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 type s of cancer but are often nephrotoxic. With a view to developing a PtC x nephrotoxicity model, the toxicity of cisplatin (cDDP), transplatin (tDDP) and carboplatin (CBDCA) was studied in primary cultures of rabb it proximal tubule (RPT) cells and in the renal epithelial OK cell lin e. The cytotoxicity of these PtCx (10-3000 muM) was assessed after 24 h exposure of confluent monolayers in terms of LDH release; their effe cts at non-cytotoxic concentrations (1 - 1000 muM) on DNA and protein synthesis, glucose transport, marker enzymes and the total glutathione concentration were also determined, together with cellular platinum u ptakes. The cytotoxieity ranking of the studied compounds differed for OK and RPT cells (cDDP>tDDP; cDDP>CBDCA and tDDP>cDDP; cDDP>CBDCA, re spectively). Only results which were obtained in RPT cells corresponde d to reported nephrotoxicity in vivo, making OK cells inappropriate fo r the study of PtCx nephrotoxicity in vitro. cDDP was about 10 times l ess cytotoxic for OK cells than for RPT cells because of lower cellula r uptake. tDDP was unable markedly to inhibit biochemical and function al parameters in RPT cells below cytotoxic concentrations. At non-cyto toxic concentrations, cDDP and CBDCA depressed synthetic activity (mai nly DNA) and, to a lesser extent, Na+-K+ATPase activity and glucose tr ansport in RPT cells. Total glutathione levels in RPT cells steadily i ncreased during exposure to cDDP, tDDP and CBDCA, before the onset of cell death, arguing against an early role of glutathione depletion in PtCx toxicity. However, brush-border enzymes (gamma-glutamyl transfera se and alkaline phosphatase) and succinate dehydrogenase were insensit ive to the action of either cDDP or CBDCA in RPT cells. On the basis o f cytotoxicity and functional impairments, the toxicity of the three P tCx for RPT cells in vitro correlated with their reported nephrotoxici ty in vivo, showing that RPT cells in primary culture are suitable for investigating the nephrotoxicity of PtCx.