Cisplatin-induced lipid peroxidation and decrease of gluconeogenesis in rat kidney cortex: different effects of antioxidants and radical scavengers.
The present in vitro study was performed to investigate the effect of the nephrotoxic anticancer agent cisplatin (CP) on lipid peroxidation, on pyruvate-stimulated gluconeogenesis and on p-aminohippurate (PAH) accumulation in rat renal cortical slices. In addition, the inhibitory effects of the antioxidants and radical scavengers N,N'-diphenyl-p-phenylenediamine (DPPD), (+)-cyanidanol-3 or alpha-tocopherol on CP-induced lipid peroxidation and CP-induced decrease of gluconeogenesis and the inhibitory effect of DPPD on CP-induced decrease of PAH accumulation were evaluated. Slices were incubated in a CP-containing medium for different periods of time (7.5-300 min) and at different concentrations (0.025-1.5 mg/ml). Lipid peroxidation was monitored by measuring the production of malondialdehyde (MDA). Accumulation of PAH was expressed as slice to medium concentration ratio. Pyruvate-stimulated gluconeogenesis, measured as glucose production, was determined after a subsequent 60- or 15-min incubation in a pyruvate-containing, CP-free medium. CP led to a time- and concentration-dependent increase in MDA production, a time- and concentration-dependent decrease of pyruvate-stimulated gluconeogenesis and a time-dependent decrease of PAH accumulation in renal cortical slices. Decrease of gluconeogenesis preceded MDA production and decrease of PAH accumulation. Antioxidants reduced CP-induced MDA production and CP-induced decrease of accumulation of PAH, but did not reverse CP-induced decrease of gluconeogenesis. This might indicate, that the generation of free radicals and subsequent lipid peroxidation may play a role, at least in part, in inducing CP nephrotoxicity. There could be more than one mechanism of CP-induced nephrotoxicity, since decrease of gluconeogenesis preceded MDA production and decrease of PAH accumulation and could not be inhibited by antioxidants and radical scavengers.
Hannemann
J
J
Department of Cell Physiology, University of Hamburg, F.R.G.
Baumann
K
K
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002392:Catechin / Q000494:pharmacology; D002945:Cisplatin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005609:Free Radicals; D005943:Gluconeogenesis / Q000187:drug effects*; D066298:In Vitro Techniques; D007672:Kidney Cortex / Q000187:drug effects* / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D010655:Phenylenediamines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D014810:Vitamin E / Q000494:pharmacology; D010130:p-Aminohippuric Acid / Q000378:metabolism
D000975:Antioxidants; D005609:Free Radicals; D010655:Phenylenediamines; D014810:Vitamin E; D008315:Malondialdehyde; D002392:Catechin; C004845:N,N'-diphenyl-4-phenylenediamine; D002945:Cisplatin; D010130:p-Aminohippuric Acid