DRUG TRANSPORT IN THE BRAIN - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 428

expressed in HeLa cells, this transporter mediates the transport of a number of
classical organic cations, including MPP + . 200 OCTN2 is present in various tissues,
including brain, kidney, skeletal muscle, heart, placenta, and others. 198 In CNS,
OCTN2 mRNA was detected in neurons from hippocampus, cerebellum, spinal
cord, and superior cervical ganglion, 198 , 211 , 217 , 228 although it was not expressed in
cerebral cortex neurons. 220 OCTN2 has also been detected in primary cultures of
human, rat, mouse, porcine, and bovine brain capillary endothelial cells. 223 Func-
tional loss of the transporter in Octn2 − / − mice is associated with decreased systemic
and brain concentration of acetyl-L-carnitine 230 ; this, along with their expression
in brain capillary endothelial cells, has led to the belief that these transporters
have luminal localization at the BBB and assist the entry of carnitine into the
brain. 223
Octn3 (Slc22a9) was first cloned from mouse testis and the protein shown to be
highly expressed in the testis and liver peroxisomes 231 but weakly in the kidney. 199
Carnitine transporter 2 (CT2, SLC22A16), on the other hand, was cloned and charac-
terized in human testis. 179 However, there is no evidence for the expression of neither
of these proteins in the CNS.

14.3.5. Nucleoside Membrane Transport Systems

Nucleotides, phosphate esters of nucleosides, are the building blocks of nucleic acids,
DNA and RNA, and are considered one of the most important molecules in the cell.
These nucleosides are divided into purines (adenosine and guanosine) and pyrimidines
(cytosine, thymidine, and uridine). Nucleotides such as cyclic AMP and cyclic GMP
serve as secondary messengers in signal transduction, while ATP serves as an energy
store. The nucleotide adenosine is also a ligand for cell surface purinergic P1 receptor
involved in physiological responses, including modulation of neural excitotoxicity, 232
coronary vasodilation, and platelet aggregation. 233
In general, nucleosides are synthesized endogenously via de novo pathway. How-
ever, a number of cells and tissues, including bone marrow cells, erythrocytes,
leukocytes, and some cells in the brain, 234 lack the enzymes required for de novo
nucleoside biosynthesis and therefore rely on salvage of extracellular nucleosides
or nucleobases for their intracellular metabolic demands. 235 The brain, is there-
fore, dependent on a constant supply of nucleosides from the blood and in situ
synthesis. 236 , 237 To achieve this, transporters on various cell membranes facilitate
the entry of nucleosides and nucleotides into the cells. It is also of interest to study
these transporters because of their involvement (uptake route) in therapeutic appli-
cations of many cytotoxic nucleotide derivatives used in the treatment of cancer,
stroke, and cardiovascular, parasitic, and viral diseases. 233 Mammalian nucleoside
transporters are classified into two structurally and mechanistically unrelated protein
families based on their sodium dependency: Na + -dependent concentrative nucleoside
transporters (CNTs), also classified as the SLC28A family, and Na + -independent
equilibrative

nucleoside transporters (ENTs) also classified as the SLC29A

family. 233 , 237 , 238