PT - JOURNAL ARTICLE AU - Sophie Potdevin AU - Françoise Courjault-Gautier AU - Bertrand Monegier Du Sorbier AU - Pierre Ripoche AU - Hervé J. Toutain TI - Role of Protein Thiols in Inhibition of Sodium-Coupled Glucose Uptake by Cisplatin in Renal Brush-Border Membrane Vesicles DP - 1998 Jan 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 142--150 VI - 284 IP - 1 4099 - http://jpet.aspetjournals.org/content/284/1/142.short 4100 - http://jpet.aspetjournals.org/content/284/1/142.full SO - J Pharmacol Exp Ther1998 Jan 01; 284 AB - 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). The American Society for Pharmacology and Experimental Therapeutics