MECHANISTIC STUDIES ON THE METABOLIC-ACTIVATION OF ACETAMINOPHEN INVIVO
MECHANISTIC STUDIES ON THE METABOLIC-ACTIVATION OF ACETAMINOPHEN INVIVO
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DOI：
10.1021/tx00015a004
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发表时间：
1990-05-01
影响因子：
4.1
通讯作者：
BAILLIE, TA
中科院分区：
文献类型：
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作者：
HOFFMANN, KJ;AXWORTHY, DB;BAILLIE, TA
以200 mg kg-1的中度肝毒性剂量对雄性BALB/c小鼠腹腔注射三种乙酰氨基酚（APAP）类似物，在特定位置分别用氧-18或氘标记，以探讨APAP在体内代谢活化的机制。存在于胆汁、尿液和粪便中的APAP的硫醚缀合物被认为是来自亲电中间体N-乙酰基-对苯醌亚胺（NAPQI），在水相衍生化后分离，通过HPLC分离，并转化为普通的挥发性衍生物用于GC分析。观察到的这些缀合物的标记模式表明APAP通过不涉及游离氧化中间体的产生的过程代谢成NAPQI，但是更可能需要从衬底上顺序去除两个电子。在这些发现的基础上，提出了一个综合的代谢方案，它调用初始细胞色素P-450介导的一代笼氧为中心的APAP自由基物种。该中间体的后续反应可以解释APAP的所有已知氧化代谢物的形成。
Three analogues of acetaminophen (APAP), labeled at specific positions with either oxygen-18 or deuterium, were administered by ip injection to male BALB/c mice at the moderately hepatotoxic dose of 200 mg kg-1 in order to probe the mechanism by which APAP undergoes metabolic activation in vivo. The thioether conjugates of APAP present in bile, urine, and feces, which are believed to derive from the electrophilic intermediate N-acetyl-p-benzoquinone imine (NAPQI), were isolated following aqueous-phase derivatization, separated by HPLC, and converted to a common volatile derivative for analysis by GC-MS. The observed labeling patterns of these conjugates indicated that APAP undergoes metabolism to NAPQI by a process that does not involve the generation of a free oxygenated intermediate, but which more likely entails the sequential removal of two electrons from the substrate. On the basis of these findings, an integrated metabolic scheme is proposed which invokes initial cytochrome P-450 mediated generation of a caged oxygen-centered APAP radical species. Subsequent reaction of this intermediate may account for the formation of all known oxidative metabolites of APAP.