N-acetylcysteine amide, a promising antidote for acetaminophen toxicity
N-acetylcysteine amide, a promising antidote for acetaminophen toxicity
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DOI：
10.1016/j.toxlet.2015.11.008
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发表时间：
2016-01-22
影响因子：
3.5
通讯作者：
Ercal, Nuran
中科院分区：
文献类型：
--
作者：
Khayyat, Ahdab;Tobwala, Shakila;Ercal, Nuran
对乙酰氨基酚（N-乙酰基-对氨基苯酚，APAP）是最广泛使用的非处方解热镇痛药物之一。它在治疗剂量下是安全的，但其过量可导致严重的肝毒性，这是美国药物引起的急性肝衰竭的主要原因。谷胱甘肽（GSH）的消耗是APAP诱导的肝毒性的起始步骤之一;因此，限制器官损伤的一种策略是通过使用GSH前药来恢复GSH水平。N-乙酰半胱氨酸（NAC），一种GSH前体，是目前唯一批准的对乙酰氨基酚过量的解毒剂。不幸的是，由于其较差的生物利用度，需要相当高的剂量和较长的治疗时间。此外，在医院环境中口服和静脉内给予NAC是费力和昂贵的。因此，我们研究了具有更高生物利用度的新型抗氧化剂N-乙酰半胱氨酸酰胺（NACA）对APAP诱导的C57 BL/6小鼠肝毒性的保护作用，并将其与NAC进行了比较。我们的研究结果表明，NACA在低剂量（106 mg/kg）下在防止氧化应激和保护免受APAP诱导的损伤方面优于NAC。NACA显著增加GSH水平和GSH/GSSG比值在肝脏中的66.5%和60.5%，分别为对照组，并降低了30%的ALT水平。然而，在所使用的剂量下，NAC不能有效对抗APAP诱导的氧化应激。因此，NACA似乎在减少APAP诱导的氧化应激方面优于NAC。因此，开发NACA等药物作为预防和治疗APAP毒性的更有效、更安全的选择，在医疗保健领域具有重要价值。(C)2015爱思唯尔爱尔兰有限公司版权所有。
Acetaminophen (N-acetyl-p-aminophenol, APAP) is one of the most widely used over the counter antipyretic and analgesic medications. It is safe at therapeutic doses, but its overdose can result in severe hepatotoxicity, a leading cause of drug-induced acute liver failure in the USA. Depletion of glutathione (GSH) is one of the initiating steps in APAP-induced hepatotoxicity; therefore, one strategy for restricting organ damage is to restore GSH levels by using GSH prodrugs. N-acetylcysteine (NAC), a GSH precursor, is the only currently approved antidote for an acetaminophen overdose. Unfortunately, fairly high doses and longer treatment times are required due to its poor bioavailability. In addition, oral and I.V. administration of NAC in a hospital setting are laborious and costly. Therefore, we studied the protective effects of N-acetylcysteine amide (NACA), a novel antioxidant with higher bioavailability, and compared it with NAC in APAP-induced hepatotoxicity in C57BL/6 mice. Our results showed that NACA is better than NAC at a low dose (106 mg/kg) in preventing oxidative stress and protecting against APAP-induced damage. NACA significantly increased GSH levels and the GSH/GSSG ratio in the liver to 66.5% and 60.5% of the control, respectively; and it reduced the level of ALT by 30%. However, at the dose used, NAC was not effective in combating the oxidative stress induced by APAP. Thus, NACA appears to be better than NAC in reducing the oxidative stress induced by APAP. It would be of great value in the health care field to develop drugs like NACA as more effective and safer options for the prevention and therapeutic intervention in APAP-induced toxicity. (C) 2015 Elsevier Ireland Ltd. All rights reserved.