Role of protein thiols in inhibition of sodium-coupled glucose uptake by cisplatin in renal brush-border membrane vesicles.
J Pharmacol Exp Ther
; 284(1): 142-50, 1998 Jan.
Article
em En
| MEDLINE
| ID: mdl-9435172
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 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).
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Base de dados:
MEDLINE
Assunto principal:
Sódio
/
Compostos de Sulfidrila
/
Cisplatino
/
Glucose
/
Rim
/
Antineoplásicos
Idioma:
En
Ano de publicação:
1998
Tipo de documento:
Article