Role of protein thiols in inhibition of sodium-coupled glucose uptake by cisplatin in renal brush-border membrane vesicles.
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 its Vmax 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).
Potdevin
S
S
Service de Biologie Cellulaire, Centre d'Etudes Nucléaires de Saclay, CEA, Gif-sur-Yvette, France.
Courjault-Gautier
F
F
Du Sorbier
B M
BM
Ripoche
P
P
Toutain
H J
HJ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002712:Chlorides / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology*; D004050:Ditiocarb / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008871:Microvilli / Q000187:drug effects / Q000378:metabolism; D011817:Rabbits; D012964:Sodium / Q000494:pharmacology*; D013438:Sulfhydryl Compounds / Q000502:physiology*
D000970:Antineoplastic Agents; D002712:Chlorides; D013438:Sulfhydryl Compounds; D004050:Ditiocarb; D012964:Sodium; D005947:Glucose; D002945:Cisplatin