Platinum complex-induced dysfunction of cultured renal proximal tubule cells. A comparative study of carboplatin and transplatin with cisplatin.
Platinum coordination complexes (PtCx) are potent against several types of cancer but are often nephrotoxic. With a view to developing a PtCx nephrotoxicity model, the toxicity of cisplatin (cDDP), transplatin (tDDP) and carboplatin (CBDCA) was studied in primary cultures of rabbit proximal tubule (RPT) cells and in the renal epithelial OK cell line. The cytotoxicity of these PtCx (10-3000 microM) was assessed after 24 h exposure of confluent monolayers in terms of LDH release; their effects at non-cytotoxic concentrations (1-1000 microM) on DNA and protein synthesis, glucose transport, marker enzymes and the total glutathione concentration were also determined, together with cellular platinum uptakes. The cytotoxicity ranking of the studied compounds differed for OK and RPT cells (cDDP > tDDP; cDDP > CBDCA and tDDP > cDDP; cDDP > CBDCA, respectively). Only results which were obtained in RPT cells corresponded to reported nephrotoxicity in vivo, making OK cells inappropriate for the study of PtCx nephrotoxicity in vitro. cDDP was about 10 times less cytotoxic for OK cells than for RPT cells because of lower cellular uptake. tDDP was unable markedly to inhibit biochemical and functional parameters in RPT cells below cytotoxic concentrations. At non-cytotoxic concentrations, cDDP and CBDCA depressed synthetic activity (mainly DNA) and, to a lesser extent, Na(+)-K(+)-ATPase activity and glucose transport in RPT cells. Total glutathione levels in RPT cells steadily increased during exposure to cDDP, tDDP and CBDCA, before the onset of cell death, arguing against an early role of glutathione depletion in PtCx toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)
Département Sécurité du Médicament, Centre de Recherche de Vitry-Alfortville, Vitry sur Seine, France.
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Courjault
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Toutain
D000818:Animals; D016190:Carboplatin / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002945:Cisplatin / Q000633:toxicity; D004247:DNA / Q000096:biosynthesis; D004798:Enzymes / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000166:cytology* / Q000187:drug effects; D008871:Microvilli / Q000187:drug effects / Q000201:enzymology; D009893:Opossums; D009944:Organoplatinum Compounds / Q000633:toxicity*; D010984:Platinum / Q000378:metabolism; D014176:Protein Biosynthesis; D011817:Rabbits; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000378:metabolism
D004798:Enzymes; D009944:Organoplatinum Compounds; C034697:transplatin; D010984:Platinum; D004247:DNA; D016190:Carboplatin; D013385:Succinate Dehydrogenase; D000254:Sodium-Potassium-Exchanging ATPase; D005978:Glutathione; D005947:Glucose; D002945:Cisplatin