Molecular cloning and functional analyses of OAT1 and OAT3 from cynomolgus monkey kidney.
OBJECTIVE
The functional characterization of monkey OAT1 (SLC22A6) and OAT3 (SLC22A8) was carried out to elucidate species differences in the OAT1- and OAT3-mediated transport between monkey and human.


METHODS
The cDNAs of monkey OAT1 and OAT3 were isolated from monkey kidney, and their stable transfectants were established in HEK293 cells (mkOAT1- and mkOAT3-HEK). Transport studies were performed using cDNA transfectants, and kinetic parameters were compared among rat, monkey and human.


RESULTS
The amino acid sequences of mkOAT1 and mkOAT3 exhibit 97% and 96% identity to their corresponding human orthologues. For OAT1, there was no obvious species difference in the K(m) values and the relative transport activities of 11 substrates with regard to p-aminohippurate transport. For OAT3, there was no species difference in the K(m) values and in the relative transport activities of nine substrates with regard to benzylpenicillin transport between monkey and human. However, the relative transport activities of indoxyl sulfate, 3-carboxy-4-methyl-5-propyl-2-furanpropionate, and estrone-3-sulfate showed a difference between primates and rat and gave a poor correlation.


CONCLUSIONS
These results suggest that monkey is a good predictor of the renal uptake of organic anions in the human.
Tahara
Harunobu
H
Graduate School of Pharmaceutical Sciences, University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan, sugiyama@mol.f.u-tokyo.ac.jp.
Shono
Masayuki
M
Kusuhara
Hiroyuki
H
Kinoshita
Hajime
H
Fuse
Eiichi
E
Takadate
Akira
A
Otagiri
Masaki
M
Sugiyama
Yuichi
Y
D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000096:biosynthesis; D015870:Gene Expression; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D008024:Ligands; D008252:Macaca fascicularis; D027362:Organic Anion Transport Protein 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity; D010130:p-Aminohippuric Acid / Q000493:pharmacokinetics*
D018076:DNA, Complementary; D008024:Ligands; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; C114338:organic anion transport protein 3; D010130:p-Aminohippuric Acid