DRUG TRANSPORT IN THE BRAIN - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 426

classes of OCT systems have been defined: (1) potential-sensitive organic cation
transporters (OCT1-3 in humans and Oct1-3 in rodents) 192 - 194 localized to the baso-
lateral membrane of various cells, usually involved in the influx of organic cations
into a cell, and (2) H + gradient-dependent novel organic cation transporters (OCTN1-
3 in humans and Octn1-3 in rodents) which mediate the cellular efflux of cationic
substrates. 195 - 201 The combined effect of these two OCT systems results in the trans-
port of cationic substrates across the renal tubular cells from the blood into the lu-
minal fluid, from the blood into the bile across the hepatocyte, or from the fetal
into the maternal blood through the placental syncytiotrophoblast, hence eliminat-
ing many endogenous amines as well as a wide array of drugs and environmental
toxins. 187
Members of the SLC22A-family share a predicted membrane topology that in-
cludes 12

-helical transmembrane (TM) domains with cytoplasmic N- and C-
termini along with a large extracellular loop (between TM1 and TM2) that has
several N-glycosylation sites and smaller intercellular loop (between TM6 and
TM7). They also possess a C-terminus that has consensus sequences for pro-
tein kinase A-, protein kinase C-, and tyrosine kinase-dependent phosphorylation
sites. 190 , 202 , 203
Oct1 (Slc22a1) was originally cloned from rat kidney, 192 followed by isolation
of the human (OCT1) homolog. 204 Although controversial, very little 92 , 205 or no 206
OCT1/Oct1 mRNA has been found in the brain (choroid plexus and astrocytes).
Oct2 (Slc22a2) expression is tissue specific and expressed primarily in the
kidney. 193 , 207 Both Oct2 and OCT2 are localized to the basolateral membranes of the
proximal renal tubules. 208 , 209 Other expression sites include human placenta, 193 neu-
rons (human hippocampal pyramidal cells, cerebral cortex, and subcortical nuclei), 210
and rat choroid plexus. 206 , 211 OCT2 in human neurons has been reported to medi-
ate the transport of endogenous substrates such as dopamine, norepinephrine, sero-
tonin, histamine, choline, and exogenous substrates such as tetraethylammonium
(TEA), 1-methyl-4-phenylpyridinium (MPP + ), muscle relaxant memantine, and the
antiparkinsonian agent amantidine. 210 Hence, in the CNS, OCT2 may be involved
in the uptake of choline into neurons and in choline reabsorption from the cere-
brospinal fluid. In other words, OCT2 in brain may help reduce concentrations of basic
neurotransmitters and their metabolites and protect the brain from neurotransmitter
excitotoxicity.
OCT3 (SLC22A3) has a relatively broad expression profile and is highly expressed
in the human placenta, liver, skeletal muscle, kidney, heart, and to a lesser extent, the
brain. 212 - 214 Oct3 mRNA expression in brain is greater than that of Oct1 and Oct2 215 .
In situ hybridization studies demonstrated its expression in cerebral cortex and cere-
bellar and hippocampal neurons of rodents. 213 , 216 Reverse transcriptase polymerase
chain reaction (RT-PCR) analysis of rat superior cervical ganglion and choroid plexus
has also detected the Oct3 transcript. 217 Apart from mediating the uptake of TEA,
desipramine, and amphetamines, OCT3 also interacts with cationic neurotoxin MPP +
and the neurotransmitters dopamine and serotonin. Expression of OCT3 in the brain
combined with its ability to interact with cationic neurotoxins and neurotransmitters
suggests that this polyspecific organic cation transporter may play a significant role