Paracetamol (acetaminophen) cytotoxicity in rat type II pneumocytes and alveolar macrophages in vitro.
Paracetamol (acetaminophen, APAP) liver and kidney cytotoxicity is associated with bioactivation by P450 and/or prostaglandin H synthetase (PGHS) to a reactive metabolite, which depletes GSH, covalently binds to proteins, and leads to oxidative stress. Although APAP may also damage the lung, little is known about the mechanism by which this occurs. We studied the in vitro 24-hr-old type II pneumocytes. A time- and concentration-dependent decrease in intracellular GSH occurred in freshly isolated type II pneumocytes and alveolar macrophages exposed to subtoxic (</= 1 mM) APAP concentrations. In 24-hr-old type II pneumocytes, there were no changes in intracellular GSH concentration after APAP exposure. Potassium ethyl xanthate (a P450 inhibitor) and indomethacin (a PGHS inhibitor) significantly decreased APAP-induced GSH depletion in freshly isolated type II pneumocytes and alveolar macrophages, suggesting that P450 and/or PGHS are involved in APAP bioactivation in these cells.
Dimova
S
S
Laboratory of Pneumology, Unit of Toxicology, K.U.Leuven, B-3000, Leuven, Belgium.
Hoet
P H
PH
Nemery
B
B
D000082:Acetaminophen / Q000633:toxicity*; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D066298:In Vitro Techniques; D008168:Lung / Q000166:cytology / Q000187:drug effects*; D016676:Macrophages, Alveolar / Q000187:drug effects*; D008297:Male; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D018712:Analgesics, Non-Narcotic; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D000082:Acetaminophen; D011451:Prostaglandin-Endoperoxide Synthases; D005978:Glutathione