N-ACETYL-PARA-BENZOQUINONE IMINE - A CYTOCHROME-P-450-MEDIATED OXIDATION-PRODUCT OF ACETAMINOPHEN
N-ACETYL-PARA-BENZOQUINONE IMINE - A CYTOCHROME-P-450-MEDIATED OXIDATION-PRODUCT OF ACETAMINOPHEN
复制标题
DOI：
10.1073/pnas.81.5.1327
复制
发表时间：
1984-01-01
期刊：
影响因子：
--
通讯作者：
NELSON, SD
中科院分区：
文献类型：
--
作者：
DAHLIN, DC;MIWA, GT;NELSON, SD
N-乙酰基-对苯二酚亚胺(NAPQI)是扑热息痛的有毒代谢物，近10年来一直被认为是扑热息痛的毒性代谢物，但从未被检测到是扑热息痛的酶促氧化产物。本文报道了细胞色素P-450和过氧化氢异丙苯直接检测对乙酰氨基酚的氧化产物NAPQI，以及细胞色素P-450、NADPH和NADPH-细胞色素P-450还原酶催化对乙酰氨基酚生成NAPQI的间接证据。NADPH和NADPH-细胞色素P-450还原酶能将NAPQI快速还原为对乙酰氨基酚，使NAPQI的稳态水平低于6.7倍的检测下限。在小鼠肝微体孵育中，NAPQI和对乙酰氨基酚的放射性标记类似物与微体蛋白共价结合，但丢失.apprxeq。乙酰基的20%为乙酰胺。谷胱甘肽与3-S-谷胱甘肽对乙酰氨基酚的结合均降低。L-抗坏血酸、NADPH和NADH也可降低NAPQI对乙酰氨基酚的结合。分配实验结果表明，NAPQI是扑热息痛的主要代谢物，其中相当一部分被迅速还原为扑热息痛。
N-acetyl-p-benzoquinone imine (NAPQI) has been proposed as the toxic metabolite of acetaminophen for the past 10 yr, although it has never been detected as enzymatic oxidation product of acetaminophen. Direct detection of NAPQI formed as an oxidation product of acetaminophen by cytochrome P-450 and cumene hydroperoxide and indirect evidence that is compelling for NAPQI formation from acetaminophen by cytochrome P-450, NADPH and NADPH-cytochrome P-450 reductase are presented. Evidence is provided for the rapid reduction of NAPQI back to acetaminophen by NADPH and NADPH-cytochrome P-450 reductase such that steady-state levels of NAPQI were below detection limits of 6.7 .times. 10-8 M. In mouse liver microsomal incubations, radiolabeled analogs of both NAPQI and acetaminophen bound covalently to microsomal protein with the loss of .apprxeq. 20% of the acetyl group as acetamide. The binding in each case was decreased by glutathione with concomitant formation of 3-S-glutathionylacetaminophen. The binding also was decreased by L-ascorbic acid, NADPH and NADH with reduction of NAPQI to acetaminophen. Results of partitioning experiments indicate that NAPQI is a major metabolite of acetaminophen, a considerable fraction of which is rapidly reduced back to acetaminophen.