Study of nephrotoxicity through glutathione metabolism by cisplatin (CDDP) and adriamycin (ADM) in rat kidneys

Abstract

We studied cytotoxicity in vitro through reduced glutathione (GSH) metabolism by cisplatin (CDDP) and adriamycin (ADM) in rat kidneys. Renal cortical slices of Fischer 344 rats were incubated with Krebs-Ringer buffer containing CDDP (0-5mM) or ADM (0-0.5 mM). GSH and glutathione reductase (GSSG reductase) in these renal cortical slices were determined. Cell viability was assessed by lactate dehydrogenase (LDH) leakage. The following results were obtained. l) Intracellular GSH in renal cortex was decreased by CDDP doseand time-dependently. 2) The activity of GSSG reductase was suppressed by CDDP, but not by ADM. 3) LDH leakage increased significantly with CDDP and ADM respectively. 4) The incubation of renal cortical slices with GSH exogenously protected the increase of LDH leakage induced by CDDP or ADM. 5) The coincubation of renal cortical slices with CDDP and ADM did not increase LDH leakage compared with single administration of ADM. 6) LDH leakage in incubation with ADM after incubation with CDDP increased remarkably. The viability of renal cortical slices was more damaged by ADM under the condition of depleted GSH by CDDP. Therefore, it seemed that the order of administration was very important in combination chemotherapy.