title: Acetaminophen and NAPQI are toxic to auditory cells via oxidative and endoplasmic reticulum stress-dependent pathways.
abstract: 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.
authors.affiliation: Department of Head & Neck Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Gilda M
authors.initials: GM
authors.lastname: Kalinec
authors.affiliation: Department of Head & Neck Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Pru
authors.initials: P
authors.lastname: Thein
authors.affiliation: Department of Head & Neck Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Arya
authors.initials: A
authors.lastname: Parsa
authors.affiliation: University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Yorgason
authors.affiliation: House Clinic, Los Angeles, CA 90057, USA.
authors.forename: William
authors.initials: W
authors.lastname: Luxford
authors.affiliation: Epigenetics and Chromatin Dynamics Laboratory, Translational Epigenomic Program, Center for Individualized Medicine (CIM) Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Raul
authors.initials: R
authors.lastname: Urrutia
authors.affiliation: Department of Head & Neck Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. Electronic address: fkalinec@mednet.ucla.edu.
authors.forename: Federico
authors.initials: F
authors.lastname: Kalinec
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D018712:Analgesics, Non-Narcotic / Q000633:toxicity*; D000818:Animals; D016227:Benzoquinones / Q000633:toxicity*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000235:genetics; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D018072:Hair Cells, Auditory, Outer / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007097:Imines / Q000633:toxicity*; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics; D017510:Protein Folding; D025941:Protein Interaction Mapping; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D051742:Transcription Factor CHOP / Q000378:metabolism
chemical_list: D018712:Analgesics, Non-Narcotic; D016227:Benzoquinones; C497250:Ddit3 protein, mouse; D015852:Eukaryotic Initiation Factor-2; D007097:Imines; D017382:Reactive Oxygen Species; D051742:Transcription Factor CHOP; D000082:Acetaminophen; C028473:N-acetyl-4-benzoquinoneimine