Pharmaceutical Research

, Volume 22, Issue 4, pp 647–660

Molecular Cloning and Functional Analyses of OAT1 and OAT3 from Cynomolgus Monkey Kidney

Authors

  • Harunobu Tahara
    • Graduate School of Pharmaceutical SciencesUniversity of Tokyo
    • Pharmaceutical Research InstituteKyowa Hakko Kogyo Co., Ltd.
  • Masayuki Shono
    • Graduate School of Pharmaceutical SciencesUniversity of Tokyo
  • Hiroyuki Kusuhara
    • Graduate School of Pharmaceutical SciencesUniversity of Tokyo
  • Hajime Kinoshita
    • Graduate School of Pharmaceutical SciencesUniversity of Tokyo
  • Eiichi Fuse
    • Pharmaceutical Research InstituteKyowa Hakko Kogyo Co., Ltd.
  • Akira Takadate
    • Daiichi College of Pharmaceutical Sciences
  • Masaki Otagiri
    • Department of Biopharmaceutics, Graduate School of Pharmaceutical SciencesKumamoto University
    • Graduate School of Pharmaceutical SciencesUniversity of Tokyo
Research Papers

DOI: 10.1007/s11095-005-2503-0

Cite this article as:
Tahara, H., Shono, M., Kusuhara, H. et al. Pharm Res (2005) 22: 647. doi:10.1007/s11095-005-2503-0

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Purpose.

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 Km values and the relative transport activities of 11 substrates with regard to p-aminohippurate transport. For OAT3, there was no species difference in the Km 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.

Key words:

OAT1OAT3organic anion transporterspecies differences

Abbreviations

α-KG

α-ketoglutarate

ACV

acyclovir

AZT

3′-azido-3′-deoxythymidine

CMD

cimetidine

CMPF

3-carboxy-4-methyl-5-propyl-2-furanpropionate

2,4-D

2,4-dichloro-phenoxy-acetate

DHEAS

dehydroepiandrosterone sulfate

E217βG

estradiol-17β-glucuronide

E1S

estrone-3-sulfate

HA

hippurate

HEK293

human embryonic kidney

hOAT

human organic anion transporter

IA

indoleacetate

IS

indoxyl sulfate

mkOAT

monkey organic anion transporter

MTX

methotrexate

NSAIDs

nonsteroidal anti-inflammatory drugs

OTA

ochratoxin A

PAH

p-amino-hippurate

PCG

benzylpenicillin

rOat

rat organic anion transporter

TBS-T

tris-buffered saline/Tween 20

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Copyright information

© Springer Science+Business Media, Inc. 2005