Acetaminophen nephrotoxicity in the CD-1 mouse. II. Protection by probenecid and AT-125 without diminution of renal covalent binding.
Acetaminophen nephrotoxicity in the CD-1 mouse. II. Protection by probenecid and AT-125 without diminution of renal covalent binding.
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对乙酰氨基酚对 CD-1 小鼠的肾毒性。
DOI：
10.1006/taap.1996.0020
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发表时间：
1996
期刊：
影响因子：
--
通讯作者：
Cohen,SD
中科院分区：
文献类型：
--
作者：
EmeighHart,SG;Wyand,DS;Khairallah,EA;Cohen,SD
对禁食18小时的3月龄雄性CD-1小鼠给予对乙酰氨基酚（APAP）（600 mg/kg，ip）导致肾曲近端小管坏死，血浆尿素氮（BUN）相应升高。在APAP前30 min给予γ-谷氨酰转肽酶抑制剂L-（αS，5S）-α-氨基-3-氯-4，5-二羟基-5-异恶唑乙酸（AT-125）（50 mg/kg，ip）可显著减轻APAP引起的组织病理学损伤和BUN升高。在APAP攻击前30分钟给予有机阴离子转运抑制剂丙磺舒（150 mg/kg，ip）也可防止APAP诱导的BUN升高和可检测的组织病理学变化。相比之下，在APAP前1小时用半胱氨酸缀合物β-裂解酶抑制剂（氨氧基）乙酸（100 mg/kg，ip）预处理小鼠并没有改变肾毒性。没有任何预处理改变APAP诱导的血浆山梨醇脱氢酶活性升高，也没有任何可检测到的变化，在APAP挑战后的肝脏组织病理学。尽管丙磺舒和AT-125对肾毒性具有保护作用，但它们并不影响APAP后4小时免疫化学可检测到的与蛋白质共价结合的水平或肾谷胱甘肽的消耗。因此，保护作用似乎与对肾脏APAP摄取或活化的影响无关，间接表明APAP-谷胱甘肽结合物可能导致观察到的肾毒性。
Acetaminophen (APAP) administration (600 mg/kg, ip) to 18-hr fasted, 3-month-old male CD-1 mice results in necrosis of the convoluted renal proximal tubules with a corresponding elevation of plasma urea nitrogen (BUN). Administration of the γ-glutamyl transpeptidase inhibitor,L-(αS,5S)-α-amino-3-chloro-4,5-dihydroxy-5-isoxazoleacetic acid (AT-125) (50 mg/kg, ip), to mice 30 min before APAP significantly diminished the APAP-induced histopathologic damage and BUN elevation. Administration of the organic-anion transport inhibitor, probenecid (150 mg/kg, ip), 30 min before APAP challenge also protected against the APAP-induced elevation of BUN and detectable histopathologic changes. By contrast, pretreatment of mice with the cysteine conjugate β-lyase inhibitor, (aminooxy)acetic acid (100 mg/kg, ip), 1 hr before APAP did not alter nephrotoxicity. None of the pretreatments altered the APAP-induced elevation of plasma sorbitol dehydrogenase activity, nor were there any detectable changes in liver histopathology after APAP challenge. Despite the protective effects of both probenecid and AT-125 against nephrotoxicity, they did not affect either the level of immunochemically detectable covalent binding to protein or the depletion of renal glutathione at 4 hr after APAP. Thus, the protection appears independent of effects on renal APAP uptake or activation and indirectly suggests that an APAP–glutathione conjugate may contribute to the observed nephrotoxicity.