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Acetaminophen at low doses depletes airway glutathione and alters respiratory reflex responses
Author(s) -
Smith Gregory J.,
Cichocki Joseph A.,
Manautou Jose E.,
Morris John B.
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1107.4
Subject(s) - glutathione , acrolein , chemistry , irritation , respiratory system , acetaminophen , respiratory tract , pharmacology , inhalation , anesthesia , medicine , biochemistry , immunology , enzyme , catalysis
The goal of this study was to determine if acetaminophen (APAP), at non‐hepatotoxic doses, causes physiologically significant depletion of the important antioxidant glutathione (GSH) in the respiratory tract. Airway GSH levels were measured in female C57Bl/6J mice after 30, 60, or 100 mg/kg APAP ip. A dose/time dependent reduction of GSH occurred with maximal depletion (~60% of control) at 1hr (liver) and 2hrs (lung, trachea, and nose). Acrolein is a pro‐oxidant vapor that is detoxified by GSH, but in sufficient concentration stimulates the trigeminal nerve Transient Receptor Potential A1 receptor to elicit the sensory irritation response. We reasoned that if the decrease in GSH induced by APAP was physiologically significant, then APAP would enhance the acrolein‐induced irritation; APAP (100 mg/kg 1 hr prior to 2 ppm acrolein exposure) increased the irritation response 75% over acrolein alone. Nasal GSH averaged to 88, 69, and 59% of control at 30, 60, and 100 mg/kg APAP, respectively. It has been hypothesized that APAP, due to its increased usage and pro‐oxidant properties, has contributed to the 2‐fold increase in asthma prevalence that has occurred since 1980. These results support this hypothesis by indicating that APAP, at doses approximating the therapeutic dose of 15 mg/kg, depletes airway GSH and modulates acute respiratory responses. (Supported by the UConn President's Research Award).