Acetaminophen and NAPQI are toxic to auditory cells via oxidative and endoplasmic reticulum stress-dependent pathways

Autor: Federico Kalinec, Gilda M. Kalinec, Joshua G. Yorgason, Arya Parsa, Pru Thein, Raul Urrutia, William M. Luxford
Rok vydání: 2014
Předmět:
Protein Folding
Time Factors
Eukaryotic Initiation Factor-2
Medical Physiology
Pharmacology
Endoplasmic Reticulum
medicine.disease_cause
Mice
Protein Interaction Mapping
Benzoquinones
Gene Regulatory Networks
Cytotoxicity
Auditory
Analgesics
Pain Research
digestive
oral
and skin physiology
Analgesics
Non-Narcotic
Endoplasmic Reticulum Stress
Sensory Systems
Hair Cells
Imines
Drug
Chronic Pain
Signal transduction
Signal Transduction
Biotechnology
medicine.drug
NAPQI
Clinical Sciences
Biology
Outer
Article
Cell Line
Dose-Response Relationship
Non-Narcotic
medicine
Animals
Acetaminophen
Dose-Response Relationship
Drug
Endoplasmic reticulum
Neurosciences
Hair Cells
Auditory
Outer
Oxidative Stress
Gene Expression Regulation
Otorhinolaryngology
Opioid
Unfolded protein response
Generic health relevance
Reactive Oxygen Species
Transcription Factor CHOP
Oxidative stress
Zdroj: Kalinec, GM; Thein, P; Parsa, A; Yorgason, J; Luxford, W; Urrutia, R; et al.(2014). Acetaminophen and NAPQI are toxic to auditory cells via oxidative and endoplasmic reticulum stress-dependent pathways. Hearing Research, 313, 26-37. doi: 10.1016/j.heares.2014.04.007. UCLA: Retrieved from: http://www.escholarship.org/uc/item/4sn0r7gx
ISSN: 0378-5955
DOI: 10.1016/j.heares.2014.04.007
Popis: 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 invitro findings should be taken into consideration when designing pharmacological strategies aimed at preventing the toxic effects of these drugs on the auditory system. © 2014 Elsevier B.V.
Databáze: OpenAIRE
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