Role of rat sodium/phosphate cotransporters in the cell membrane transport of arsenate

Inorganic arsenate (AsV) is a common contaminant of underground water. Following oral exposure, it is assumed that AsV 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 AsV 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 AsV (Ki ~ 3.8 mM), similar to the Pi transport system in aortic vascular smooth muscle cells (Ki 1.5 mM). The type II renal isoforms, NaPi-IIa and NaPi-IIc, were also poorly inhibited by AsV (Ki ~ 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 Ki of 51 μM, 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 AsV exposures, we have determined that the contribution by Na/Pi cotransporters to AsV membrane transport is negligible, given that 10–15 mM AsV 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 AsV 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.