title: Hearing, reactive metabolite formation, and oxidative stress in cochleae after a single acute overdose of acetaminophen: an in vivo study.
abstract: BACKGROUND
  Although the liver is the primary target organ in acetaminophen (APAP) toxicity, other organs are affected. Previous data suggested that chronic APAP abuse can be ototoxic and the mechanism involves APAP-induced oxidative stress and reactive metabolite (N-acetyl-p-benzoquinone imine, NAPQI)-induced endoplasmic reticulum stress. However, the effect of a single acute overdose on hearing has not been tested.
  
  
  OBJECTIVE
  To determine if a single acute APAP overdose causes hearing damage, and to explore possible mechanisms of APAP ototoxicity.
  
  
  METHODS
  Male C57BL/6 J mice were treated with a single human-relevant overdose of APAP (300 mg APAP per kg bodyweight). Blood, liver and cochleae were harvested at 0, 2, 6 and 24 h post-APAP. In some mice, auditory brainstem responses (ABRs) to a range of frequencies were measured at 24 h. The furosemide plus kanamycin (FS/K) model of drug ototoxicity was used as a positive control for hearing loss. NAPQI formation after APAP was assessed by measuring glutathione depletion and covalent protein binding, and oxidative stress was assessed by measuring glutathione disulfide.
  
  
  RESULTS
  There was no evidence of reactive metabolite formation or hearing loss after a single overdose of APAP at a clinically relevant dose. However, there was a transient increase in oxidative stress.
  
  
  CONCLUSIONS
  Although a single acute overdose was not ototoxic, there was evidence of oxidative stress which may support a role for oxidative stress in hearing loss due to chronic APAP abuse.
  
  
  CONCLUSIONS
  A single human-relevant acute overdose of APAP causes transient oxidative stress in cochleae but not hearing loss.
authors.affiliation: a Department of Pharmacology , Toxicology and Therapeutics and.
authors.forename: Mitchell R
authors.initials: MR
authors.lastname: McGill
authors.affiliation: b Department of Otolaryngology - Head and Neck Surgery , University of Kansas Medical Center , Kansas City , KS , USA.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Kennon-McGill
authors.affiliation: b Department of Otolaryngology - Head and Neck Surgery , University of Kansas Medical Center , Kansas City , KS , USA.
authors.forename: Dianne
authors.initials: D
authors.lastname: Durham
authors.affiliation: a Department of Pharmacology , Toxicology and Therapeutics and.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Jaeschke
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000503:physiopathology; D003051:Cochlea / Q000187:drug effects* / Q000378:metabolism; D062787:Drug Overdose / Q000378:metabolism / Q000503:physiopathology; D019803:Glutathione Disulfide / Q000097:blood; D006309:Hearing / Q000187:drug effects*; D008297:Male; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects*; D011485:Protein Binding
chemical_list: D000082:Acetaminophen; D000410:Alanine Transaminase; D019803:Glutathione Disulfide
keywords: Hepatotoxicity; ototoxicity; protein binding; reactive oxygen species