Organic anion transporter 3 (OAT3) and renal transport of the metal chelator 2,3-dimercapto-1-propanesulfonic acid (DMPS).
Recent investigations involving intact rabbit renal proximal tubules indicated that organic anion transporter 3 (OAT3) may be involved in the transport of 2,3-dimercapto-1-propanesulfonic acid (DMPS). Therefore, we evaluated the interaction of OAT3 with DMPS to determine the effect of OAT3 on basolateral DMPS uptake. We used stably transfected HEK293 cells expressing human and rabbit orthologs of the exchanger OAT1 and OAT3. Using 6-carboxyfluorescein (6-CF) as a substrate, the IC50 determinations for reduced DMPS (DMPSH) revealed a stronger interaction with OAT1 than with OAT3 (rbOAT1, 123.3 +/- 13.7; hOAT1, 85.1 +/- 8.8; rbOAT3, 171.7 +/- 22.3; and hOAT3, 172.2 +/- 36.4 micromol/L). However, inhibition of 6-CF uptake by the oxidized form of DMPS (DMPSS), the main form of DMPS in the blood, showed a greater affinity for OAT3 (rbOAT1, 237.4 +/- 23; hOAT1, 104.6 +/- 13.1; rbOAT3, 52.4 +/- 7.6; and hOAT3, 31.6 +/- 6.6 micromol/L). To determine whether DMPSH and DMPSS are substrates for OAT3, we performed efflux studies with [14C]glutarate and inwardly directed gradients of glutarate. The inhibitors trans-stimulated the efflux of [14C]glutarate, suggesting that OAT3 may be able to transport both forms of DMPS. On the basis of the substantial interaction of OAT3 with DMPSS, we conclude that OAT3 represents the dominant basolateral player in renal detoxification processes resulting from use of DMPS.
Rödiger
Matthias
M
Zentrum für Physiologie und Pathophysiologie, Abt. Vegetative Physiologie, Humboldtallee 23, Universität Göttingen, Göttingen 37073, Germany.
Zhang
Xiaohong
X
Ugele
Bernhard
B
Gersdorff
Nikolaus
N
Wright
Stephen H
SH
Burckhardt
Gerhard
G
Bahn
Andrew
A
D000818:Animals; D002460:Cell Line; D002614:Chelating Agents / Q000378:metabolism*; D005452:Fluoresceins / Q000378:metabolism; D005456:Fluorescent Dyes / Q000378:metabolism; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019216:Metals, Heavy / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D010084:Oxidation-Reduction / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D011817:Rabbits; D014494:Unithiol / Q000378:metabolism*
D002614:Chelating Agents; D005452:Fluoresceins; D005456:Fluorescent Dyes; D019216:Metals, Heavy; D029362:Organic Anion Transporters, Sodium-Independent; C114338:organic anion transport protein 3; C024098:6-carboxyfluorescein; D014494:Unithiol