Rankin G O, Shih H C, Teets V J, Yang D J, Nicoll D W, Brown P I
Department of Pharmacology, Marshall University School of Medicine, Huntington, WV 25755-9310.
Toxicology. 1991;68(3):307-25. doi: 10.1016/0300-483x(91)90077-e.
The agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) induces nephrotoxicity via one or more metabolites. Previous studies suggested that glutathione is important for mediating NDPS-induced nephropathy. The purpose of this study was to examine the possibility that a glutathione or cysteine conjugate of NDPS or an NDPS metabolite might be the penultimate or ultimate nephrotoxic species. In one set of experiments, male Fischer 344 rats were administered intraperitoneally (i.p.) NDPS (0.4 or 1.0 mmol/kg) 1 h after pretreatment with the gamma glutamyltranspeptidase inhibitor AT-125 (acivicin) (10 mg/kg, i.p.) and renal function was monitored at 24 and 48 h. In general, AT-125 pretreatment had few effects on NDPS-induced nephropathy. In a second set of experiments, rats were treated i.p. or orally (p.o.) with a putative glutathione (S-(2-(N-(3,5-dichlorophenyl)succinimidyl)glutathione (NDPSG), a cysteine (S-(2-(N-(3,5-dichlorophenyl)succinimidyl)cysteine (NDPSC) (as the methyl ester) or N-acetylcysteine (S-(2-(N-(3,5-dichlorophenyl)succinimidyl)-N-acetylcysteine (NDPSN) conjugate of NDPS (0.2, 0.4 or 1.0 mmol/kg) or vehicle and renal function was monitored at 24 and 48 h. An intramolecular cyclization product of NDPSC, 5-carbomethoxy-2-(N-(3,5-dichlorophenyl)carbamoylmethyl)-1,4-th iazane-3-one (NDCTO) was also examined for nephrotoxic potential. None of the compounds produced toxicologically important changes in renal function or morphology. The in vitro ability of the conjugates to alter organic ion accumulation by cortical slices was also examined. All of the conjugates tested caused a reduction in p-aminohippurate (PAH) accumulation at a conjugate bath concentration of 10(-4) M, but none of the conjugates reduced tetraethylammonium (TEA) uptake. In a third experiment, the ability of the cysteine conjugate beta-lyase inhibitor aminooxyacetic acid (AOAA) (0.5 mmol/kg, i.p.) to alter the nephrotoxicity induced by two NDPS metabolites, N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS) or N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (NDHSA) (0.2 mmol/kg, i.p.), was examined. AOAA pretreatment had no effect on NDHS- or NDHSA-induced nephrotoxicity. These results do not support a role for a glutathione or cysteine conjugate of NDPS or and NDPS metabolite as being the penultimate or ultimate nephrotoxic species.
农用杀菌剂N-(3,5-二氯苯基)琥珀酰亚胺(NDPS)通过一种或多种代谢物诱导肾毒性。先前的研究表明，谷胱甘肽对于介导NDPS诱导的肾病很重要。本研究的目的是检验NDPS或NDPS代谢物的谷胱甘肽或半胱氨酸共轭物可能是倒数第二个或最终肾毒性物质的可能性。在一组实验中，雄性Fischer 344大鼠在腹腔注射γ-谷氨酰转肽酶抑制剂AT-125(阿西维辛)(10mg/kg，腹腔注射)1小时后，腹腔注射NDPS(0.4或1.0mmol/kg)，并在24小时和48小时监测肾功能。一般来说，AT-125预处理对NDPS诱导的肾病影响很小。在第二组实验中，大鼠腹腔注射或口服假定的谷胱甘肽(S-(2-(N-(3,5-二氯苯基)琥珀酰亚胺基)谷胱甘肽(NDPSG)、半胱氨酸(S-(2-(N-(3,5-二氯苯基)琥珀酰亚胺基)半胱氨酸(NDPSC)(作为甲酯)或NDPS的N-乙酰半胱氨酸(S-(2-(N-(3,5-二氯苯基)琥珀酰亚胺基)-N-乙酰半胱氨酸(NDPSN)共轭物(0.2、0.4或1.0mmol/kg)或赋形剂，并在24小时和48小时监测肾功能。还检测了NDPSC的分子内环化产物5-甲氧羰基-2-(N-(3,5-二氯苯基)氨基甲酰甲基)-1,4-噻唑烷-3-酮(NDCTO)的肾毒性潜力。这些化合物均未在肾功能或形态学上产生毒理学上重要的变化。还检测了共轭物在体外改变皮质切片有机离子蓄积的能力。所有测试的共轭物在共轭物浴浓度为10(-4)M时均导致对氨基马尿酸(PAH)蓄积减少，但没有一种共轭物降低四乙铵(TEA)摄取。在第三个实验中，检测了半胱氨酸共轭物β-裂解酶抑制剂氨氧基乙酸(AOAA)(0.5mmol/kg，腹腔注射)改变两种NDPS代谢物N-(3,5-二氯苯基)-2-羟基琥珀酰亚胺(NDHS)或N-(3,5-二氯苯基)-2-羟基琥珀酰胺酸(NDHSA)(0.2mmol/kg，腹腔注射)诱导的肾毒性的能力。AOAA预处理对NDHS或NDHSA诱导的肾毒性没有影响。这些结果不支持NDPS或NDPS代谢物的谷胱甘肽或半胱氨酸共轭物作为倒数第二个或最终肾毒性物质的作用。
