MECHANISM OF CIS-PLATINUM NEPHROTOXICITY .1. EFFECTS OF SULFHYDRYL-GROUPS IN RAT KIDNEYS

Abstract

Cis-Diamminedichloroplatinum (CP), an important antineoplastic chemotherapeutic agent, produces acute renal failure by an unknown mechanism. Other heavy metals, such as Hg, are thought to be nephrotoxic by reacting with sulfhydryl (SH) groups. To investigate the mechanism of CP nephrotoxicity, F344 rats were injected once with 6 mg CP/kg. After 96 h, the blood urea nitrogen rose to 140 mg/100 ml. The SH concentration in control kidneys was 20.4 .+-. 0.1 .mu.ml/g wet wt. Total renal SH groups decreased to a maximum of 14% at 120 h (P < 0.01). The fall in SH groups was entirely due to a decrease of protein-bound SH groups. Cell fractionation studies showed that the greatest decline of SH groups occurred in the mitochondrial and cytosol fractions. These fractions also had the highest Pt concentrations. There was no stoichiometric relationship between Pt accumulation and the change in SH groups. In vitro studies demonstrated that CP does not directly interact with SH groups. To determine if the change in renal SH groups was a nonspecific effect of acute injury, renal failure was induced with glycerol (5 g/kg i.m.). Total SH groups per kidney increased after glycerol. The decrease in renal SH groups produced by CP is not due to nonspecific tubular necrosis. The nephrotoxic effects of CP may be related to depletion of SH groups. A direct cause-effect relationship has not been established.