Heavy metals inhibit Pi-induced currents through human brush-border NaPi-3 cotransporter in Xenopus oocytes.
Heavy metal intoxication with Hg2+, Pb2+ and Cd2+ commonly leads to phosphaturia. In this study, we examined the effects of these heavy metals on Pi-induced currents (Ip) through NaPi-3, the human renal cotransporter for Na+ and Pi. Hg2+ inhibited Ip in a dose- and time-dependent fashion. Hg2+ decreased the extrapolated maximal current but did not alter the apparent affinity for Pi. This inhibition was also observed with the membrane-permeable oxidizing agent 2,2'-dithio-bis(5-nitropyridine) (DTNP) but not with the membrane-impermeable 5,5'-dithiobis(2-nitrobenzoic acid). Hg(2+)- and DTNP-mediated inhibition of Ip was reversible only in the presence of the reducing agent 2,3-dihydroxybutane-1,4-dithiol. Cd2+ and Pb2+ also inhibited Ip. However, while CD2+ did not significantly alter the apparent affinity for Pi, the apparent concentration needed for half-maximal current (Km) for Pi was increased by Pb2+. In contrast to Hg2+, the inhibition of Ip by Cd2+ and Pb2+ was rapidly reversible upon washout. In the presence of the Na(+)-K(+)-adenosinetriphosphatase inhibitor ouabain, Ip was not reduced, and the effects of the heavy metals were maintained. In summary, the three heavy metals Hg2+, Cd2+, and Pb2+ inhibit Ip through the Na+/Pi cotransporter NaPi-3 by distinct mechanisms. Heavy metal-mediated inhibition of NaPi-3 may be responsible for the phosphaturia observed after intoxication with these compounds.
Wagner
C A
CA
Institute of Physiology 1, Eberhard-Karls-Universität Tübingen, Germany.
Waldegger
S
S
Osswald
H
H
Biber
J
J
Murer
H
H
Busch
A E
AE
Lang
F
F
D015082:2,2'-Dipyridyl / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002104:Cadmium / Q000494:pharmacology*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D004220:Disulfides / Q000494:pharmacology; D004228:Dithionitrobenzoic Acid / Q000494:pharmacology; D004553:Electric Conductivity; D005260:Female; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D018374:LLC-PK1 Cells / Q000378:metabolism; D007854:Lead / Q000494:pharmacology*; D008628:Mercury / Q000494:pharmacology*; D008871:Microvilli / Q000378:metabolism; D010710:Phosphates / Q000494:pharmacology*; D050608:Sodium-Phosphate Cotransporter Proteins; D013552:Swine; D027981:Symporters; D014981:Xenopus
D002352:Carrier Proteins; D004220:Disulfides; D010710:Phosphates; D050608:Sodium-Phosphate Cotransporter Proteins; D027981:Symporters; D002104:Cadmium; C001105:2,2'-dipyridyl disulfide; D007854:Lead; D015082:2,2'-Dipyridyl; D004228:Dithionitrobenzoic Acid; D008628:Mercury