ACETAMINOPHEN-INDUCED HEPATOTOXICITY
ACETAMINOPHEN-INDUCED HEPATOTOXICITY
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DOI：
10.1016/0024-3205(81)90278-2
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发表时间：
1981-01-01
期刊：
影响因子：
6.1
通讯作者：
GILLETTE, JR
中科院分区：
文献类型：
--
作者：
HINSON, JA;POHL, LR;GILLETTE, JR
在大剂量下，常用的止痛药对乙酰氨基酚会在人和实验动物中造成小叶中心肝坏死。这种毒性是由肝微粒体中细胞色素P-450混合功能氧化酶系统形成的反应性代谢产物介导的。在治疗剂量后，反应性代谢物可被谷胱甘肽有效解毒。然而，在大剂量后，肝脏总谷胱甘肽浓度下降到正常水平的20%左右，反应性代谢产物与蛋白质共价结合。不同治疗引起的蛋白质共价结合的变化与肝坏死的发生率和严重程度的变化相关。这种反应性代谢物被认为是N-乙酰亚胺对苯二酚，显然是由细胞色素P-450以前未知的机制形成的。
In large doses the commonly used analgesic acetaminophen produces a centrilobular hepatic necrosis in man and experimental animals. The toxicity is mediated by a reactive metabolite formed by a cytochrome P-450 mixed-function oxidase system in hepatic microsomes. Following therapeutic doses the reactive metabolite is efficiently detoxified by glutathione. Following large doses, however, the total hepatic glutathione concentration is decreased to approximately 20% of normal and the reactive metabolite covalently binds to protein. Changes in protein covalent binding caused by various treatments correlates with changes in the incidence and severity of the hepatic necrosis. The reactive metabolite is believed to be N-acetylimidoquinone and is apparently formed by a previously uncharacterized mechanism for cytochrome P-450.