Rankin G O, Yang D J, Richmond C D, Teets V J, Wang R T, Brown P I
Toxicology. 1987 Sep;45(3):269-89. doi: 10.1016/0300-483x(87)90018-7.
N-(3,5-Dichlorophenyl)succinimide (NDPS) is an experimental agricultural fungicide which has been shown to be a selective nephrotoxin. The purpose of this study was to determine if a NDPS metabolite contributes to acute NDPS-induced nephrotoxicity. Male Sprague-Dawley or Fischer 344 rats were pretreated with a microsomal enzyme inducer [phenobarbital (PB) or 3-methylcholanthrene (3-MC)] or inhibitor [cobalt chloride (CoCl2) or piperonyl butoxide (PIBX)] followed by a single intraperitoneal injection of NDPS (0.2, 0.4 or 1.0 mmol/kg) or vehicle (sesame oil, 2.5 ml/kg). Renal function was monitored at 24 and 48 h. CoCl2 or PIBX pretreatment reduced NDPS-induced diuresis, proteinuria and hematuria, and reduced the increases seen in the blood urea nitrogen (BUN) concentration and kidney weight. NDPS-induced decreases in organic ion accumulation were not markedly altered by CoCl2 or PIBX pretreatment. PB pretreatment enhanced all NDPS- (0.2 mmol/kg) induced renal effects, while 3-MC pretreatment protected against NDPS-induced diuresis, proteinuria, hematuria, and increases in the BUN concentration observed in both rat strains. Kidney weight and organic ion uptake changes were not substantially different between NDPS-treated rats with or without 3-MC pretreatment. It was concluded that a metabolite(s) contributes to or is responsible for acute NDPS-induced nephrotoxicity and that at least 1 toxic metabolite might be of extrarenal origin.
N-(3,5-二氯苯基)琥珀酰亚胺（NDPS）是一种实验性农用杀菌剂，已被证明是一种选择性肾毒素。本研究的目的是确定NDPS的一种代谢产物是否会导致急性NDPS诱导的肾毒性。雄性Sprague-Dawley或Fischer 344大鼠先用微粒体酶诱导剂[苯巴比妥（PB）或3-甲基胆蒽（3-MC）]或抑制剂[氯化钴（CoCl2）或胡椒基丁醚（PIBX）]进行预处理，然后单次腹腔注射NDPS（0.2、0.4或1.0 mmol/kg）或赋形剂（芝麻油，2.5 ml/kg）。在24小时和48小时监测肾功能。CoCl2或PIBX预处理可减轻NDPS诱导的多尿、蛋白尿和血尿，并降低血尿素氮（BUN）浓度和肾脏重量的增加。CoCl2或PIBX预处理对NDPS诱导的有机离子蓄积减少没有明显影响。PB预处理增强了所有NDPS（0.2 mmol/kg）诱导的肾脏效应，而3-MC预处理可预防两种大鼠品系中观察到的NDPS诱导的多尿、蛋白尿、血尿和BUN浓度增加。有无3-MC预处理的NDPS处理大鼠之间的肾脏重量和有机离子摄取变化没有实质性差异。得出的结论是，一种或多种代谢产物导致或促成急性NDPS诱导的肾毒性，并且至少有一种有毒代谢产物可能来源于肾外。
