DRUG TRANSPORT IN THE BRAIN - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 427

in the handling of neuroactive compounds in the brain. 215 Due to the localization of
OCT3 on cortical astrocytes and its ability to mediate influx of catecholamines and
neurotoxic organic cations such as MPP + , this transporter has also been termed the
extraneuronal monoamine transporter (EMT), known also as the uptake system. 218
However, the true role of OCT3 in the brain is not yet known, partly because distri-
bution of dopamine and serotonin are not highly localized to the regions of the brain
where OCT3 is expressed. 215

Novel Organic Cation Transporters Thus far, three isoforms in rodents (Octn1-3)
and two isoforms in humans (OCTN1-2) have been cloned and characterized. 188
These transporters mediate substrate uptake across membranes of renal proximal
tubules, fetal liver, trachea, placenta, skeletal muscle, and cardiac muscle. All OCTN
members transport organic cations and carnitine, 187 , 199 and translocation of this en-
dogenous substrate together with Na + -and/or organic cations is H + -gradient de-
pendent. L-Carnitine ( -trimethylaminobutyric acid) is a small, highly

polar zwitterion at physiological condition that plays an important role in the
cotransport of long-chain fatty acids across the inner mitochondrial membrane
for

-hydroxy-

-oxidation and ATP generation. This compound, along with its metabolite,
acetyl-L-carnitine, is present in the CNS and has been proposed to have differ-
ent physiological roles, including the control of acetyl moiety level in the brain
parenchyma for the synthesis of acetylcholine. 220 Furthermore, administration of
carnitine or acetyl-L-carnitine to Alzheimer's patients has shown improvement in
memory functions. 221 These observations suggest that L-carnitine and acetyl-L-
carnitine are transported from the circulating blood into the brain across the BBB.
In the BBB there are several transport systems for nutrients and xenobiotics to
maintain the homeostasis in the CNS. 222 Therefore, it is likely that carnitine and
acetyl-L-carnitine are transported into the CNS via specific transporters across the
BBB. 223
OCTN1 (SLC22A4) has been cloned from human and rodent tissue. 197 , 199 , 201 , 224
There is, however, large species difference in localization and function of OCTN1.
Humans OCTN1 is expressed primarily in the fetal liver (absent in adult liver), lung,
kidney (brush border membrane), bone marrow, trachea, and to a lesser extent in
skeletal muscle, placenta, and prostate, 197 while rat Octn1 mRNA is expressed in the
spinal cord choroid plexus, hippocampus, cortex, and cerebellum. 92 , 201 , 211 Among
many others, substrates transported by OCTN1 include carnitine, TEA, quinidine,
choline, nicotine, cimetidine, and clonidine. 224 OCTN1 localization has been pro-
posed at the apical membranes of polarized cells to aid in the secretion of organic
cations. 211
OCTN2 (SLC22A5) was first cloned from human placenta, 200 followed by iso-
lation of the mouse and rat homologs. 225 , 226 OCTN2 functions as a polyspecific
and Na + -independent cation uniporter. 198 , 219 , 227 , 228 Octn2/OCTN2 has also been
characterized as high-affinity Na + -dependent plasmalemmal carnitine electrogenic
transporter 227 , 229 (also known as carnitine transporter 1, CT1), although it also
transports TEA, albeit with lower activity compared to that of carnitine. When