![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 63, Issue 3, 590-596, March 2003
Laboratory of Pharmacology and Chemistry, National Institute of
Environmental Health Sciences, Research Triangle Park, North Carolina
(A.G.A., Y.-H.H., X.-P.Y., J.B.P.); and Division of Basic Medical
Sciences, Mercer University, School of Medicine, Macon, Georgia
(R.K.Z.)
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-Hg2+ conjugate was most
cytotoxic, inducing greater than 50% cellular death over 18 h at
a concentration of 100 µM. 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 
-ketoglutarate, glutarate, and adipate, but not by succinate, a
nonexchangeable dicarboxylate. 203Hg-uptake studies showed
probenecid-sensitive uptake of mercury-thiol conjugates in the
hOAT1-transfected cells. The apparent Km for the NAC-Hg2+ conjugate was 44 ± 9 µM. Uptake of the
NAC-Hg2+ conjugate was cis-inhibited by
glutarate, but not by methylsuccinate, paralleling their effects on
toxicity. Probenecid-sensitive transport of the NAC-Hg2+
conjugate was also shown to occur in Xenopus laevis
oocytes expressing the hOAT1 or the rOAT3 transporters, suggesting that
OAT3 may also transport thiol-Hg2+ conjugates. Thus, renal
accumulation and toxicity of thiol-Hg2+ conjugates may
depend in part on the activity of the organic transport system.
This article has been cited by other articles:
|
|
 |
|
  N. Bakhiya, M. Batke, J. Laake, B. H. Monien, H. Frank, A. Seidel, W. Engst, and H. Glatt Directing Role of Organic Anion Transporters in the Excretion of Mercapturic Acids of Alkylated Polycyclic Aromatic Hydrocarbons Drug Metab. Dispos., October 1, 2007; 35(10): 1824 - 1831. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. H. Lash, D. A. Putt, and R. K. Zalups Influence of Compensatory Renal Growth on Susceptibility of Primary Cultures of Renal Cells to Chemically Induced Injury Toxicol. Sci., December 1, 2006; 94(2): 417 - 427. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. C. Bridges and R. K. Zalups System B0,+ and the Transport of Thiol-S-Conjugates of Methylmercury J. Pharmacol. Exp. Ther., November 1, 2006; 319(2): 948 - 956. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. J. Bow, J. L. Perry, J. D. Simon, and J. B. Pritchard The Impact of Plasma Protein Binding on the Renal Transport of Organic Anions J. Pharmacol. Exp. Ther., January 1, 2006; 316(1): 349 - 355. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. H. Lash, S. E. Hueni, D. A. Putt, and R. K. Zalups Role of Organic Anion and Amino Acid Carriers in Transport of Inorganic Mercury in Rat Renal Basolateral Membrane Vesicles: Influence of Compensatory Renal Growth Toxicol. Sci., December 1, 2005; 88(2): 630 - 644. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. K. Zalups and S. Ahmad Handling of the Homocysteine S-Conjugate of Methylmercury by Renal Epithelial Cells: Role of Organic Anion Transporter 1 and Amino Acid Transporters J. Pharmacol. Exp. Ther., November 1, 2005; 315(2): 896 - 904. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. K. Zalups and S. Ahmad Transport of N-Acetylcysteine S-Conjugates of Methylmercury in Madin-Darby Canine Kidney Cells Stably Transfected with Human Isoform of Organic Anion Transporter 1 J. Pharmacol. Exp. Ther., September 1, 2005; 314(3): 1158 - 1168. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-K. Jo, X. Hu, P. S.T. Yuen, A. G. Aslamkhan, J. B. Pritchard, J. W. Dear, and R. A. Star Delayed DMSO Administration Protects the Kidney from Mercuric Chloride-Induced Injury J. Am. Soc. Nephrol., October 1, 2004; 15(10): 2648 - 2654. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. C. Bridges and R. K. Zalups Homocysteine, System b0,+ and the Renal Epithelial Transport and Toxicity of Inorganic Mercury Am. J. Pathol., October 1, 2004; 165(4): 1385 - 1394. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. K. Zalups and S. Ahmad Homocysteine and the Renal Epithelial Transport and Toxicity of Inorganic Mercury: Role of Basolateral Transporter Organic Anion Transporter 1 J. Am. Soc. Nephrol., August 1, 2004; 15(8): 2023 - 2031. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. C. Bridges, C. Bauch, F. Verrey, and R. K. Zalups Mercuric Conjugates of Cysteine Are Transported by the Amino Acid Transporter System b0,+: Implications of Molecular Mimicry J. Am. Soc. Nephrol., March 1, 2004; 15(3): 663 - 673. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Eraly, K. T. Bush, R. V. Sampogna, V. Bhatnagar, and S. K. Nigam The Molecular Pharmacology of Organic Anion Transporters: from DNA to FDA? Mol. Pharmacol., March 1, 2004; 65(3): 479 - 487. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Aslamkhan, Y.-H. Han, R. Walden, D. H. Sweet, and J. B. Pritchard Stoichiometry of organic anion/dicarboxylate exchange in membrane vesicles from rat renal cortex and hOAT1-expressing cells Am J Physiol Renal Physiol, October 1, 2003; 285(4): F775 - F783. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
