Hong S K, Anestis D K, Brown P I, Rankin G O
Department of Pharmacology, Marshall University School of Medicine, Huntington, WV 25704-9388, USA.
Toxicology. 1999 Jan 1;132(1):43-55. doi: 10.1016/s0300-483x(98)00140-1.
The agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) is an acute nephrotoxicant in rats. Our previous studies have strongly suggested that glucuronide conjugation of NDPS metabolites might be a bioactivation step mediating NDPS nephrotoxicity. In this study, effects of substrates and/or inhibitors of primarily glucuronidation on NDPS nephrotoxicity were examined to explore further the role of glucuronidation in NDPS nephrotoxicity. Male Fischer 344 rats (4-6/group) were administered one of the following intraperitoneal (i.p.) pretreatments (dose, pretreatment time) prior to NDPS (0.4 mmol/kg) or NDPS vehicle (sesame oil, 2.5 ml/kg): (1) no pretreatment; (2) borneol (900 mg/kg, 30 min); (3) eugenol (500 mg/kg per day, 3 days); (4) clofibric acid (400 mg/kg, 15 min before (1/2 dose) and 3 h after (1/2 dose)), or (5) valproic acid, sodium salt (1.0 mmol/kg, 15 min). Following NDPS or NDPS vehicle administration, renal function was monitored at 24 and 48 h. Pretreatment with borneol or eugenol, substrates for ether glucuronidation and sulfation (mainly glucuronidation), afforded complete protection against NDPS nephrotoxicity. Substrates for acyl glucuronidation, clofibric acid or valproic acid, mildly reduced or had little effect on NDPS nephrotoxicity, respectively. These results suggest that ether glucuronide conjugates of NDPS metabolites, rather than acyl glucuronide conjugates, may be the primary ultimate nephrotoxicant species mediating NDPS nephrotoxicity.
农业杀菌剂N-(3,5-二氯苯基)琥珀酰亚胺(NDPS)对大鼠是一种急性肾毒物。我们之前的研究强烈提示，NDPS代谢物的葡萄糖醛酸结合可能是介导NDPS肾毒性的生物活化步骤。在本研究中，检测了主要葡萄糖醛酸化的底物和/或抑制剂对NDPS肾毒性的影响，以进一步探究葡萄糖醛酸化在NDPS肾毒性中的作用。雄性Fischer 344大鼠(每组4 - 6只)在给予NDPS(0.4 mmol/kg)或NDPS溶媒(芝麻油，2.5 ml/kg)之前，接受以下腹腔内(i.p.)预处理之一(剂量、预处理时间)：(1)不预处理；(2)冰片(900 mg/kg，30分钟)；(3)丁香酚(500 mg/kg/天，3天)；(4)氯贝酸(400 mg/kg，(1/2剂量)前15分钟和(1/2剂量)后3小时)，或(5)丙戊酸钠(1.0 mmol/kg，15分钟)。给予NDPS或NDPS溶媒后，在24小时和48小时监测肾功能。用冰片或丁香酚预处理，即醚葡萄糖醛酸化和硫酸化(主要是葡萄糖醛酸化)的底物，可完全保护大鼠免受NDPS肾毒性。酰基葡萄糖醛酸化的底物氯贝酸或丙戊酸，分别轻度降低或对NDPS肾毒性影响很小。这些结果提示，NDPS代谢物的醚葡萄糖醛酸结合物而非酰基葡萄糖醛酸结合物，可能是介导NDPS肾毒性的主要最终肾毒物。
