Nephrotoxicity of cisplatin, carboplatin and transplatin

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Abstract
The present study was designed to compare the nephrotoxicity induced by the three platinum compounds cisplatin (CDDP), carboplatin (CBDCA) and transplatin (TDDP) in vitro and to obtain information to elucidate the mechanism of platinum compound-induced nephrotoxicity. Rat or rabbit renal cortical slices were incubated for different periods of time in platinum compound-containing media (0.42 or 1.67 mM) and thereafter monitored for platinum content, tetraethylammonium(TEA) and paraaminohippurate(PAH) accumulation and gluconeogenesis. Malondialdehyde(MDA) content of slices was determined as a parameter of lipid peroxidation. Activity of glucose-6-phosphatase of rat renal microsomes was investigated after platinum-compound exposure. In all series of experiments the effect of the antioxidant N,N′diphenyl-p-phenylenediamine (DPPD) was tested. CBDCA showed no effects on all parameters of renal cell function at all concentrations and all time points investigated, except for the activity of glucose-6-phosphatase, which was slightly affected by CBDCA. CBDCA-induced MDA production was lower, compared to CDDP, which showed marked toxic effects on TEA and PAH accumulation, gluconeogenesis and glucose-6-phosphatase activity. The onset of CDDP-induced alterations was dependent on drug concentration. MDA production was reduced by DPPD. Protection against the platinum compound-induced decrease in TEA and PAH accumulation was observed after the use of DPPD. DPPD had no protective effect on CDDP-induced inhibition of gluconeogenesis and glucose-6-phosphatase, which might indicate an effect on gluconeogenesis by direct inhibition of glucose-6-phosphatase. DPPD did not alter uptake of platinum compounds in rat renal cortical slices. TDDP showed different in vitro properties compared to in vivo conditions. In conclusion, association of CDDP-induced nephrotoxicity with lipid peroxidation was shown. CBDCA induced less generation of lipid peroxidation products and only very small nephrotoxic effects. Antioxidants may restrict CDDP-induced alterations in renal cell function.

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