The Cell - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 34

Organic Cation/Carnitine Transporters
The organic cation/carnitine transporters are a part of the large SLC22 (solute car-
rier) type of membrane proteins that are secondary active transporters. Carnitine
(-hydroxy-- N -trimethylaminobutyric acid), a zwitterion, is a necessity for the
metabolism of lipids, acting as a cofactor. Hence, it has a role in the production of
energy. l l-Carnitine is required for several functions in the body like oxidation of fatty
acids, enhancing the flux of long-chain fatty acids across the mitochondrial inner
membrane as acylcarnitine esters and changes in intracellular coenzyme A homeo-
stasis. The four members of the family have been identified as OCTN1, OCTN2,
OCTN, and hCT2. They facilitate the movement of carnitine as well as other
substrates like its esters. Different organic carnitine transporters possess different
affinities and specificities toward substrates and tissue distribution. The transport-
ers are most abundantly expressed in the kidney. Of all the members, OCTN2 has
the highest affinity toward carnitine, with wide tissue distribution. Genetic defects
in the transporters may cause systemic carnitine deficiency syndrome. This group of
transporters modulate the biodistribution of many drugs like valproate, verapamil,
pyrilamine, and -lactam antibiotics, apart from excretion of toxins and endogenous
metabolites into the urine. Their role is important to maintain anion balance in the
body [112,11] .
Organic Anion Transporters
Organic anion transporters (OATs) are the secondary/tertiary active transporter pro-
teins that regulate anion balance in the body. They are primarily expressed in the
kidney and liver and control the excretion of common drugs, toxins, and endoge-
nous metabolites into the urine. They utilize the electrochemical gradient of substrate
or other ions to operate. The OATs that have been identified are OAT1-6, URAT1,
and some other orphan members. OATs have been identified to contain 12 -helical
transmembrane domains (TMDs). Several isoforms of the transporters exist because
of genetic variation. These are known to be very important in mediating and regulat-
ing renal absorption and excretion of drugs besides several other anionic endogenous
and xenobiotic substrates [11].
Organic Anion-Transporting Polypeptides
The organic anion-transporting polypeptides (OATPs) make up a large family that
plays a role in the transport of drugs as well as endobiotic substrates. OATPs are com-
posed of 12 transmembrane units. A differential feature is their sodium-independent
transport of a wide variety of substrates with broad specificity. They can regulate
the flux of material in both directions, and they themselves are regulated by signal
transduction through protein phosphorylation. Their expression is often controlled
by transcription factors. OATP1A2 has the widest specificity for substrate, which
includes acidic, basic, and neutral substrates [115,116] .