Cojocel C, Laeschke K H, Inselmann G, Baumann K
Toxicology. 1985 Jun 28;35(4):295-305. doi: 10.1016/0300-483x(85)90063-0.
The present study was designed to elucidate whether cephaloridine-induced lipid peroxidation is inhibited by probenecid, cobalt chloride and antioxidants such as alpha-tocopherol and N,N'-diphenyl-p-phenylenediamine (DPPD). Kidney slices obtained from the renal cortex of male Wistar rats were incubated for 1 h in a cephaloridine or cefotaxime (1.25-10 mg/ml) containing medium. In another series of experiments, kidney slices were incubated with cephaloridine or cefotaxime (5 mg/ml) for different periods of time (30-120 min). Lipid peroxidation was monitored by measuring the production of malondialdehyde (MDA). Subsequently, kidney slices were incubated in both series of experiments, in a cephalosporin free medium containing tetraethylammonium (TEA). Accumulation of TEA in renal cortical slices, expressed as slice to medium ratio (S/M), was used to measure changes in the transport capacity of the kidney cells. While cefotaxime had only a slight effect, cephaloridine induced a significant time- and concentration-dependent increase of MDA production and a significant time- and concentration-dependent decrease of TEA accumulation. Inhibition of the renal uptake of cephaloridine by probenecid induced a decrease in MDA production and complete recovery of TEA accumulation. The antioxidants DPPD and alpha-tocopherol inhibited cephaloridine-induced lipid peroxidation in a concentration-dependent manner. Recovery of TEA accumulation accompanied the decrease in lipid peroxidation. DPPD was a more potent inhibitor of lipid peroxidation than alpha-tocopherol. Cobalt chloride, known for its ability to decrease cellular concentration of cytochrome P-450, effectively decreased cephaloridine-induced lipid peroxidation. Thus, these findings support the concept that lipid peroxidation has an important role in the development of cephaloridine-induced nephrotoxicity.
本研究旨在阐明丙磺舒、氯化钴以及抗氧化剂如α-生育酚和N,N'-二苯基对苯二胺（DPPD）是否能抑制头孢噻啶诱导的脂质过氧化。从雄性Wistar大鼠肾皮质获取的肾切片在含有头孢噻啶或头孢噻肟（1.25 - 10 mg/ml）的培养基中孵育1小时。在另一系列实验中，肾切片与头孢噻啶或头孢噻肟（5 mg/ml）孵育不同时间（30 - 120分钟）。通过测量丙二醛（MDA）的生成来监测脂质过氧化。随后，在这两个系列实验中，肾切片在不含头孢菌素但含有四乙铵（TEA）的培养基中孵育。以切片与培养基的比率（S/M）表示的TEA在肾皮质切片中的积累，用于测量肾细胞转运能力的变化。虽然头孢噻肟只有轻微影响，但头孢噻啶诱导MDA生成显著的时间和浓度依赖性增加以及TEA积累显著的时间和浓度依赖性降低。丙磺舒抑制头孢噻啶的肾摄取导致MDA生成减少以及TEA积累完全恢复。抗氧化剂DPPD和α-生育酚以浓度依赖性方式抑制头孢噻啶诱导的脂质过氧化。脂质过氧化减少的同时TEA积累恢复。DPPD比α-生育酚更有效地抑制脂质过氧化。以其降低细胞色素P - 450细胞浓度的能力而闻名的氯化钴，有效降低了头孢噻啶诱导的脂质过氧化。因此，这些发现支持脂质过氧化在头孢噻啶诱导的肾毒性发展中起重要作用这一概念。
