Acetaminophen decreases intracellular glutathione levels and modulates cytokine production in human alveolar macrophages and type II pneumocytes in vitro

Int J Biochem Cell Biol. 2005 Aug;37(8):1727-37. doi: 10.1016/j.biocel.2005.03.005. Epub 2005 Apr 26.


Recent epidemiological observations suggest that acetaminophen (paracetamol) may contribute to asthma morbidity. Impaired endogenous antioxidant defences may have a role in the pathogenesis of a number of inflammatory pulmonary diseases, including asthma. We studied the effect of acetaminophen on the intracellular level of reduced glutathione (GSH) with and without inhibitors of cytochrome P450 or prostaglandin H synthetase, and TNF-alpha, IL-6 and IL-8 protein production in human alveolar macrophages and type II pneumocytes in vitro. Following a 20 h incubation with acetaminophen, cytotoxicity was apparent from > or = 5 and > or = 10 mM in macrophages and type II pneumocytes, respectively. A time- and concentration-dependent decrease of intracellular GSH occurred after acetaminophen (0.05-1 mM) exposure (1-4 h) in pulmonary macrophages (up to 53%) and type II pneumocytes (up to 34%). Diethyldithiocarbamic acid, potassium ethyl xanthate, and indomethacin decreased significantly acetaminophen-induced GSH depletion in the two cell types tested, suggesting the involvement of cytochrome P450 (mainly CYP2E1) and/or prostaglandin H synthetase. In macrophages, acetaminophen decreased the secretion of TNF-alpha (at 4 and 24 h, concentration-related) and IL-6 (at 24 h, at 0.1 mM), and did not affect significantly IL-8 production. These in vitro observations demonstrate that clinically relevant concentrations of acetaminophen decreased: (i) intracellular GSH in human pulmonary macrophages and type II pneumocytes and (ii) the secretion of TNF-alpha and possibly IL-6 by human pulmonary macrophages. These findings provide experimental plausibility to the challenging observations that frequent use of APAP may be a risk factor for asthma morbidity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetaminophen / pharmacology*
  • Aged
  • Cytokines / biosynthesis*
  • Enzyme Inhibitors / pharmacology
  • Glutathione / metabolism*
  • Humans
  • In Vitro Techniques
  • Lung / cytology
  • Lung / drug effects*
  • Lung / metabolism
  • Lung / ultrastructure
  • Macrophages, Alveolar / drug effects*
  • Macrophages, Alveolar / metabolism
  • Macrophages, Alveolar / ultrastructure
  • Microscopy, Electron
  • Middle Aged


  • Cytokines
  • Enzyme Inhibitors
  • Acetaminophen
  • Glutathione