Yang D J, Lahoda E P, Brown P I, Rankin G O
Toxicol Lett. 1986 Jun;31(3):219-28. doi: 10.1016/0378-4274(86)90129-3.
Previous studies have shown that the experimental agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) produces acute nephrotoxicity via a reactive intermediate in Sprague-Dawley and Fischer-344 rats. The purpose of this study was to examine if an arene oxide intermediate is a toxic metabolite contributing to NDPS-induced nephropathy in rats. N-(3,4,5-Trichlorophenyl)succinimide (NTPS) was prepared to prevent arene oxide formation of NDPS, and its nephrotoxic potential was determined in Sprague-Dawley and Fischer-344 rats. Rats were administered a single intraperitoneal injection of NTPS (0.4 or 1.0 mmol/kg) or sesame oil (2.5 ml/kg), and renal function was monitored at 24 and 48 h. NTPS (0.4 or 1.0 mmol/kg) administration produced diuresis, proteinuria, glucosuria, hematuria, decreased accumulation of p-aminohippurate (PAH) and tetraethylammonium (TEA), and increased blood urea nitrogen (BUN) and kidney weight in both strains. Extensive proximal tubular necrosis was observed in both strains of rat. The magnitude of these effects was similar to those previously reported for NDPS-induced nephrotoxicity in Sprague-Dawley and Fischer-344 rats. It was concluded that an arene oxide metabolite does not contribute to the nephrotoxic potential of NDPS. The results of the present study indicate that lipophilic character alone is not a good predictor of the nephrotoxic potential for NDPS and NTPS.
先前的研究表明，实验性农用杀菌剂N-(3,5-二氯苯基)琥珀酰亚胺(NDPS)在Sprague-Dawley和Fischer-344大鼠中通过活性中间体产生急性肾毒性。本研究的目的是检验芳烃氧化物中间体是否是导致大鼠NDPS诱导的肾病的有毒代谢物。制备N-(3,4,5-三氯苯基)琥珀酰亚胺(NTPS)以防止NDPS形成芳烃氧化物，并在Sprague-Dawley和Fischer-344大鼠中测定其肾毒性潜力。给大鼠单次腹腔注射NTPS(0.4或1.0 mmol/kg)或芝麻油(2.5 ml/kg)，并在24和48小时监测肾功能。给予NTPS(0.4或1.0 mmol/kg)导致两种品系大鼠出现利尿、蛋白尿、糖尿、血尿、对氨基马尿酸(PAH)和四乙铵(TEA)蓄积减少，以及血尿素氮(BUN)和肾脏重量增加。在两种品系大鼠中均观察到广泛的近端肾小管坏死。这些效应的程度与先前报道的Sprague-Dawley和Fischer-344大鼠中NDPS诱导的肾毒性相似。得出的结论是，芳烃氧化物代谢物对NDPS的肾毒性潜力没有影响。本研究结果表明，仅亲脂性特征并不是NDPS和NTPS肾毒性潜力的良好预测指标。
