Transport of ochratoxin A by renal multispecific organic anion transporter 1.
In the present study, we investigated the transport of ochratoxin A (OTA) by kidney-specific organic anion transporter 1 (OAT1). When expressed in Xenopus laevis oocytes, OAT1 mediated sodium-independent uptake of OTA (Km = 2.1 microM). Piroxicam, which has been shown to prevent the nephrotoxicity of OTA, inhibited OAT1-mediated uptake of OTA. By contrast, another protective compound, aspartame, did not. Using a cell line derived from the mouse kidney terminal proximal tubule (S3) transfected with OAT1 cDNA, we investigated the transport of OTA and also its effect on cell proliferation and cell viability. S3 cells expressing OAT1 mediated the saturable transport of OTA (Km = 0.57 microM). Cell proliferation was suppressed in S3 cells expressing OAT1 when exposed to 2 and 10 microM OTA. This suppression was rescued by the coaddition of 1 mM p-aminohippurate in the media. The present study indicates that OTA is transported by OAT1 and that the accumulation of OTA via OAT1 in proximal tubular cells is the primary event in the development of OTA nephrotoxicity.
Tsuda
M
M
Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Mitaka, Tokyo, Japan.
Sekine
T
T
Takeda
M
M
Cha
S H
SH
Kanai
Y
Y
Kimura
M
M
Endou
H
H
D000818:Animals; D027321:Anion Transport Proteins; D001692:Biological Transport / Q000187:drug effects; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D007668:Kidney / Q000502:physiology*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D007700:Kinetics; D051379:Mice; D009793:Ochratoxins / Q000493:pharmacokinetics / Q000494:pharmacology*; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D010894:Piroxicam / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D014982:Xenopus laevis; D010130:p-Aminohippuric Acid / Q000493:pharmacokinetics / Q000494:pharmacology
D027321:Anion Transport Proteins; D002352:Carrier Proteins; D009793:Ochratoxins; D011994:Recombinant Proteins; D010894:Piroxicam; C025589:ochratoxin A; D010130:p-Aminohippuric Acid