The agricultural fungicide, N-(3,5-dichlorophenyl)succinimide (NDPS) induces acute polyuric renal failure which is attenuated by pretreatment with the glutathione depletors, diethyl maleate or buthionine sulfoximine (BSO). In the present study, the temporal aspects of BSO attenuation of NDPS nephrotoxicity were investigated. In addition, the ability of BSO to alter the renal accumulation of selected organic ions was examined as a possible mechanism for BSO's ability to attenuate NDPS nephrotoxicity. In the first set of experiments, NDPS (0.2 or 0.4 mmol/kg) or vehicle (sesame oil, 2.5 ml/kg) was administered intraperitoneally (i.p.) to groups of male Fischer 344 rats (4-8 rats/group) 0.25 or 2 h prior to BSO (890 mg/kg, i.p.) and renal function was monitored at 24 and 48 h. NDPS (0.4 mmol/kg) nephrotoxicity was markedly attenuated by administration of BSO at 0.25 h post-NDPS, but was not substantially altered by injection of BSO at 2 h post-NDPS. NDPS (0.2 mmol/kg)-induced renal effects were not potentiated by BSO injected at 0.25 h post-NDPS, and only 1 of 8 rats exhibited marked nephrotoxicity when BSO was administered at 2 h post-NDPS. In the second set of experiments, rats (4/group) were administered BSO (890 mg/kg, i.p.) or vehicle (0.9% saline, 10 ml/kg) and kidneys harvested at 2 or 5 h post-treatment. The ability of renal cortical slices to accumulate organic ions (p-aminohippurate [PAH], alpha-aminoisobutryic acid [AIB] or tetraethylammonium [TEA]) during a 90 min incubation was studied. Only TEA accumulation by renal cortical slices prepared from the 2 h post-treatment group was reduced. Studies were also conducted to examine the in vitro effects of BSO (10(-7)-10(-4) M) on the accumulation of PAH, AIB and TEA by renal cortical slices following 5, 15 or 90 min co-incubations of BSO and an organic ion BSO had no significant effects on the accumulation of any organic ion studied at any time point. These results indicate that BSO can still attenuate NDPS nephrotoxicity when administered at 0.25 h post-NDPS, but BSO loses effectiveness when given 2 h post-NDPS. These results also suggest that BSO is attenuating NDPS nephrotoxicity via glutathione depletion rather than altering renal accumulation of NDPS metabolites via renal PAH, TEA or AIB transporters.

中文翻译：

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丁硫氨酸亚砜亚胺（BSO）和N-（3,5-二氯苯基）琥珀酰亚胺肾毒性：BSO给药的时间方面和BSO对肾脏转运系统的影响。

农业杀真菌剂N-（3,5-二氯苯基）琥珀酰亚胺（NDPS）诱导急性多尿性肾衰竭，可通过用谷胱甘肽耗竭剂，马来酸二乙酯或丁硫氨酸亚砜（BSO）进行预处理来减轻这种急性肾衰竭。在本研究中，研究了BSO减弱NDPS肾毒性的时间方面。此外，还检查了BSO改变所选有机离子在肾脏中积累的能力，作为BSO减弱NDPS肾毒性能力的可能机制。在第一组实验中，将NDPS（0.2或0.4 mmol / kg）或媒介物（芝麻油，2.5 ml / kg）腹膜内（ip）给予雄性Fischer 344只大鼠（4-8只大鼠/组）0.25或BSO前2 h（890 mg / kg，ip），在24和48 h监测肾功能。NDPS（0。在NDPS后0.25小时通过BSO给药可明显减轻4 mmol / kg）的肾毒性，但在NDPS后2 h注射BSO并没有实质性改变。在NDPS后0.25小时注射BSO不能增强NDPS（0.2 mmol / kg）诱导的肾功能，并且在NDPS后2小时给予BSO时，八只大鼠中只有1只显示出明显的肾毒性。在第二组实验中，对大鼠（4只/组）给予BSO（890 mg / kg，腹腔内）或赋形剂（0.9％盐水，10 ml / kg），并在治疗后2或5小时收获肾脏。研究了在90分钟的孵育过程中，肾皮质切片积聚有机离子（对氨基马尿酸盐[PAH]，α-氨基异丁酸[AIB]或四乙铵[TEA]）的能力。仅减少了从治疗后2 h组制备的肾皮质切片的TEA积累。还进行了研究，以研究BSO（10（-7）-10（-4）M）在5、15或90分钟的共孵育后肾皮质切片对PAH，AIB和TEA积累的体外作用。 BSO和有机离子BSO对任何时间点研究的任何有机离子的累积均无显着影响。这些结果表明，在NDPS后0.25小时给药时，BSO仍可减弱NDPS的肾毒性，但在NDPS后2小时给药时，BSO则失去效力。这些结果还表明，BSO通过谷胱甘肽耗竭来减轻NDPS的肾毒性，而不是通过肾脏PAH，TEA或AIB转运蛋白改变NDPS代谢产物在肾脏的蓄积。BSO和有机离子共孵育15或90分钟BSO对在任何时间点研究的任何有机离子的积累均无显着影响。这些结果表明，在NDPS后0.25小时给药时，BSO仍可减弱NDPS的肾毒性，但在NDPS后2小时给药时，BSO则失去效力。这些结果还表明，BSO通过谷胱甘肽消耗来减轻NDPS的肾毒性，而不是通过肾脏PAH，TEA或AIB转运蛋白改变NDPS代谢产物的肾脏积累。BSO和有机离子共孵育15或90分钟BSO对在任何时间点研究的任何有机离子的积累均无显着影响。这些结果表明，在NDPS后0.25小时给药时，BSO仍可减弱NDPS的肾毒性，但在NDPS后2小时给药时，BSO则失去效力。这些结果还表明，BSO通过谷胱甘肽耗竭来减轻NDPS的肾毒性，而不是通过肾脏PAH，TEA或AIB转运蛋白改变NDPS代谢产物在肾脏的蓄积。