DRUG TRANSPORT IN THE KIDNEY - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 470

proximal tubular cells. 40 , 41 In the brain, OAT3 is localized at the luminal membrane of
choroid plexus cells 42 , 43 and in capillary endothelial cells. 44 Similar to OAT1, OAT3
recognizes a broad spectrum of substrates, which mediates the high-affinity transport
of PAH, estrone sulfate, ochratoxin A, and various drugs, including the cationic drug
cimetidine, in exchange for dicarboxylates inside cells. 35-37 , 45-48

OAT4 OAT4 was cloned from human kidneys. 49 OAT4 mRNA is expressed in the
kidneys and is localized at the apical membrane of proximal tubular cells. In the
placenta, OAT4 is expressed on the fetal side of the syncytiotrophoblast cells. 50 When
expressed in Xenopus oocytes, OAT4 mediates the Na + -independent, high-affinity
transport of estrone sulfate, dehydroepiandrosterone sulfate, ochratoxin A, and PGE 2 ,
PGF 2

, and urate. 35 , 37 , 46 , 49 , 51 , 52 A recent study demonstrated that OAT4 functions as
an organic anion-dicarboxylate exchanger. 53

URAT1 URAT1 is expressed exclusively in the kidneys, where it is located in the
apical membrane of proximal tubular cells. 54 URAT1 exhibits Na + -independent up-
take of urate and regulates the serum urate level; genetic defects in URAT1 are
the predominant causes of idiopathic renal hypouricemia. In a study using URAT1
cRNA-injected Xenopus oocytes, the cis -inhibitory effect of uricosuric drugs (e.g.,
probenecid, benzbromarone, sulfinpyrazone, losartan) and the trans -stimulatory ef-
fect of antiuricosuric drugs (e.g., pyrazinoic acid, the metabolite of the antituberculous
agent pyrazinamide) on the URAT1-mediated transport of urate were demonstrated. 54

Oat5 Oat5 was recently identified from mouse 55 and rat. 56 It is expressed exclusively
in the kidneys, and rat Oat5 is localized at the apical side of the proximal tubules. 56
Oat5 mediates the transport of steroid sulfates as well as ochratoxin A. 55-57

Other than these six clones, Sun et al. has reported two OAT-related clones and desig-
nated them as hOAT4 and hOAT5, respectively. 58 However, they did not demonstrate
any transport function, and human OAT4, identified by Cha and colleagues, 49 and

mouse and rat Oat5, 55 , 56

are not identical to these two clones.

OrganicAnion-TransportingPolypeptideFamily SLC21/SLC0 The first member of
this family, oatp1, was identified from the rat liver by an expression cloning method
as a sodium-independent bile acid transporter. 59 Thus far, 11 human isoforms and
14 rat isoforms have been identified in the OATP family. 60 Although some OATPs are
involved selectively in the hepatic uptake of bulky and relatively hydrophobic organic
anions, most OATPs are expressed in many tissues, such as the blood-brain barrier,
choroids plexus, lungs, heart, intestine, kidneys, placenta, and testes. 60 To clarify
the confusing and species-dependent “old” nomenclature, a novel nomenclature has
recently been assigned to the OATP family (Table 15.1). The OATP superfamily was
subdivided into several families (40% amino acid sequence identity) and subfamilies
(60% amino acid sequence identity). 60 The OATP family is now divided into six
families (OATP1 to OATP6). There are considerable species differences in the OATP