Interactions of human organic anion as well as cation transporters with indoxyl sulfate.
Various uremic toxicants including indoxyl sulfate exert a number of biological effects on uremic patients. In order to elucidate the molecular mechanisms for the pharmacokinetics of indoxyl sulfate in human, we examined the interactions of human organic anion transporters (human-OATs) and human organic cation transporters (human-OCTs) with indoxyl sulfate using stable transfectants. Indoxyl sulfate inhibited human-OAT1, human-OAT3 and human-OAT4, but not human-OAT2, human-OCT1 and human-OCT2. Kinetic analysis revealed that the K(i) values for human-OAT1, human-OAT3 and human-OAT4 were 22.7, 168.7 and 181.3 microM, respectively. Human-OAT1 and human-OAT3 mediated the uptake of indoxyl sulfate and human-OAT4 mediated not only the uptake but also the efflux of indoxyl sulfate. In conclusion, by comparing the K(i) values with the plasma concentration of unbound indoxyl sulfate, it was predicted that human-OAT1 and human-OAT3 mediate the transport of indoxyl sulfate in vivo. In addition, it was suggested that human-OAT1 and human-OAT3 are involved in the urinary excretion of indoxyl sulfate, the exacerbation of renal dysfunction and the induction of uremic encephalopathy by indoxyl sulfate.
Enomoto
Atsushi
A
Department of Clinical Preventive Medicine, Nagoya University School of Medicine, Nagoya, Japan.
Takeda
Michio
M
Taki
Kentarou
K
Takayama
Fumio
F
Noshiro
Rie
R
Niwa
Toshimitsu
T
Endou
Hitoshi
H
D000818:Animals; D001692:Biological Transport; D027682:Cation Transport Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D007200:Indican / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D007687:Kidney Tubules, Proximal / Q000166:cytology; D027362:Organic Anion Transport Protein 1 / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism*; D051381:Rats; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3
D027682:Cation Transport Proteins; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; C490280:SLC22A7 protein, human; C498886:SLC22A9 protein, human; C088800:Slc22a7 protein, rat; C421207:Slco1b2 protein, rat; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; C114338:organic anion transport protein 3; D007200:Indican