Dissimilar alterations of sodium-coupled uptake by platinum-coordination complexes in renal proximal tubular cells in primary culture.
The potent anticancer drug cis-diamminedichloroplatinum (II) (CDDP) interferes early with electrolyte transport by the renal proximal tubule. To study the early effects of platinum coordination complexes on apical Na(+)-coupled transport systems, we examined the effect of increasing concentrations of CDDP, trans-diamminedichloroplatinum (II) (TDDP) and cis-diammine-1,1-cyclobutane-dicarboxylate platinum (II) (CBDCA) on Na(+)-coupled uptake of P(i), methyl-alpha-D-glucopyranoside (MGP) and L-alanine by rabbit proximal tubule cells in primary culture. At 17 microM CDDP and 540 microM CBDCA, 1) cell viability (lactate dehydrogenase release) and ATP content were unaffected, 2) Na(+)-K(+)-ATPase activity was reduced by 40%, 3) Na(+)-coupled uptake of MGP and P(i) was reduced, whereas 4) Na(+)-coupled uptake of alanine rose to twice the control value. Alterations of Na(+)-coupled uptake of P(i), MGP and alanine were due to changes in Km, with no significant change in Vmax. At 333 microM TDDP, Na(+)-dependent P(i) and MGP uptake decreased, whereas Na(+)-independent uptake increased markedly and was associated with a decline in cell viability and ATP content. We conclude that 1) the TDDP-induced decrease in Na+/P(i) and Na+/glucose cotransport was associated with reduced cell viability, 2) both CDDP and CBDCA had different effects on Na+/P(i), Na+/glucose and Na+/alanine cotransport, arguing against an alteration of the Na+ gradient due to reduced Na(+)-K(+)-ATPase activity and 3) CBDCA induced alterations of Na(+)-coupled uptake similar to those of CDDP at concentrations 20 to 30 times higher.(ABSTRACT TRUNCATED AT 250 WORDS)
Courjault-Gautier
F
F
Institut National de la Santé et de la Recherche Médicale U.251, LEM, Faculté de Médecine Xavier Bichat, Paris, France.
Hoet
D
D
Leroy
D
D
Toutain
H J
HJ
D000409:Alanine / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D016190:Carboplatin / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002945:Cisplatin / Q000031:analogs & derivatives / Q000494:pharmacology*; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008757:Methylglucosides / Q000378:metabolism; D011817:Rabbits; D012964:Sodium / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013237:Stereoisomerism
D008757:Methylglucosides; C027020:methylglucoside; D012964:Sodium; D016190:Carboplatin; D000254:Sodium-Potassium-Exchanging ATPase; D000409:Alanine; D002945:Cisplatin