DRUG TRANSPORT IN THE BRAIN - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 415

Abluminal Luminal Basolateral Apical

TJ TJ TJ

TJ TJ

BBB

ENT2

CP

ENT2

EN T 2

ENT2

OCTN2

CNT2

ENT1

ENT1

P-gp

Pept2

CNT2

CNT3

OAT1

BCRP

Oatp2

OAT3

OAT3

MRP1

Oatp14

P-gp

OCT2

Mrp2 MRP1

Oatp2

OCT3

MRP4

MRP4

P-gp

Mrp5

Oatp1
Oatp3
Oatp14
rPGT
MRP4

OATP-A

rPGT

TJ TJ

Brain

Blood

CSF

TJ TJ TJ

FIGURE 14.1. Xenobiotic transport mechanisms at the brain barriers. The proposed expres-
sion of ABC superfamily transporters, organic anion and cation transporters, nucleoside trans-
porters, and peptide transporters is depicted at the BBB endothelium and at the choroid plexus
epithelium. Although expression of these transporters has been shown, localization and function
remain to be demonstrated. The arrows indicate the direction of substrate transport. References
are indicated in the text. ( See insert for color representation of figure. )

in the cellular compartments of the brain parenchyma. In the following section we
summarize the current knowledge on the CNS localization and functional expres-
sion of these membrane drug transporters. Localization of various transporters at the
brain barriers is presented in Figure 14.1. Similarly, transporter localization in cellular
compartments of the brain parenchyma is depicted in Figure 14.2.

14.3.1. ATP-Binding Cassette Drug Transporters

The ATP-binding cassette (ABC) transporter superfamily consists of membrane-
bound ATP-driven proteins that extrude from cells xenobiotics and their metabolites.
ABC family members are classified according to the presence of various consensus
sequences, including two ATP binding motifs (Walker A and Walker B) and the ABC
signature C motif (ALSGGQ). 38 To date, there are 48 known human ABC family
members belonging to seven different subfamilies. A comprehensive list of currently
known mammalian ABC transporters compiled by Michael Muller (Wageningen Uni-
versity, The Netherlands) can be found at http://nutrigene.4t.com/humanabc.htm. Mu-
tations in some of the ABC genes are the underlying cause of genetic disorders such as
cystic fibrosis, anemia, Dubin-Johnson syndrome, and retinal degeneration. 39 ABC