Plasma and liver acetaminophen-protein adduct levels in mice after acetaminophen treatment: dose-response, mechanisms, and clinical implications.
Plasma and liver acetaminophen-protein adduct levels in mice after acetaminophen treatment: dose-response, mechanisms, and clinical implications.
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DOI：
10.1016/j.taap.2013.03.026
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发表时间：
2013-06-15
影响因子：
3.8
通讯作者：
Jaeschke, Hartmut
中科院分区：
文献类型：
--
作者：
McGill, Mitchell R.;Lebofsky, Margitta;Norris, Hye-Ryun K.;Slawson, Matthew H.;Bajt, Mary Lynn;Xie, Yuchao;Williams, C. David;Wilkins, Diana G.;Rollins, Douglas E.;Jaeschke, Hartmut
在治疗剂量下，对乙酰氨基酚（APAP）是一种安全有效的止痛药。然而，在西方，过量的APAP是急性肝衰竭的主要原因。APAP的反应性代谢物（NAPQI）与蛋白质的结合被认为是肝毒性机制中的起始事件。早期的研究表明，如果没有谷胱甘肽（GSH）的消耗，apap -蛋白的结合就不会发生，而且可能只有在毒性剂量下才会发生。此外，我们发现蛋白质来源的apap -半胱氨酸只有在肝损伤发生后才能在血清中检测到。在此基础上，最近有人提出血清APAP-半胱氨酸可作为APAP过量的诊断指标。然而，尚未进行全面的剂量反应和时间过程研究。此外，尚未研究合并症对该参数的影响。我们用多种剂量的APAP治疗各组小鼠，并在不同时间点测量肝脏GSH以及肝脏和血浆APAP-蛋白加合物。我们的研究结果表明，蛋白结合可以在没有太多谷胱甘肽损失的情况下发生。重要的是，这些数据证实了早期的研究结果，即蛋白质来源的apap -半胱氨酸可以在没有肝损伤的情况下出现在血浆中。体外实验表明，这可能涉及多种机制，包括内合蛋白的分泌和NAPQI直接扩散到血浆中。亚毒性剂量APAP后，缺血再灌注诱导肝坏死显著增加血浆蛋白源性APAP-半胱氨酸浓度。虽然我们的数据通常支持临床中血清apap蛋白加合物的测量，但建议在解释该参数时要谨慎。
At therapeutic doses, acetaminophen (APAP) is a safe and effective analgesic. However, overdose of APAP is the principal cause of acute liver failure in the West. Binding of the reactive metabolite of APAP (NAPQI) to proteins is thought to be the initiating event in the mechanism of hepatotoxicity. Early work suggested that APAP-protein binding could not occur without glutathione (GSH) depletion, and likely only at toxic doses. Moreover, it was found that protein-derived APAP-cysteine could only be detected in serum after the onset of liver injury. On this basis, it was recently proposed that serum APAP-cysteine could be used as diagnostic marker of APAP overdose. However, comprehensive dose-response and time course studies have not yet been done. Furthermore, the effects of co-morbidities on this parameter have not been investigated. We treated groups of mice with APAP at multiple doses and measured liver GSH and both liver and plasma APAP-protein adducts at various timepoints. Our results show that protein binding can occur without much loss of GSH. Importantly, the data confirm earlier work that showed that protein-derived APAP-cysteine can appear in plasma without liver injury. Experiments performed in vitro suggest that this may involve multiple mechanisms, including secretion of adducted proteins and diffusion of NAPQI directly into plasma. Induction of liver necrosis through ischemia-reperfusion significantly increased the plasma concentration of protein-derived APAP-cysteine after a subtoxic dose of APAP. While our data generally support the measurement of serum APAP-protein adducts in the clinic, caution is suggested in the interpretation of this parameter.
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影响因子：
25.7
作者：
Antoine, Daniel J.;Jenkins, Rosalind E.;Dear, James W.;Williams, Dominic P.;McGill, Mitchell R.;Sharpe, Matthew R.;Craig, Darren G.;Simpson, Kenneth J.;Jaeschke, Hartmut;Park, B. Kevin
通讯作者：
Park, B. Kevin
影响因子：
5.9
作者：
Jaeschke H;McGill MR;Ramachandran A
通讯作者：
Ramachandran A
影响因子：
3.8
作者：
Gujral, JS;Knight, TR;Jaeschke, H
通讯作者：
Jaeschke, H
影响因子：
3.8
作者：
Bajt, ML;Knight, TR;Jaeschke, H
通讯作者：
Jaeschke, H
影响因子：
5.1
作者：
AXWORTHY, DB;HOFFMANN, KJ;BAILLIE, TA
通讯作者：
BAILLIE, TA