Renal necrosis, glutathione depletion, and covalent binding after acetaminophen.
Renal necrosis, glutathione depletion, and covalent binding after acetaminophen.
复制标题
对乙酰氨基酚后肾坏死、谷胱甘肽耗竭和共价结合。
DOI：
10.1016/0041-008x(78)90139-4
复制
发表时间：
1978
影响因子：
3.8
通讯作者：
J. Mitchell
中科院分区：
文献类型：
--
作者：
R. Mcmurtry;W. Snodgrass;J. Mitchell
单次皮下注射对乙酰氨基酚后，雄性Fischer大鼠发生剂量依赖性急性肾坏死。引起大鼠肾脏和肝脏坏死的[3 H]对乙酰氨基酚剂量（750-900 mg/kg）显著消耗靶器官谷胱甘肽，并导致大量放射性标记代谢物与肾脏和肝脏蛋白结合。氯化钴（一种肝脏和肾脏药物代谢抑制剂）预处理可降低靶器官组织中代谢物的不可逆结合和谷胱甘肽耗竭，同时保护组织免受损伤。3-甲基胆蒽预处理增强肝坏死和共价结合的代谢产物，肝蛋白在体内和微粒体蛋白在体外，但对相应的肾脏参数的影响不大。放射性标记的对乙酰氨基酚与大鼠肾或肝微粒体的共价结合具有酶依赖性，需要NADPH和氧气。因此，对乙酰氨基酚诱导的肾和肝坏死显然是由对乙酰氨基酚原位活化为能够共价结合靶器官大分子的化学反应性物质引起的。
A dose-dependent, acute renal necrosis occurred in male Fischer rats following a single subcutaneous injection of acetaminophen. Doses of [3H]acetaminophen (750–900 mg/kg) causing renal and hepatic necrosis in rats markedly depleted target organ glutathione and resulted in large amounts of radiolabeled metabolite being bound to renal and hepatic protein. Pretreatment with cobalt chloride, an inhibitor of hepatic and renal drug metabolism, decreased both the irreversible binding of metabolite and the glutathione depletion in target organ tissues while concomitantly protecting against tissue damage. Pretreatment with 3-methylcholanthrene enhanced hepatic necrosis and covalent binding of metabolite to hepatic protein in vivo and to microsomal protein in vitro but had little effect on the corresponding renal parameters. Covalent binding of radiolabeled acetaminophen to rat renal or hepatic microsomes was enzyme dependent and required NADPH and oxygen. Thus, acetaminophen-induced renal and hepatic necrosis apparently result from in situ activation of acetaminophen to a chemically reactive species capable of covalently binding to target organ macromolecules.