Yang D J, Lahoda E P, Brown P I, Rankin G O
Fundam Appl Toxicol. 1985 Dec;5(6 Pt 1):1119-27. doi: 10.1016/0272-0590(85)90148-4.
Previous studies have shown that reducing the chlorine content of the experimental agricultural fungicide N-(3,5-dichlorophenyl)succinimide (3,5-NDPS) produces compounds with reduced nephrotoxic potential. The purpose of this study was to determine the importance of the ring position of the two chlorine atoms for the nephrotoxic potential of 3,5-NDPS in rats. Male Sprague-Dawley or Fischer 344 rats were administered a single intraperitoneal injection of a N-(dichlorophenyl)succinimide (0.4 or 1.0 mmol/kg) or vehicle (2.5 ml/kg), and renal function was monitored at 24 and 48 hr. The most nephrotoxic NDPS isomer in both rat strains was 3,5-NDPS. In Sprague-Dawley rats 2,4-, 2,5- and 3,4-NDPS were weakly nephrotoxic. In Fischer 344 rats, 2,4-NDPS (1.0 mmol/kg) and 3,5-NDPS (0.4 mmol/kg) produced similar nephrotoxicity. Weak renal effects were produced by 3,4-NDPS in Fischer 344 rats. The order of increasing nephrotoxicity did not correlate well with the increasing partition coefficients or fungicidal activities of the compounds. These results indicate that 3,5-NDPS is the most nephrotoxic NDPS isomer in rats, and that partition coefficients alone are not good predictors of nephrotoxic potential in this series. In addition, these results do not support a correlation between the fungicidal and nephrotoxic mechanisms of action of these compounds.
先前的研究表明，降低实验性农用杀菌剂N-(3,5-二氯苯基)琥珀酰亚胺(3,5-NDPS)的氯含量可产生肾毒性潜力降低的化合物。本研究的目的是确定两个氯原子的环位置对大鼠体内3,5-NDPS肾毒性潜力的重要性。给雄性Sprague-Dawley或Fischer 344大鼠单次腹腔注射N-(二氯苯基)琥珀酰亚胺(0.4或1.0 mmol/kg)或赋形剂(2.5 ml/kg)，并在24和48小时监测肾功能。两种大鼠品系中肾毒性最强的NDPS异构体是3,5-NDPS。在Sprague-Dawley大鼠中，2,4-、2,5-和3,4-NDPS具有弱肾毒性。在Fischer 344大鼠中，2,4-NDPS(1.0 mmol/kg)和3,5-NDPS(0.4 mmol/kg)产生相似的肾毒性。3,4-NDPS在Fischer 344大鼠中产生微弱的肾脏效应。肾毒性增加的顺序与化合物分配系数或杀菌活性的增加没有很好的相关性。这些结果表明，3,5-NDPS是大鼠中肾毒性最强的NDPS异构体，并且仅分配系数不是该系列中肾毒性潜力的良好预测指标。此外，这些结果不支持这些化合物的杀菌作用机制与肾毒性作用机制之间的相关性。
