Holme J A, Hongslo J K, Bjørge C, Nelson S D
Department of Environmental Medicine, National Institute of Public Health, Oslo, Norway.
Biochem Pharmacol. 1991 Aug 8;42(5):1137-42. doi: 10.1016/0006-2952(91)90299-k.
Toxic effects of acetaminophen (paracetamol, N-acetyl-p-aminophenol, APAP) in monolayer cultures of mouse hepatocytes developed over a period of 18 hr. N-Acetyl-m-aminophenol (AMAP) was approximately 10-fold less toxic than APAP, despite the fact that it bound covalently to a greater extent to hepatocyte macromolecules. AMAP did not deplete glutathione to as great an extent as APAP, indicating that their reactive metabolites may bind to different proteins or that oxidative damage in addition to arylation of proteins may be involved in the development of cell death. The toxicity of 3-methoxy-acetyl-p-aminophenol was similar to that of APAP, whereas the other hydroquinone and quinone metabolites were 8-10 times more cytotoxic than APAP. The potencies of these analogs were in the order: acetyl-m-aminophenol-p-benzoquinoneimine greater than or equal to 2,5-dihydroxyacetanilide greater than or equal to 3-methoxy-p-benzoquinone greater than or equal to N-acetyl-p-benzoquinone imine (NAPQI) greater than or equal to acetyl-m-aminophenol-o-benzoquinone greater than or equal to 3-hydroxy-acetyl-p-aminophenol. The relative toxic potencies of the hydroquinone and quinone metabolites of AMAP were comparable to that of NAPQI, and do not readily explain the marked difference between the cytotoxic effects of AMAP and APAP.
对乙酰氨基酚（扑热息痛、N - 乙酰 - 对氨基苯酚，APAP）对小鼠肝细胞单层培养物的毒性作用在18小时内逐渐显现。N - 乙酰 - 间氨基苯酚（AMAP）的毒性比APAP低约10倍，尽管它与肝细胞大分子的共价结合程度更高。AMAP对谷胱甘肽的消耗程度不如APAP，这表明它们的反应性代谢产物可能与不同的蛋白质结合，或者除了蛋白质芳基化之外的氧化损伤可能参与细胞死亡的发生。3 - 甲氧基 - 乙酰 - 对氨基苯酚的毒性与APAP相似，而其他对苯二酚和醌类代谢产物的细胞毒性比APAP高8 - 10倍。这些类似物的效力顺序为：乙酰 - 间氨基苯酚 - 对苯醌亚胺≥2,5 - 二羟基乙酰苯胺≥3 - 甲氧基 - 对苯醌≥N - 乙酰 - 对苯醌亚胺（NAPQI）≥乙酰 - 间氨基苯酚 - 邻苯醌≥3 - 羟基 - 乙酰 - 对氨基苯酚。AMAP的对苯二酚和醌类代谢产物的相对毒性效力与NAPQI相当，这并不能轻易解释AMAP和APAP细胞毒性作用之间的显著差异。
