Human renal organic anion transporter 1-dependent uptake and toxicity of mercuric-thiol conjugates in Madin-Darby canine kidney cells.

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Aslamkhan AG, Han YH, Yang XP, Zalups RK, Pritchard JB

Human renal organic anion transporter 1-dependent uptake and toxicity of mercuric-thiol conjugates in Madin-Darby canine kidney cells.

Mol Pharmacol. 2003 Mar;63(3):590-6.

PubMed ID

12606766 [ View in PubMed

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Abstract

Mercuric ions are highly reactive and form a variety of organic complexes or conjugates in vivo. The renal proximal tubule is a primary target for mercury uptake and toxicity, and circumstantial evidence implicates organic anion transporters in these processes. To test this hypothesis directly, the transport and toxicity of mercuric-thiol conjugates were characterized in a Madin-Darby canine kidney cell line stably transfected with the human organic anion transporter 1 (hOAT1). 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-terazolium bromide assays (for mitochondrial dehydrogenase) confirmed that mercuric conjugates of the thiols N-acetylcysteine (NAC), cysteine, or glutathione were more toxic in hOAT1-transfected cells than in the nontransfected cells. The NAC-Hg(2+) conjugate was most cytotoxic, inducing greater than 50% cellular death over 18 h at a concentration of 100 microM. The cytotoxic effects were fully reversed by probenecid (an OAT1 inhibitor) and partially reversed by p-aminohippurate (an OAT1 substrate). Toxicity of this conjugate was reduced by the OAT1-exchangeable dicarboxylates alpha-ketoglutarate, glutarate, and adipate, but not by succinate, a nonexchangeable dicarboxylate. (203)Hg-uptake studies showed probenecid-sensitive uptake of mercury-thiol conjugates in the hOAT1-transfected cells. The apparent K(m) for the NAC-Hg(2+) conjugate was 44 +/- 9 microM. Uptake of the NAC-Hg(2+) conjugate was cis-inhibited by glutarate, but not by methylsuccinate, paralleling their effects on toxicity. Probenecid-sensitive transport of the NAC-Hg(2+) conjugate was also shown to occur in Xenopus laevis oocytes expressing the hOAT1 or the rOAT3 transporters, suggesting that OAT3 may also transport thiol-Hg(2+) conjugates. Thus, renal accumulation and toxicity of thiol-Hg(2+) conjugates may depend in part on the activity of the organic transport system.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Acetylcysteine	Solute carrier family 22 member 6	Protein	Humans	Unknown	Substrate	Details