Role of rat sodium/phosphate cotransporters in the cell membrane transport of arsenate.
Inorganic arsenate (As(V)) is a common contaminant of underground water. Following oral exposure, it is assumed that As(V) is distributed and crosses cell membranes through inorganic phosphate (Pi) transporters. We have tested this hypothesis by studying the inhibition of rat Na/Pi cotransporters by As(V) in Xenopus laevis oocytes and in several rat tissues. The ubiquitously expressed type III Pi transporters (PiT-1 and PiT-2) showed a low affinity for As(V) (K(i) approximately 3.8 mM), similar to the Pi transport system in aortic vascular smooth muscle cells (K(i) 1.5 mM). The type II renal isoforms, NaPi-IIa and NaPi-IIc, were also poorly inhibited by As(V) (K(i) approximately 1 mM), similar to the Pi transport from kidney cortex brush-border membrane (BBM) vesicles. Conversely, the high-affinity intestinal transporter, NaPi-IIb, was very efficiently inhibited with a K(i) of 51 microM, similar to the Pi transport from intestinal BBM vesicles. Taking into account the 1.1 mM Pi in blood and renal ultrafiltrate, and the nanomolar range of As(V) exposures, we have determined that the contribution by Na/Pi cotransporters to As(V) membrane transport is negligible, given that 10-15 mM As(V) would be necessary in these fluids to be significantly transported. Intestinal transport is an exception, because Pi competition is weak, thereby considering that its concentration in lumen mainly depends on low Pi levels from ingested fresh water, and because As(V) very efficiently inhibits Pi intestinal transport. Our data agree with current toxicokinetic knowledge, and they explain the asymmetric excretion of trivalent and pentavalent arsenic species into bile and urine.
Villa-Bellosta
Ricardo
R
Laboratory of Molecular Toxicology, University of Zaragoza, E50013 Zaragoza, Spain. rvilla@unizar.es
Sorribas
Víctor
V
D000818:Animals; D001149:Arsenates / Q000378:metabolism* / Q000633:toxicity; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D003001:Cloning, Molecular; D004305:Dose-Response Relationship, Drug; D007413:Intestinal Mucosa / Q000378:metabolism; D007421:Intestine, Small / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D007700:Kinetics; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D009865:Oocytes; D051381:Rats; D050608:Sodium-Phosphate Cotransporter Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D050611:Sodium-Phosphate Cotransporter Proteins, Type III / Q000378:metabolism; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa / Q000378:metabolism; D050614:Sodium-Phosphate Cotransporter Proteins, Type IIb / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D050615:Sodium-Phosphate Cotransporter Proteins, Type IIc / Q000378:metabolism; D014874:Water Pollutants, Chemical / Q000378:metabolism* / Q000633:toxicity; D014982:Xenopus laevis
D001149:Arsenates; C493588:Slc20a1 protein, rat; C493566:Slc20a2 protein, rat; C493556:Slc34a1 protein, rat; C493559:Slc34a2 protein, rat; D050608:Sodium-Phosphate Cotransporter Proteins; D050611:Sodium-Phosphate Cotransporter Proteins, Type III; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa; D050614:Sodium-Phosphate Cotransporter Proteins, Type IIb; D050615:Sodium-Phosphate Cotransporter Proteins, Type IIc; D014874:Water Pollutants, Chemical; C025657:arsenic acid