DRUG TRANSPORT IN THE BRAIN - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 429

Concentrative Nucleoside Transporter Family CNTs are present in both prokary-
otes and eukaryotes and mediate the concentrative accumulation of nucleosides inside
the cell. 239 Six functionally different transport activities have been described based
on their substrate specificity. These are cit (pyrimidine nucleosides and adenosine),
cif (purine nucleosides and uridine), cib (purine and pyrimidine nucleosides), cit -
like (pyrimidine selective but also transports adenosine and guanosine), cs (selective
for adenosine and its analogs), and csg (guanosine selective). 240 - 243 Three different
proteins, CNT1, CNT2, and CNT3, have been described that are insensitive to ni-
trobenzylmercaptopurine riboside (NBMPR) and are responsible for the cit , cif , and
cib activities, respectively. Molecular identities responsible for cit -like, cs , and csg
activity, which are NBMPR-sensitive, have not yet been identified. 244 CNT1, -2, and
-3 couple uphill transport of nucleosides to downhill transport of sodium ions, and in
the case of CNT3, also to downhill transport of protons. 245 With respect to topology,
CNTs are integral proteins with 13 transmembrane -helices with a large putatively

extracellular glycosylated extracellular C-terminus. 246 However, unlike ENTs, which
are found ubiquitously in many cell types, CNTs are found primarily in special-
ized cell types, including macrophages, 247 microglia, 248 choroid plexus, 249 leukemia
cells, 250 and renal and gastrointestinal epithelia, 241 , 243 suggesting an important role
in absorption, secretion, distribution, and elimination of physiologic nucleosides and
nucleoside-analog drugs. CNTs have also been characterized in bacteria, insects,
hagfish, 251 Candida albicans , 252 and Caenorhabditis elegans , 253 and unlike ENTs,

many prokaryotes also express this group of transporters.
CNT1 (SLC28A1) is expressed primarily in epithelial tissues, including kidney,
small intestine enterocytes, and liver, and is localized to the apical membrane, where
it works in concert with ENTs that are localized predominantly in the basolateral
membrane to mediate transepithelial nucleoside flux. 254 The Cnt1 gene transcript is
also expressed in many regions of the rat brain, including cerebral cortex, cerebellum,
hippocampus, striatum, brain stem, superior colliculus, posterior hypothalamus, and
choroid plexus. 255 , 256 However, there is no evidence for the expression of the protein at
the BBB, 257 although expression of cit nucleoside transport system at the blood-brain
and BCSF barriers has been reported. 258 CNT1 mediates the cellular accumulation
of various nucleoside analogs used in the treatment of HIV (zidovudine, lamivudine,
and zalcitabine) and cancer tumors (cytarabine and gemcitabine). 259
Messenger RNA for human CNT2 (SLC28A2) has been detected in various tis-
sues, including liver, kidney, spleen, heart, placenta, colon, rectum, pancreas, small
intestine, skeletal muscle, and brain. 255 , 260 , 261 CNT2 protein is localized at the apical
membranes of polarized kidney cells. 262 At the blood-brain and BCSF barriers, CNT2
is limited to the membrane facing interstitial and cerebrospinal fluid, respectively. 263
CNT2 is considered as the BBB adenosine transporter and transports adenosine,
guanosine, and certain pyrimidine nucleosides such as uridine. 264 Therefore, this
transporter is named sodium-dependent purine nucleoside transporter (SPNT). Lo-
calization of this CNT2 at the blood-brain and BCSF barriers suggests likely roles in
removing adenosine from brain extracellular fluids. 263 Antiviral compounds such as
didanosine and ribavirin, used in the treatment of HIV and hepatitis C, respectively,
are also substrates of CNT2. 265