Yang D J, Teets V J, Bolton B, Brown P I, Rankin G O
Toxicology. 1987 Jul;45(1):25-44. doi: 10.1016/0300-483x(87)90112-0.
N-(3,5-Dichlorophenyl)succinimide (NDPS), an experimental agricultural fungicide, has been shown to be a selective nephrotoxin in Sprague-Dawley and Fischer 344 rats. Previous studies have demonstrated that a toxic metabolite contributes to or is responsible for acute NDPS-induced nephrotoxicity. The purpose of this study was to investigate the role of glutathione in NDPS-induced renal effects. In 1 set of experiments, male Sprague-Dawley or Fischer 344 rats received a single intraperitoneal (i.p.) injection of NDPS (0.4 or 1.0 mmol/kg) or sesame oil (2.5 ml/kg). Rats were killed at 1, 3, 6 or 24 h, and reduced (GSH) and oxidized (GSSG) glutathione concentrations determined in liver and renal cortex. In both rat strains NDPS (0.4 or 1.0 mmol/kg) administration produced small decreases in GSH concentrations (1 and 3 h) but moderate increases in GSSG concentrations (1 and 3 h) in liver and kidney. At 24 h both GSH and GSSG concentrations were increased, particularly in kidney. In a second set of experiments, rats were pretreated with the glutathione depletor diethyl maleate (DEM) (0.4 ml/kg, i.p.) 1 h prior to NDPS (0.2, 0.4 or 1.0 mmol/kg, i.p.) or sesame oil (2.5 ml/kg, i.p.) administration, and renal function monitored at 24 and 48 h. DEM pretreatment attenuated the increase in urine volume (24 and 48 h), proteinuria, glucosuria, hematuria and elevated blood urea nitrogen (BUN) concentration produced by NDPS (0.4 or 1.0 mmol/kg) in both Sprague-Dawley and Fischer 344 rats. NDPS-induced increases in kidney weight also were generally prevented by DEM pretreatment. Proximal tubular necrosis produced by NDPS administration was reduced by DEM but not prevented. Pretreatment with the cysteine conjugate beta-lyase inhibitor amino-oxyacetic acid (0.5 mmol/kg, i.p.) 1 h prior to NDPS (0.4 or 1.0 mmol/kg) markedly attenuated all NDPS-induced effects on renal function and morphology. These results suggest that glutathione does not play a protective role against NDPS-induced renal effects and that a glutathione or cysteine conjugate of NDPS might contribute to NDPS-induced nephrotoxicity.
N-(3,5-二氯苯基)琥珀酰亚胺（NDPS）是一种实验性农用杀菌剂，已被证明对斯普拉格-道利大鼠和费希尔344大鼠具有选择性肾毒性。先前的研究表明，一种有毒代谢物导致或引发了急性NDPS诱导的肾毒性。本研究的目的是探讨谷胱甘肽在NDPS诱导的肾脏效应中的作用。在一组实验中，雄性斯普拉格-道利大鼠或费希尔344大鼠单次腹腔注射NDPS（0.4或1.0 mmol/kg）或芝麻油（2.5 ml/kg）。在1、3、6或24小时处死大鼠，测定肝脏和肾皮质中还原型（GSH）和氧化型（GSSG）谷胱甘肽的浓度。在两种大鼠品系中，给予NDPS（0.4或1.0 mmol/kg）后，肝脏和肾脏中的GSH浓度在1和3小时出现小幅下降，但GSSG浓度在1和3小时出现中度升高。在24小时时，GSH和GSSG浓度均升高，尤其是在肾脏中。在第二组实验中，大鼠在给予NDPS（0.2、0.4或1.0 mmol/kg，腹腔注射）或芝麻油（2.5 ml/kg，腹腔注射）前1小时，先用谷胱甘肽消耗剂马来酸二乙酯（DEM）（0.4 ml/kg，腹腔注射）进行预处理，并在24和48小时监测肾功能。DEM预处理减弱了NDPS（0.4或1.0 mmol/kg）在斯普拉格-道利大鼠和费希尔344大鼠中引起的尿量增加（24和48小时）、蛋白尿、糖尿、血尿以及血尿素氮（BUN）浓度升高。NDPS诱导的肾脏重量增加通常也可被DEM预处理阻止。DEM可减轻NDPS给药引起的近端肾小管坏死，但不能完全阻止。在给予NDPS（0.4或1.0 mmol/kg）前1小时，用半胱氨酸共轭β-裂解酶抑制剂氨基氧乙酸（0.5 mmol/kg，腹腔注射）进行预处理，可显著减弱NDPS对肾功能和形态的所有影响。这些结果表明，谷胱甘肽对NDPS诱导的肾脏效应不发挥保护作用，并且NDPS的谷胱甘肽或半胱氨酸共轭物可能导致NDPS诱导的肾毒性。
