Covalent binding of metabolites of acetaminophen to kidney protein and depletion of renal glutathione.
Covalent binding of metabolites of acetaminophen to kidney protein and depletion of renal glutathione.
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对乙酰氨基酚代谢物与肾蛋白的共价结合和肾谷胱甘肽的消耗。
DOI：
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发表时间：
1978
影响因子：
3.5
通讯作者：
G. Duggin
中科院分区：
文献类型：
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作者：
G. Mudge;M. Gemborys;G. Duggin
在 CD-1 小鼠和 Sprague-Dawley 大鼠中进行实验，以确定先前描述的对乙酰氨基酚急性肝毒性的生化变化可能适用于肾脏的程度。腹腔注射对乙酰氨基酚后，测量肝脏、肾皮质和肾乳头的组织谷胱甘肽以及对乙酰氨基酚氚化代谢物与组织蛋白的共价结合。小鼠中的谷胱甘肽还原程度高于大鼠，肝脏中的谷胱甘肽还原程度高于肾脏，但在任一组织中均未出现氧化型谷胱甘肽。同样，小鼠中的共价结合高于大鼠，肝脏中的共价结合高于肾脏中的共价结合。共价结合的测定对标记药物的痕量放射化学杂质极其敏感。先前给予3-甲基胆蒽后，肝脏中引起的变化远大于肾脏中的变化，这表明对乙酰氨基酚反应性代谢物的形成在每个器官中通过略有不同的机制发生。当剂量低于与可证实的急性毒性相关的剂量时，肾乳头与蛋白质共价结合的持续时间比肾皮质或肝脏的更长。该结果可能适用于急性和慢性肾毒性的发病机制。
Experiments in CD-1 mice and Sprague-Dawley rats were carried out to determine the extent to which biochemical changes described previously for acute acetaminophen-induced hepatotoxicity might be applicable to the kidney. After intraperitoneal injection of acetaminophen, tissue glutathione and covalent binding of tritiated metabolites of acetaminophen to tissue protein were measured for liver, kidney cortex and kidney papilla. Glutathione was reduced more in mice than in rats, and more in liver than in kidney, without appearance of oxidized glutathione in either tissue. Covalent binding was likewise greater in mice than in rats and greater in liver than in kidney. The determination of covalent binding was extremely sensitive to the trace radiochemical impurities of the labeled drug. With prior administration of 3-methyl-cholanthrene, the induced changes were far greater in liver than in kidney, suggesting that the formation of a reactive metabolite from acetaminophen occurred in each organ by slightly different mechanisms. At doses less than those associated with demonstrable acute toxicity, the duration of covalent binding to protein was longer for renal papilla than for renal cortex or for liver. The results may be applicable to the pathogenesis of both acute and chronic nephrotoxicity.