ORGANIC ANION TRANSPORTERS - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 52

in the body. Organic anion transporters (OATs), the proteins that underlie the OA secre-
tory system, typify secondary (and/or tertiary) active membrane transporters, which
translocate substrates across the cell membrane by utilizing a transmembrane elec-
trochemical gradient of the substrate itself or of another solute. 1 To date, the OATs
identified include OAT1 (originally, NKT), OAT2 (originally, NLT), OAT3 (origi-
nally, Roct), OAT4, OAT5, mouse OAT6, and URAT1 (originally, RST) (Table 4.1).
as well as a number of orphan family members. 2 − 7
OATs belong to the largest family of secondary active membrane transporters:
the major facilitator superfamily (MFS), which is conserved from bacteria to mam-
mals. 8 − 10 MFS transporters function as transmembrane uniporters, symporters, and
antiporters, and transport a wide range of hydrophilic and amphiphilic substrates, 11
including inorganic ions (Na + ,Cl − , HCO 3 − , etc.), endogenous metabolites (amino
acids, sugars, neurotransmitters, etc.) and xenobiotics (drugs and toxins). However,
OATs specialize in transporting organic anions, and most of the accumulated knowl-
edge concerning OAT function has been found by studying prototypical substrates
such as p -aminohippurate and estrone 3-sulfate. Within this superfamily, the OATs
are members of the solute carrier family SLC22a, which includes the structurally and
functionally related organic cation transporters (OCTs), organic carnitine transporters
(OCTNs), unknown soluble transporters (USTs), and flylike putative transporters
(Flipts) (http://www.bioparadigms.org/slc/intro.asp). 12
OATs are heavily expressed in excretory organs such as the kidney, suggesting a
critical role in maintaining endogenous homeostasis. Of note, the OATs are impli-
cated in several clinical disorders and are important modulators of drug efficacy and
toxicity, due to their ability to transport a large number of the most commonly pre-
scribed pharmaceuticals, such as angiotensin-converting enzyme (ACE) inhibitors,
loop and thiazide diuretics, β -lactam antibiotics, methotrexate, and nonsteroidal anti-

inflammatory drugs. 13
In recent years there has been considerable progress in understanding the molec-
ular basis of the renal secretory process, owing to the continued identification of
organic anion transporters that mediate basolateral and apical organic anion uptake.
Furthermore, these transporters have also been found to be present in numerous ep-
ithelial tissues other than the kidney, including the olfactory mucosa, liver, choroid
plexus, retina, and placenta, 14 which potentially implicates OATs more broadly in
secretory processes. Moreover, the sequencing of the human genome has uncovered
the chromosomal organization of OAT genes, enabling a deeper picture of the OATs
at the molecular, evolutionary, and regulatory levels.

4.2. GENOMICS OF OATs

Aside from their obvious structural and functional conformity (Figure 4.1), the OATs
also manifest similar tissue expression patterns. 15 OATs are expressed predominantly
in the kidney; however, functionally similar genes such as OAT1 and OAT3 are also
both found in choroid plexus, and hOAT5 and UST3 are both found in the liver.
Therefore, there may be regulatory elements that function to link expression of these
genes in certain tissues.