Incubation of rat renal cortical slices with 2 mM cisplatin (CDDP) at 37 degrees C for different periods of time (15-180 min) increased malondialdehyde (MDA) formation, decreased intracellular glutathione (GSH), and inhibited gluconeogenesis in the slices. CDDP-induced MDA formation increased by 53% after 180 min of incubation and GSH decreased by 35% after 60 min of incubation. Both depletion of GSH and inhibition of gluconeogenesis preceded MDA formation. Procaine (2 mM) completely inhibited CDDP-induced lipid peroxidation without affecting depletion of GSH, but even potentiated gluconeogenesis inhibition, while 2 mM dithiothreitol (DTT) largely reversed all of these biochemical indices. After 240 min of incubation, 2 mM CDDP produced marked cytotoxicities, characterized by an increase in leakage of alkaline phosphatase (ALP) (132%), lactate dehydrogenase (LDH) (115%) and N-acetyl-beta-glucosaminidase (NAG) (157%), decrease in intracellular K+ (64%), and change in total water contents in the slices. Procaine (2 mM) showed protection against CDDP-induced cytotoxicities to a certain extent. These results suggest that depletion of GSH might be a determinant step in the oxidative stress and subsequent cytotoxicity, and that procaine is a powerful antioxidant and would be a promising drug for ameliorating some of the adverse effects of CDDP.

1 The protective effects of dithiothreitol (DTT) on cisplatin-induced nephrotoxicity were investigated with rat renal cortical slices. 2 The nephrotoxic effects of cisplatin (2 mmol l-1) were manifested in several ways: the Na+ and water content were increased while K+ was decreased. The malondiadehyde (MDA) concentration in the slices and the lactate dehydrogenase (LDH) released into the medium were increased. The uptake of p-aminohippurate (PAH), the synthesis of glucose and the glutathione (GSH) concentration in the slices were all decreased. 3 Despite a DTT-related increase in platinum (Pt) uptake by the slices, DTT (0.5-2 mmol I-1 ) ameliorated all these toxic effects of cisplatin in a concentration related manner. 4 The results suggest that the protective mechanism of DTT is its antioxidative action, DTT is also a metal chelator, however, and so a protective effect via chelation of Pt by DTT cannot be excluded.