ROLE OF PROTEIN THIOLS IN INHIBITION OF SODIUM-COUPLED GLUCOSE-UPTAKEBY CISPLATIN IN RENAL BRUSH-BORDER MEMBRANE-VESICLES

The potent anticancer drug cis-diamminedichloroplatinum (II) (cDDP) im pairs glucose reabsorption by renal proximal tubular cells, which lead s 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-d ependent inhibition of the Na+/glucose cotransport system, by decreasi ng its V-max value and, to a lesser extent, its affinity, and 2) plati num binding to BBM vesicles, associated with decreases in protein-boun d thiols. cDDP produced weaker inhibition of the Na+/glucose cotranspo rt system and platinum binding to BBM vesicles than did highly reactiv e cDDP hydrated derivatives, with similar decreases in protein-bound t hiols. Treatment with diethyldithiocarbamic acid (a drug protecting ag ainst cDDP nephrotoxicity), immediately after cDDP exposure, 1) partia lly lifted the cDDP-induced inhibition of the Na+/glucose cotransporte r, 2) reduced platinum binding to BBM vesicles, but 3) did not modify the cDDP-induced decrease in protein-bound thiols. Our findings strong ly suggest that cDDP-induced inhibition oi the Na+/glucose cotransport system is mainly mediated by direct chemical binding of cDDP and/or i ts hydrated derivatives to essential sulfhydryl groups of the transpor t protein and may also involve other nucleophilic groups (e.g., the -S CH3 group of methionines).