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Vol. 62, Issue 5, 1128-1136, November 2002
Zentrum für Physiologie und Pathophysiologie, Abt. Vegetative
Physiologie, Universität Göttingen, Göttingen,
Germany (A.B., M.K., Y.H., M.R., S.G., G.B.); Department of Physiology,
College of Medicine, University of Arizona, Tucson, Arizona (D.S.G.,
K.K.E., S.H.W.)
The metal chelator DMPS (2,3-dimercapto-1-propanesulfonate) is used to
treat heavy metal intoxication because it increases renal excretion of
these toxins, which are accumulated in proximal tubule cells. To
evaluate the involvement of the organic anion transporter 1 (OAT1) in
the renal flux of DMPS, we examined the effect of DMPS on transport
mediated by the rabbit ortholog of OAT1 and compared these
characteristics with those observed in intact isolated rabbit proximal
tubules. The rabbit OAT1 (rbOAT1) cDNA consisted of 2124 base pairs
encoding a protein of 551 amino acids. Heterologous expression in COS-7
cells revealed rbOAT1-mediated transport of
p-aminohippurate (PAH; Kt = 16 µM). A
1 mM concentration of unlabeled PAH, 
-ketoglutarate, urate, or
probenecid inhibited [3H]PAH uptake by 70 to 90%.
cis-Inhibition and trans-stimulation experiments using several Krebs cycle intermediates implicated -ketoglutarate as the main intracellular exchange anion. Reduced DMPS inhibited rbOAT1-mediated fluorescein transport with an apparent Ki of 102 µM. These characteristics
paralleled those observed in isolated rabbit proximal tubules. PAH was
transported into nonperfused single proximal tubule S2
segments with a Kt of 76 µM. DMPS
inhibited FL uptake into single tubule segments with a
Ki-app of 71 µM. Fluorescein efflux from
preloaded tubules was trans-stimulated by 1 mM PAH and 1 mM DMPS, consistent with DMPS entry into tubule cells by rbOAT1. In
summary, rbOAT1 mediates basolateral uptake of DMPS into proximal
tubule cells, implicating this process in the detoxification process of
heavy metals in the kidneys.
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