Abstract-cis-Diamminedichloroplatinum II (cisplatin) is a potent anticancer chemotherapeutic agent.The major limitation in its use is nephrotoxicity, caused by an unknown mechanism.Injection of cisplatin into rats caused a decrease in body weight and an increase in blood urea nitrogen (BUN).These effects were modified by giving a radical scavenger, a-tocopherol, before the cisplatin injection.

Abstract-Cisplatin(cis-diamminedichloroplatinum II), an anticancer chemo therapeutic agent with the dose-limiting side effect of nephrotoxicity, caused a statistically significant increase in lipid peroxidation, monitored by measuring the production of malondialdehyde, in rat kidney 72 hr after injection. Treatment of rats beforehandwith the antioxidant a-tocopherol or N-N'-diphenyl-p-phenyl enediamine (DPPD) effectively decreased such peroxidation. DPPD was a more effective inhibitor than a-tocopherol, since it is known for its ability to scavenge free radicals more powerfully.The ability of renal cortical slices to accumulate p-aminohippurate (PAH) was examined as a biochemical parameter that would change in nephrotoxicity.The ability to accumulate PAH by the incubated slices decreased 72 hr after administration of cisplatin. The pretreatment with DPPD prevented the decrease in PAH accumulation in the slices from rats treated with cisplatin.

Abstract-Cisplatin(cis-diamminedichloroplatinum II), an antitumor agent with a dose-limiting adverse effect of nephrotoxicity, increased lipid peroxidation in a time and concentration-dependent manner in rat renal slices incubated in vitro.

Abstract-We examined the effect of lithium on rat renal handling of p-amino hippurate (PAH) and accumulation of organic ions by rat kidney cortical slices. When infused intravenously with lithium at the rate of 0.13 mmoles/kg/min, de creased renal clearance of PAH as well as no significant changes in glomerular filtration rate and plasma PAH level was observed at the first clearance period during lithium infusion.As we expected, tubular secretion of PAH also was decreased sig nificantly by the infusion of lithium. Therefore, it is suggested that the decrease in the clearance of PAH was due to the decrease in the tubular secretion of PAH. After four days of injections with lithium (4 mmoles/kg, i.p., once a day), a sig nificant decrease in PAH accumulation in the slices was detected.No inhibition of tetraethylammonium accumulation was observed. Lithium pretreatment did not alter water content and extracellular space of the slices. The results suggest that lithium selectively inhibits the organic anion transport system in kidney with the in vivo treatment and follows our previous work in which we showed the in vitro effect of lithium on organic anion accumulation in the slices.

The effect of lithium on p-aminohippurate (PAH) transport was studied using slices and basolateral membrane vesicles prepared from rat kidney cortex. The addition of lithium in concentrations ranging from 0.5 to 5 mM caused a concentration-dependent inhibition of PAH accumulation in the slices. Lithium inhibited PAH accumulation in the slices, not only during the rapid uptake period (after 10 min) but also during the approach to equilibrium (after 30 min). The effect of lithium (2 mM) in the slices was irreversible. The inhibitory effect of lithium was not the result of changes in the water distribution and the concentrations of ATP, sodium and potassium in the slices during incubation. The effect of lithium on the kinetic parameters for PAH accumulation was to decrease V_max, while apparent K_m remained constant. There was no lithium effect on the efflux of PAH from the slices back into the incubation medium, indicating that lithium inhibited PAH influx to the kidney cells. No evidence was obtained to indicate that lithium (1 mM) directly affected PAH uptake by isolated basolateral membrane vesicles. These results suggest that lithium seems to affect metabolism linked to the carriers for PAH transport other than ATP production and sodium gradient and then seems to decrease the mobility of the carriers in the membranes.