Rankin G O, Yang D J, Teets V J, Lo H H, Brown P I
Toxicology. 1987 May;44(2):181-92. doi: 10.1016/0300-483x(87)90148-x.
N-(3,5-Dichlorophenyl)succinimide (NDPS), an experimental agricultural fungicide, has been shown to produce selective nephrotoxicity in rats. Previous studies have shown that a metabolite(s) of extrarenal origin contributes to acute NDPS-induced nephrotoxicity. The purpose of this study was to determine if the organic acid transport inhibitor probenecid could modify the renal toxicity produced by NDPS administration. Male Fischer 344 rats were administered a single intraperitoneal (i.p.) injection of probenecid (60, 90 and 120 mg/kg) or 0.9% saline (1.0 ml/kg) followed 30 min later by NDPS (0.4 or 1.0 mmol/kg, i.p.) or sesame oil (2.5 ml/kg, i.p.) Renal function was monitored at 24 h and 48 h. Probenecid (60 mg/kg) did not markedly alter NDPS-induced renal effects on either post-treatment day. However, pretreatment with probenecid (90 or 120 mg/kg) blocked or attenuated the diuresis, increased proteinuria, decreased tetraethylammonium (TEA), uptake, elevation in blood urea nitrogen (BUN) concentration and increased kidney weight produced by NDPS (0.4 mmol/kg) administration. Only increased kidney weight and BUN concentration, and decreased lactate-stimulated p-aminohippurate (PAH) uptake were altered by probenecid (120 mg/kg) pretreatment when NDPS (1.0 mmol/kg) was given. NDPS-induced changes in renal morphology were not prevented by pretreatment with any probenecid dose. These results suggest that at least one nephrotoxic metabolite of NDPS is an organic acid. However, this acidic metabolite might not be the major nephrotoxic metabolite or a precursor to the major nephrotoxic metabolite(s). The identity of these metabolites remains to be determined.
N-(3,5-二氯苯基)琥珀酰亚胺（NDPS）是一种实验性农用杀菌剂，已被证明会在大鼠中产生选择性肾毒性。先前的研究表明，肾外来源的一种或多种代谢产物会导致急性NDPS诱导的肾毒性。本研究的目的是确定有机酸转运抑制剂丙磺舒是否能改变NDPS给药所产生的肾毒性。对雄性Fischer 344大鼠进行单次腹腔注射丙磺舒（60、90和120 mg/kg）或0.9%生理盐水（1.0 ml/kg），30分钟后再腹腔注射NDPS（0.4或1.0 mmol/kg）或芝麻油（2.5 ml/kg）。在24小时和48小时监测肾功能。丙磺舒（60 mg/kg）在任何一个治疗后日都未显著改变NDPS诱导的肾脏效应。然而，用丙磺舒（90或120 mg/kg）预处理可阻断或减轻NDPS（0.4 mmol/kg）给药所产生的利尿、蛋白尿增加、四乙铵（TEA）摄取减少、血尿素氮（BUN）浓度升高和肾脏重量增加。当给予NDPS（1.0 mmol/kg）时，只有肾脏重量增加和BUN浓度升高以及乳酸刺激的对氨基马尿酸（PAH）摄取减少可被丙磺舒（120 mg/kg）预处理所改变。用任何丙磺舒剂量预处理都不能预防NDPS诱导的肾脏形态学变化。这些结果表明，NDPS至少有一种肾毒性代谢产物是一种有机酸。然而，这种酸性代谢产物可能不是主要的肾毒性代谢产物或主要肾毒性代谢产物的前体。这些代谢产物的身份仍有待确定。
