Yang D J, Richmond C D, Teets V J, Brown P I, Rankin G O
Toxicology. 1985 Oct;37(1-2):65-77. doi: 10.1016/0300-483x(85)90113-1.
N-(3,5-Dichlorophenyl)succinimide (NDPS) has proven to be an effective experimental agricultural fungicide. However, NDPS produces marked nephrotoxicity in Sprague-Dawley and Fischer 344 rats. The purpose of this study was to determine the importance of an intact, unsubstituted succinimide ring for acute NDPS-induced nephrotoxicity. Structural modifications included ring opening, reduction of one or both carbonyl groups, breaking the ethylene carbon-carbon bond and mono- or dialkyl substitution on the succinimide ring. Sprague-Dawley or Fischer 344 rats were administered NDPS or an NDPS analog (0.1, 0.2, 0.4, 0.8 or 1.0 mmol/kg) or sesame oil (2.5 ml/kg, i.p.) and renal function was monitored at 24 h and 48 h. All structural modifications produced compounds with markedly reduced nephrotoxic potential in both Sprague-Dawley and Fischer 344 rats when compared to NDPS. However, N,N-diacetyl-3,5-dichloroaniline and N-(3,5-dichlorophenyl)pyrrolidine-2-one were more lethal than NDPS. The reduced renal effects of the NDPS analogs did not correlate with lipophilic character. These results indicate that an intact, unsubstituted succinimide ring is optimal for acute NDPS-induced nephrotoxicity.
N-(3,5-二氯苯基)琥珀酰亚胺（NDPS）已被证明是一种有效的实验性农用杀菌剂。然而，NDPS在Sprague-Dawley和Fischer 344大鼠中会产生明显的肾毒性。本研究的目的是确定完整、未取代的琥珀酰亚胺环对于NDPS急性诱导肾毒性的重要性。结构修饰包括开环、一个或两个羰基的还原、破坏乙烯碳-碳键以及在琥珀酰亚胺环上进行单烷基或二烷基取代。给Sprague-Dawley或Fischer 344大鼠给予NDPS或NDPS类似物（0.1、0.2、0.4、0.8或1.0 mmol/kg）或芝麻油（2.5 ml/kg，腹腔注射），并在24小时和48小时监测肾功能。与NDPS相比，所有结构修饰产生的化合物在Sprague-Dawley和Fischer 344大鼠中的肾毒性潜力均显著降低。然而，N,N-二乙酰基-3,5-二氯苯胺和N-(3,5-二氯苯基)吡咯烷-2-酮比NDPS更具致死性。NDPS类似物降低的肾脏效应与亲脂性特征无关。这些结果表明，完整、未取代的琥珀酰亚胺环对于NDPS急性诱导的肾毒性是最佳的。
