ORGANIC ANION TRANSPORTERS - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 55

OCTNs
and Flipts

OCTs

UST1

OATs

UST3
OAT5
OAT4
RST/URAT1

Liver

OAT2

OAT1

Kidney,
Brain

Kidney,
Placenta

OAT3

Chr 11: 65 Mb
O AT 1 OA T3

66 Mb 67 Mb

OA T 5 UST 3 O AT 4 U R AT1

10 kb

FIGURE 4.2. Pairing, phylogeny, and tissue distribution of the OATs. Ovals indicate gene
pairing, and the adjacent text boxes indicate their tissue distributions. The gene pairs are
represented schematically in the rectangle below the dendrogram (to the scale in the lower
right corner of the figure). Genes are drawn as arrows that indicate transcription direction and
the intergenic regions between paired genes as line segments. The approximate chromosomal
locations of the gene pairs are indicated (in megabases from the p telomere of chromosome 11).
(From ref. 13.)

HNF1). 20 For example, some putative transcription factor binding sites present in
OAT noncoding regions may play a role in proximal tubule differentiation. Further-
more, experiments have shown that liver-enriched hepatocyte nuclear factor HNF-4 α

(nuclear receptor 2A1) can bind to and transactivate the SLC22A7/OAT2 promoter. 21
Although we are only at the early stages of understanding regulation of the expres-
sion of these transporters, earlier physiological studies have provided some insight
into the regulation of OATs. Postnatal maturation of OA transport has been found
to be influenced by a number of factors, including substrate availability, age, and
gender. For example, increased OA uptake into renal cortical slices can be induced by
prior exposure to organic anions. Since the increase could be prevented by the protein
synthesis inhibitor, cycloheximide, substrate exposure is believed to induce the syn-
thesis of either the OATs themselves or of other proteins required for OA uptake. 22 , 23
OA transport has also been shown to be under endocrine regulation. Transport of the
prototypical OAT substrate, p -aminohippurate (PAH), can be stimulated by treatment
with dexamethasone or thyroid hormones, particularly in young rats. 24 , 25 Such regu-
lation may be one potential mechanism by which organic anion transport is activated
during a critical period for OAT synthesis: neonatal development.