DRUG TRANSPORT IN THE BRAIN - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 431

hippocampus, granule neurons of the dentate gyrus, Purkinje and granule neurons of
the cerebellum, cortical and striatal neurons and astrocytes. 261 , 276 In humans, ENT1
protein has been localized at frontal and parietal lobes of the cerebral cortex, thala-
mus, midbrain, and basal ganglia. 275 Colocalization of ENT1 with adenosine A 1 in
human brain suggests that this transporter may regulate the neuromodulatory actions
of adenosine. 275 Human ENT1 is involved in the transport of such nucleoside analogs
as cladribine and cytarabine used in cancer treatment. 277
ENT2 (SLC29A2) mRNA is highly expressed in human skeletal muscle as well
as other tissues, including pancreas, prostate, kidney, heart, thymus, placenta, and
brain, 278 and is localized to the basolateral as well as nuclear membranes of canine
kidney cells transfected with plasmid encoding the ENT2 gene. 274 Human ENT2 pro-
tein is highly expressed in the cerebellum, thalamus, medulla, midbrain, and brain-
stem regions, particularly the pons, and is expressed weakly in cerebral cortex and
basal ganglia. 275 Because of ENT2 localization in brain regions rich in glial cells,
involvement of the transporter with nucleoside transport into the glial cells has been
speculated. 261 , 275 Furthermore, Ent2 has been identified as the primary functional
nucleoside transporter in rat C6 glioma cells. 279 In contrast to ENT1, ENT2 protein,
when expressed in Xenopus oocytes, can transport the antiretroviral nucleoside analog
zidovudine. 278 , 280
ENT3 (SLC29A3) protein, particularly abundant in the placenta, is widely dis-
tributed in human and rodent tissues and some neoplasias. ENT3 gene transcript has
been detected in brain of both species. 271 Unlike ENT1, -2, and -4, which are found
predominantly at the cell surface, ENT3 is localized intercellularly at the lysosomal
membranes and thus may function as a organellar transporter. 281 ENT3 has broad
substrate specificity, and the antiviral purines and pyrimidine nucleoside analogs di-
danosine, zalcitabine, and zidovudine are transported efficiently by this protein. 281
ENT4 (SLC29A4) protein is expressed ubiquitously in human tissue, particularly
in the brain, and is a low-affinity nucleoside transporter at the cell surface. 282 ENT4
transports dopamine, serotonin, and neurotoxin MPP + efficiently and is therefore
called plasma membrane monoamine transporter (PMAT). This transporter has been
proposed to maintain homeostasis of monoamine levels, and under certain conditions
might supplement the role of high-affinity transporters such as dopamine, serotonin,
and norepinephrine transporters in the brain. 282

14.3.6. Peptide Transporters

The intestine and kidney play key roles in the absorption and reabsorption of di-
etary nutrients. 283 Several transporters have been identified at these sites that as-
sist in the uptake of peptides from the small intestine and renal tubular lumen into
the blood. 284 , 285 Peptide transporters (PTs) belong to family 15 of the solute car-
rier superfamily (SLC15A) of proton-dependent oligopeptide transporters (POT) and
consist of four members: PEPT1, PEPT2, PHT1, and PHT2. 286 , 287 They have been
reported in mammals, including human, mice, rat, and rabbit, 288 , 289 as well as in

bacteria, fungi, yeast, and plants. 290 All members of the POT family consist of 12

putative -helical transmembrane domains with cytosolic N- and C-termini. The