP-binding region. 103
Since other half-transporters, such as ABCG5 and ABCG8, have been observed to
dimerize and form functional homo- or heterodimers, 104 it has been hypothesized
that ABCG2 may also form functional dimers. ABCG2 has significant overlap in
substrate-specificity profile with Pgp and has been shown to recognize a vast array
of sulfoconjugated organic anions and hydrophobic and amphiphilic compounds. 105
Examples of well-established ABCG2 substrates include fluoroquinolone antibiotics
(ciprofloxacin,

ofloxacin, norfloxacin), mitoxantrone, camphothecin derivatives

-glucuronide. 106 - 109 ABCG2
may also transport physiologic substrates such as glutathione, steroid hormones, and
folic acid. 105 , 106
Several recent studies have demonstrated the expression of ABCG2 in the brain,
particularly along the luminal side of the BBB. 110 , 111 Zhang and colleagues reported
the gene and protein expression of ABCG2 in both primary cultures of human brain
microvessel endothelial cells. 112 Overexpression of human ABCG2 in an immortal-
ized rat brain endothelial cell line resulted in enhanced basolateral-to-apical transport
of mitoxantrone, an established ABCG2 substrate. 112 In the porcine brain, ABCG2
appears to be expressed predominantly in brain microvessel endothelial cells and to
a lesser extent in choroid plexus epithelial cells and pericytes. 113 Lee and colleagues
reported ABCG2 gene and protein expression along the luminal side of mouse brain
capillaries. 114 Taken together, these data suggest that ABCG2 may play a role in
limiting the brain uptake of several xenobiotics. With respect to brain parenchyma,
low expression of ABCG2 has been shown in primary cultures of rat astrocytes and
microglia as well as in the MLS-9 cell line 115 and in human fetal astrocytes. 112
Although expression of ABCG2 in brain cellular compartments has been demon-
strated clearly, data on the functional activity of ABCG2 at this site remain inconclu-
sive. ABCG2 transport activity at the BBB has been demonstrated in cultured human
and rat brain microvessel endothelial cells, but these cell systems were transfected to
overexpress the exogenous protein of interest. 111 , 112 Studies in primary cultures of hu-
man brain endothelial cells and the RBE4 cell line have shown that the accumulation
of mitoxantrone, an established ABCG2 substrate, could not be enhanced in the pres-
ence of standard ABCG2 inhibitors (e.g., Ko143, FTC), suggesting lack of ABCG2
efflux activity in these cell systems. 115 The same study also reported an absence of
ABCG2-mediated efflux of mitoxantrone in primary cultures of rat astrocytes and in

(topotecan, irinotecan), dipyridamole, and estradiol-17