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
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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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