Goldstein R S, Pasino D A, Hewitt W R, Hook J B
Toxicol Appl Pharmacol. 1986 Apr;83(2):261-70. doi: 10.1016/0041-008x(86)90303-0.
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.
这些实验旨在阐明介导头孢菌素（CPH）肾毒性的起始生化事件。将未接触过药物的雄性Fischer-344大鼠的肾皮质切片在37℃下于含有0、1、5或10 mM CPH的磷酸盐或碳酸氢盐缓冲培养基中孵育。切片孵育15、30、45、60、90、120和180分钟，并评估有机离子（对氨基马尿酸盐（PAH）和四乙铵（TEA））的积累、丙酮酸刺激的糖异生、丙二醛（MDA）的产生以及还原型谷胱甘肽（GSH）的含量。早在孵育120和90分钟时，5和10 mM CPH就分别降低了肾皮质切片对PAH和TEA的积累。CPH诱导肾皮质切片产生MDA的作用先于CPH对有机离子积累的影响。CPH与抗氧化剂异丙嗪和N，N'-二苯基对苯二胺共同孵育可抑制CPH诱导的脂质过氧化和有机离子积累的变化。相比之下，5或10 mM CPH在所有检测的时间点均抑制糖异生能力，这种作用不受抗氧化剂处理的影响。孵育30分钟后，5或10 mM CPH使肾皮质GSH明显耗竭，且也不受抗氧化剂处理的影响。这些结果支持脂质过氧化介导CPH对肾有机离子转运作用的假说。CPH对糖异生的早期和显著抑制表明，糖异生的生化途径要么靠近CPH肾毒性的靶点，要么就是其主要靶点。
