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Research ArticleArticle

Relation of Cysteine Conjugate Nephrotoxicity to Transport by the Basolateral Organic Anion Transport System in Isolated S2 Segments of Rabbit Proximal Renal Tubules

William H. Dantzler, Kristen K. Evans, Carlotta E. Groves, John R. Welborn, Jason North, James L. Stevens and Stephen H. Wright
Journal of Pharmacology and Experimental Therapeutics July 1998, 286 (1) 52-60;
William H. Dantzler
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Kristen K. Evans
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Carlotta E. Groves
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John R. Welborn
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Jason North
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James L. Stevens
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Stephen H. Wright
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Abstract

We examined basolateral transport of the radiolabeled zwitterionic nephrotoxic cysteine S-conjugate,S-(1,2-dichlorovinyl)-l-cysteine (DCVC), inhibition of such transport and the effects of inhibition of transport on the toxicity produced by DCVC in isolated S2 segments of rabbit proximal tubules. High concentrations of unlabeled DCVC itself and an unlabeled nontoxic cysteine S-conjugate,S-(2-benzothiazole)-l-cysteinecis-inhibited the basolateral uptake of radiolabeled DCVC by ∼80 to 85%. High concentrations of para-aminohippurate, the prototype substrate for the basolateral organic anion transport system, and probenecid, a well-known inhibitor of basolateral organic anion transport, cis-inhibited the basolateral uptake of radiolabeled DCVC by ∼70%, whereas a high concentration ofl-phenylalanine had little effect. High concentrations ofS-(2-benzothiazole)-l-cysteine and para-aminohippurate in the bathing medium with DCVC inhibited the loss of 86Rb (used as a K+ surrogate to measure toxicity) from S2 segments produced by DCVC alone to approximately the same extent as they inhibited uptake of DCVC. Under the same circumstances, probenecid completely inhibited 86Rb loss. These data indicate that in rabbit proximal renal S2 tubules basolateral entry of DCVC can occur to a major extent via the organic anion transport pathway and that inhibition of such entry can reduce toxicity to approximately the same extent that entry is reduced. They also suggest that probenecid provides additional protection from DCVC toxicity.

Footnotes

  • Send reprint requests to: Dr. William H. Dantzler, Department of Physiology, College of Medicine, University of Arizona, Tucson, Arizona 85724-5051.

  • ↵1 This work was supported by National Institutes of Health Research Grant ES-06757, Training Grants HL-07249, NS-07309 and GM-08400 and Grant ES-06694 for the Southwest Environmental Health Sciences Center.

  • ↵2 Current address: Department of Physiological Sciences, School of Veterinary Medicine, University of Florida, Gainesville, FL 32611.

  • ↵3 Cis refers to the compartment from which the labeled flux originates; trans refers to the compartment toward which the labeled flux moves.

  • Abbreviations:
    DCVC
    S-(1,2-dichlorovinyl)-l-cysteine
    PAH
    para-aminohippurate
    αKG
    α-ketoglutarate
    HEPES
    N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid
    TCA
    trichloroacetic acid
    BTC
    S-(2-benzothiazole)-l-cysteine
    TEA
    tetraethylammonium
    • Received November 25, 1997.
    • Accepted March 24, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 286, Issue 1
1 Jul 1998
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Research ArticleArticle

Relation of Cysteine Conjugate Nephrotoxicity to Transport by the Basolateral Organic Anion Transport System in Isolated S2 Segments of Rabbit Proximal Renal Tubules

William H. Dantzler, Kristen K. Evans, Carlotta E. Groves, John R. Welborn, Jason North, James L. Stevens and Stephen H. Wright
Journal of Pharmacology and Experimental Therapeutics July 1, 1998, 286 (1) 52-60;

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Research ArticleArticle

Relation of Cysteine Conjugate Nephrotoxicity to Transport by the Basolateral Organic Anion Transport System in Isolated S2 Segments of Rabbit Proximal Renal Tubules

William H. Dantzler, Kristen K. Evans, Carlotta E. Groves, John R. Welborn, Jason North, James L. Stevens and Stephen H. Wright
Journal of Pharmacology and Experimental Therapeutics July 1, 1998, 286 (1) 52-60;
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