Benzyl alcohol protects against acetaminophen hepatotoxicity by inhibiting cytochrome P450 enzymes but causes mitochondrial dysfunction and cell death at higher doses
Benzyl alcohol protects against acetaminophen hepatotoxicity by inhibiting cytochrome P450 enzymes but causes mitochondrial dysfunction and cell death at higher doses
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DOI：
10.1016/j.fct.2015.10.016
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发表时间：
2015-12-01
影响因子：
4.3
通讯作者：
Jaeschke, Hartmut
中科院分区：
文献类型：
--
作者：
Du, Kuo;McGilll, Mitchell R.;Jaeschke, Hartmut
对乙酰氨基酚（APAP）肝毒性在西方国家是一个严重的公共卫生问题。目前APAP中毒的治疗选择是有限的，需要新的治疗干预策略。最近的一份出版物表明，苯甲醇（BA）可防止APAP肝毒性，并可作为APAP中毒的有希望的解毒剂。为了评估BA的保护机制，用400 mg/kg APAP和/或270 mg/kg BA处理C56 B1/6 J小鼠。APAP单独在APAP后6 h和24 h引起广泛的肝损伤。BA联合处理可减轻这种损伤。蛋白加合物形成的评估表明，BA抑制APAP代谢活化。在支持这一点，在体外实验也表明，BA剂量依赖性地抑制细胞色素P450的活动。与BA的肝保护作用相关，APAP诱导的氧化应激和线粒体功能障碍减轻。在原代小鼠肝细胞中获得了类似的结果。有趣的是，BA单独在高剂量下引起线粒体膜电位损失和细胞毒性，其保护作用不能在原代人肝细胞（PHH）中重现。我们的结论是，BA主要通过抑制细胞色素P450酶对APAP肝毒性的保护。考虑到其毒性作用和PHH中保护作用的丧失，BA不是APAP过量患者的临床有用治疗选择。(C)2015爱思唯尔有限公司版权所有。
Acetaminophen (APAP) hepatotoxicity is a serious public health problem in western countries. Current treatment options for APAP poisoning are limited and novel therapeutic intervention strategies are needed. A recent publication suggested that benzyl alcohol (BA) protects against APAP hepatotoxicity and could serve as a promising antidote for APAP poisoning. To assess the protective mechanisms of BA, C56B1/6J mice were treated with 400 mg/kg APAP and/or 270 mg/kg BA. APAP alone caused extensive liver injury at 6 h and 24 h post-APAP. This injury was attenuated by BA co-treatment. Assessment of protein adduct formation demonstrated that BA inhibits APAP metabolic activation. In support of this, in vitro experiments also showed that BA dose-dependently inhibits cytochrome P450 activities. Correlating with the hepatoprotection of BA, APAP-induced oxidant stress and mitochondrial dysfunction were reduced. Similar results were obtained in primary mouse hepatocytes. Interestingly, BA alone caused mitochondrial membrane potential loss and cell toxicity at high doses, and its protective effect could not be reproduced in primary human hepatocytes (PHH). We conclude that BA protects against APAP hepatotoxicity mainly by inhibiting cytochrome P450 enzymes in mice. Considering its toxic effect and the loss of protection in PHH, BA is not a clinically useful treatment option for APAP overdose patient. (C) 2015 Elsevier Ltd. All rights reserved.