Acetaminophen and NAPQI are toxic to auditory cells via oxidative and endoplasmic reticulum stress-dependent pathways.
Acetaminophen and NAPQI are toxic to auditory cells via oxidative and endoplasmic reticulum stress-dependent pathways.
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DOI：
10.1016/j.heares.2014.04.007
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发表时间：
2014-07
期刊：
影响因子：
2.8
通讯作者：
Kalinec, Federico
中科院分区：
文献类型：
--
作者：
Kalinec, Gilda M.;Thein, Pru;Parsa, Arya;Yorgason, Joshua;Luxford, William;Urrutia, Raul;Kalinec, Federico
含有N-乙酰-对氨基苯酚(又称APAP、对乙酰氨基酚或扑热息痛)的止痛药与阿片类麻醉剂联合使用是美国最畅销的药物。滥用这些药物60天的人可能会发生耳鸣和进行性双侧感音神经性听力损失。最近发表的研究表明，APAP及其代谢产物N-乙酰-对苯二酚亚胺(NAPQI)是这类止痛药的主要耳毒性药物。然而，这些药物对听觉细胞有害影响的潜在机制仍未完全确定。在这项研究中，我们报道了细胞、基因组和蛋白质组学实验表明，APAP和NAPQI对永生化小鼠™来源的HEI-OC1细胞的细胞毒性涉及两条不同的途径，涉及ROS过量产生、内质网形态改变、池内伴侣蛋白的重新分布、eIF2α-CHOP途径的激活以及ER应激和蛋白质折叠反应标记的变化。因此，氧化应激和内质网应激都是APAP和NAPQI在这些细胞中产生细胞毒性作用的细胞和分子机制的一部分。我们建议，在设计旨在防止这些药物对听觉系统的毒性影响的药理策略时，应考虑这些体外研究结果。
Pain relievers containing N-acetyl-para-aminophenol, also called APAP, acetaminophen or paracetamol, in combination with opioid narcotics are top-selling pharmaceuticals in the U.S. Individuals who abuse these drugs for as little as sixty days can develop tinnitus and progressive bilateral sensorineural hearing loss. Recently published studies indicate that APAP and its metabolic product N-acetyl-p-benzoquinoneimine (NAPQI) are the primary ototoxic agents in this type of pain relievers. However, the mechanisms underlying the deleterious effects of these drugs on auditory cells remain to be fully characterized. In this study, we report cellular, genomic, and proteomic experiments revealing that cytotoxicity by APAP and NAPQI involves two different pathways in Immortomouse™-derived HEI-OC1 cells, implicating ROS overproduction, alterations in ER morphology, redistribution of intra-cisternal chaperones, activation of the eIF2α-CHOP pathway, as well as changes in ER stress and protein folding response markers. Thus, both oxidative and ER stress are part of the cellular and molecular mechanisms that contribute to the cytotoxic effects of APAP and NAPQI in these cells. We suggest that these in vitro findings should be taken into consideration when designing pharmacological strategies aimed at preventing the toxic effects of these drugs on the auditory system.
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