CYTO-TOXIC EFFECTS OF N-ACETYL-PARA-BENZOQUINONE IMINE, A COMMON ARYLATING INTERMEDIATE OF PARACETAMOL AND N-HYDROXYPARACETAMOL
CYTO-TOXIC EFFECTS OF N-ACETYL-PARA-BENZOQUINONE IMINE, A COMMON ARYLATING INTERMEDIATE OF PARACETAMOL AND N-HYDROXYPARACETAMOL
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DOI：
10.1016/0006-2952(84)90232-6
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发表时间：
1984-01-01
影响因子：
5.8
通讯作者：
DYBING, E
中科院分区：
文献类型：
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作者：
HOLME, JA;DAHLIN, DC;DYBING, E
在离体大鼠肝细胞悬液中研究了N-乙酰基-对苯醌亚胺（NAPQI）（对乙酰氨基酚（pHAA）[一种镇痛剂]的假定最终反应性代谢产物）的细胞毒性作用。用0.1- 0.5mM NAPQI孵育细胞10-300分钟导致浓度依赖性细胞损伤，如通过增加的台盼蓝排除、乳酸脱氢酶释放和谷胱甘肽（GSH）消耗所确定的。NAPQI和N-羟基对乙酰氨基酚（N-OH-pHAA）（一种假定的pHAA近似代谢物）在相同浓度范围内引起细胞毒性效应。相比之下，pHAA（≤ 0.001）没有毒性作用。mM）可以证明。由于NAPQI的半衰期较短，预计在2分钟孵育期后，加入的NAPQI中只有不到0.5%留在孵育培养基中。然而，10-120分钟（取决于NAPQI的浓度）后，细胞才响应增加的膜渗透性。NAPQI引起的初始损伤必须在毒性变得明显之前进行后续细胞步骤。在NAPQI暴露期间添加N-乙酰半胱氨酸、GSH或抗坏血酸盐完全保护肝细胞免受NAPQI损伤。当在5分钟NAPQI暴露期后加入这些药物时，显示出较小的影响。显然，NAPQI是由pHAA形成的最终反应物。
The cytotoxic effects of N-acetyl-p-benzoquinone imine (NAPQI), a postulated ultimate reactive metabolite of paracetamol (pHAA) [an analgesic] was studied in suspensions of isolated rat hepatocytes. Incubation of cells for 10-300 min with 0.1-0.5 mM NAPQI led to concentration dependent cell damage, as determined by increased trypan blue exclusion, lactate dehydrogenase release and glutathione (GSH) depletion. NAPQI and N-hydroxyparacetamol (N-OH-pHAA), a postulated proximate metabolite of pHAA, caused cytotoxic effects in the same concentration range. In contrast, no toxic effects of pHAA (.ltoreq. mM) could be demonstrated. With the short half-life of NAPQI, less than 0.5% of the NAPQI added is expected to be left in the incubation medium after a 2-min incubation period. Nevertheless, 10-120 min (depending on the concentration of NAPQI) elapsed before the cells responded with increased membrane permeability. The initial damage caused by NAPQI must be followed by subsequent cellular steps before toxicity becomes apparent. The addition of N-acetylcysteine, GSH or ascorbate during the NAPQI exposure period fully protected the hepatocytes from NAPQI damage. Lesser effects were demonstrated when these agents were added after the 5-min NAPQI exposure period. Evidently, NAPQI is the ultimate reactive formed from pHAA.