title: Acetaminophen decreases intracellular glutathione levels and modulates cytokine production in human alveolar macrophages and type II pneumocytes in vitro.
abstract: 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.
authors.affiliation: Laboratory of Pneumology, Unit of Toxicology, K.U. Leuven, Herestraat 49, B-3000 Leuven, Belgium.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Dimova
authors.forename: Peter H M
authors.initials: PH
authors.lastname: Hoet
authors.forename: David
authors.initials: D
authors.lastname: Dinsdale
authors.forename: Benoit
authors.initials: B
authors.lastname: Nemery
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology*; D000368:Aged; D016207:Cytokines / Q000096:biosynthesis*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008168:Lung / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008854:Microscopy, Electron; D008875:Middle Aged
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; D000082:Acetaminophen; D005978:Glutathione