Biochemical mechanisms of cephaloridine nephrotoxicity: time and concentration dependence of peroxidative injury.
These experiments were designed to elucidate the initiating biochemical events mediating cephaloridine (CPH) nephrotoxicity. Renal cortical slices from naive male Fischer-344 rats were incubated at 37 degrees C in a phosphate- or bicarbonate-buffered medium containing 0, 1, 5, or 10 mM CPH. Slices were incubated for 15, 30, 45, 60, 90, 120, and 180 min and evaluated for accumulation of organic ions [p-aminohippurate (PAH) and tetraethylammonium (TEA)], pyruvate-stimulated gluconeogenesis, malondialdehyde (MDA) production, and reduced glutathione (GSH) content. Renal cortical slice accumulation of PAH and TEA was decreased by 5 and 10 mM CPH as early as 120 and 90 min of incubation, respectively. CPH-induced MDA production by renal cortical slices preceded the effects of CPH on organic ion accumulation. Coincubation of CPH with the antioxidants promethazine and N,N'-diphenyl-p-phenylenediamine inhibited CPH-induced lipid peroxidation and changes in organic ion accumulation. In contrast, 5 or 10 mM CPH inhibited gluconeogenic capacity at all time points examined, an effect which was not influenced by antioxidant treatment. Depletion of renal cortical GSH by 5 or 10 mM CPH was evident following 30 min of incubation and was also unaffected by antioxidant treatment. These results support the hypothesis that lipid peroxidation mediates the effects of CPH on renal organic ion transport. The early and profound inhibition of gluconeogenesis by CPH suggests that the biochemical pathways of gluconeogenesis are either proximal to or represent a primary target for CPH nephrotoxicity.
D000818:Animals; D002509:Cephaloridine / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000431:Ethanol / Q000494:pharmacology; D005943:Gluconeogenesis / Q000187:drug effects*; D005978:Glutathione / Q000096:biosynthesis; D066298:In Vitro Techniques; D007672:Kidney Cortex / Q000187:drug effects*; D008297:Male; D008315:Malondialdehyde / Q000096:biosynthesis; D010655:Phenylenediamines / Q000494:pharmacology; D011398:Promethazine / Q000494:pharmacology; D051381:Rats; D019789:Tetraethylammonium; D013757:Tetraethylammonium Compounds / Q000096:biosynthesis; D010130:p-Aminohippuric Acid / Q000096:biosynthesis
D010655:Phenylenediamines; D013757:Tetraethylammonium Compounds; D000431:Ethanol; D008315:Malondialdehyde; D019789:Tetraethylammonium; C004845:N,N'-diphenyl-4-phenylenediamine; D011398:Promethazine; D005978:Glutathione; D002509:Cephaloridine; D010130:p-Aminohippuric Acid