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Journal of Pharmacology and Experimental Therapeutics

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OtherRENAL PHARMACOLOGY

Role of Protein Thiols in Inhibition of Sodium-Coupled Glucose Uptake by Cisplatin in Renal Brush-Border Membrane Vesicles

Sophie Potdevin, Françoise Courjault-Gautier, Bertrand Monegier Du Sorbier, Pierre Ripoche and Hervé J. Toutain
Journal of Pharmacology and Experimental Therapeutics January 1998, 284 (1) 142-150;
Sophie Potdevin
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Françoise Courjault-Gautier
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Bertrand Monegier Du Sorbier
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Pierre Ripoche
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Hervé J. Toutain
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Abstract

The potent anticancer drug cis-diamminedichloroplatinum (II) (cDDP) impairs glucose reabsorption by renal proximal tubular cells, which leads to glucosuria. We investigated the direct effect of cDDP (0.04–2 mM) on the Na+/glucose cotransport system in brush-border membrane (BBM) vesicles from the rabbit renal cortex. cDDP induced 1) concentration-dependent inhibition of the Na+/glucose cotransport system, by decreasing itsVmax value and, to a lesser extent, its affinity, and 2) platinum binding to BBM vesicles, associated with decreases in protein-bound thiols. cDDP produced weaker inhibition of the Na+/glucose cotransport system and platinum binding to BBM vesicles than did highly reactive cDDP hydrated derivatives, with similar decreases in protein-bound thiols. Treatment with diethyldithiocarbamic acid (a drug protecting against cDDP nephrotoxicity), immediately after cDDP exposure, 1) partially lifted the cDDP-induced inhibition of the Na+/glucose cotransporter, 2) reduced platinum binding to BBM vesicles, but 3) did not modify the cDDP-induced decrease in protein-bound thiols. Our findings strongly suggest that cDDP-induced inhibition of the Na+/glucose cotransport system is mainly mediated by direct chemical binding of cDDP and/or its hydrated derivatives to essential sulfhydryl groups of the transport protein and may also involve other nucleophilic groups (e.g., the -SCH3 group of methionines).

Footnotes

  • Send reprint requests to: Hervé J. Toutain, Département Sécurité du Médicament, CRVA, Rhône-Poulenc Rorer S.A., 13 quai Jules Guesde, BP 14, 94403 Vitry sur Seine Cedex, France.

  • Abbreviations:
    HEPES
    N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid
    BBM
    brush-border membrane
    MGP
    methyl-α-d-glucopyranoside
    cDDP
    cis-diamminedichloroplatinum (II) (cisplatin)
    DDTC
    diethyldithiocarbamic acid
    SH
    sulfhydryl
    SHL/PtB molar ratio
    molar ratio of protein-bound SH loss to platinum binding
    • Received March 26, 1997.
    • Accepted September 2, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 284, Issue 1
1 Jan 1998
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OtherRENAL PHARMACOLOGY

Role of Protein Thiols in Inhibition of Sodium-Coupled Glucose Uptake by Cisplatin in Renal Brush-Border Membrane Vesicles

Sophie Potdevin, Françoise Courjault-Gautier, Bertrand Monegier Du Sorbier, Pierre Ripoche and Hervé J. Toutain
Journal of Pharmacology and Experimental Therapeutics January 1, 1998, 284 (1) 142-150;

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OtherRENAL PHARMACOLOGY

Role of Protein Thiols in Inhibition of Sodium-Coupled Glucose Uptake by Cisplatin in Renal Brush-Border Membrane Vesicles

Sophie Potdevin, Françoise Courjault-Gautier, Bertrand Monegier Du Sorbier, Pierre Ripoche and Hervé J. Toutain
Journal of Pharmacology and Experimental Therapeutics January 1, 1998, 284 (1) 142-150;
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  • Effects of Trimetazidine on Lipid Peroxidation and Phosphorus Metabolites during Cold Storage and Reperfusion of Isolated Perfused Rat Kidneys
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