DRUG TRANSPORT IN THE BRAIN - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 421

the MLS-9 cell line. 115 Data from recent in vivo studies in ABCG2 knockout mice
are controversial. Some studies have implied that ABCG2 is not functional at the
BBB, 114 - 116 whereas others have suggested that ABCG2 is in fact active at this brain
barrier. 117 , 118 Further studies are needed to clarify the functional significance of this
transporter at the BBB.

14.3.2. Organic Anion-Transporting Polypeptides

Organic anion transporting polypeptides (OATPs in humans; Oatps in rodents)
are a group of membrane solute carriers involved in the transport of amphipathic
substrates. 119 Although several members of this family are expressed selectively in
hepatic tissue, many OATPs/Oatps are present in multiple regions of the rodent and hu-
man body, including the CNS. Previous studies have suggested that OATPs/Oatps have
overlapping and partially distinct substrate preferences for many solutes, including
bile salts, organic dyes, steroid conjugates, thyroid hormones, anionic polypeptides,
and numerous xenobiotics. 119
Hydropathy analysis has predicted that OATP/Oatp membrane topology consists
of 12 transmembrane domains. However, the 12-transmembrane-domain model pre-
dicted has not been tested experimentally. All OATPs/Oatps share many structural
features, including a large extracellular loop between transmembrane domains 9 and
10 which contains many conserved cysteine residues that resemble the zinc fin-
ger motifs of DNA-binding proteins. 119 OATP/Oatp family members also possess
N-glycosylation sites in extracellular loops 2 and 5. In addition, all OATP/Oatp family
members have a conserved amino acid sequence, known as the OATP superfamily sig-
nature , located at the border between extracellular loop 3 and transmembrane domain
6. Conserved charged amino acids are found at the boundaries of the transmembrane
domains as well as within the membrane itself. 119 The role of these conserved amino
acids for transmembrane substrate transport has yet to be determined.
OATP/Oatp genes are classified within the solute carrier family 21A (humans:
SLC21A; rodent: Slc21a). 119 To date, 11 rat, 8 mouse, and 9 human OATPs/Oatps
have been identified 119 ; however, not all of these isoforms are expressed in the brain.
The information provided below summarizes the molecular (i.e., gene and protein)
expression, localization, and substrate profile of those OATP/Oatp isoforms that have
been identified in the CNS. Since the human OATPs and rodent Oatps are distinctly
different in terms of gene and protein expression and substrate profiles, they are
considered separately.

Human OATP Isoforms Previous studies have shown the expression of OATP iso-
forms in human brain tissue. Immunofluorescence staining of human brain frontal
cortex tissue fixed in situ demonstrated the localization of OATP-A along the bor-
der of brain capillary and microvessel endothelial cells. 120 Astrocytes and neurons
were immunonegative, suggesting that these cells do not express OATP-A. 120 Stud-
ies in Xenopus laevis oocytes have shown that OATP-A is involved in the uptake of

-opioid receptor agonists such as D-penicillamine(2,5)-enkephalin and deltorphin
II, 120 which implies that this transporter may be prominently involved in the brain