title: Microsomal oxidative damage promoted by acetaminophen metabolism.
abstract: Adverse reactions of acetaminophen have been associated to oxidative stress, which may be elicited by reactive oxygen species (ROS) and/or production of the metabolite NAPQI. Both phenomena would arise through the activity of liver cytochrome P450 (CYP450) system, but their contribution to this oxidative stress is yet to be clarified. A NADPH oxidase activity has been proposed in rat liver microsomes. This activity may be due to the presence of NAD(P)H oxidase (NOX) isoforms in liver endoplasmic reticulum. Both NOX and the CYP450 system activities can catalyze ROS generation using NADPH as a cofactor. Therefore, acetaminophen biotransformation, which requires NADPH, may promote ROS generation through either activity or both. To discriminate between these possibilities, rat liver microsomes were incubated with acetaminophen and NADPH in the presence or absence of specific inhibitors. Incubation with NADPH and acetaminophen elicited lipid peroxidation and decreased thiol content and glutathione-S-transferase (GST) activity. The NOX inhibitors apocynin and plumbagin prevented all these phenomena but the decrease in thiol content. In contrast, this decrease was completely prevented by the specific CYP450 system inhibitor SKF-525A. These data suggest that ROS generation following incubation of microsomes with acetaminophen and NADPH appears to be mainly caused by a NOX activity. In light of these data, toxicity of acetaminophen is discussed.
authors.affiliation: Laboratory of Pharmacology and Toxicology, Department of Pharmacological and Toxicological Chemistry, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago 8380492, Chile. mel@ciq.uchile.cl
authors.forename: María Eugenia
authors.initials: ME
authors.lastname: Letelier
authors.forename: Miguel
authors.initials: M
authors.lastname: López-Valladares
authors.forename: Liliana
authors.initials: L
authors.lastname: Peredo-Silva
authors.forename: Daniel
authors.initials: D
authors.lastname: Rojas-Sepúlveda
authors.forename: Paula
authors.initials: P
authors.lastname: Aracena
mesh_terms: D000082:Acetaminophen / Q000378:metabolism* / Q000633:toxicity*; D018712:Analgesics, Non-Narcotic / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D058633:Antipyretics / Q000378:metabolism / Q000633:toxicity*; D002392:Catechin / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects*; D009249:NADP / Q000378:metabolism; D009285:Naphthoquinones / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D011335:Proadifen / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D018712:Analgesics, Non-Narcotic; D058633:Antipyretics; D065607:Cytochrome P-450 Enzyme Inhibitors; D009285:Naphthoquinones; D000082:Acetaminophen; D009249:NADP; D002392:Catechin; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; D005982:Glutathione Transferase; C014758:plumbagin