Conversion of acetaminophen to the bioactive N-acylphenolamine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system.
Acetaminophen (paracetamol) is a popular domestic analgesic and antipyretic agent with a weak anti-inflammatory action and a low incidence of adverse effects as compared with aspirin and other non-steroidal anti-inflammatory drugs. Here we show that acetaminophen, following deacetylation to its primary amine, is conjugated with arachidonic acid in the brain and the spinal cord to form the potent TRPV1 agonist N-arachidonoylphenolamine (AM404). This conjugation is absent in mice lacking the enzyme fatty acid amide hydrolase. AM404 also inhibits purified cyclooxygenase (COX)-1 and COX-2 and prostaglandin synthesis in lipopolysaccharide-stimulated RAW264.7 macrophages. This novel metabolite of acetaminophen also acts on the endogenous cannabinoid system, which, together with TRPV1 and COX, is present in the pain and thermoregulatory pathways. These findings identify fatty acid conjugation as a novel pathway for drug metabolism and provide a molecular mechanism for the occurrence of the analgesic N-acylphenolamine AM404 in the nervous system following treatment with acetaminophen.
Högestätt
Edward D
ED
Division of Clinical Chemistry and Pharmacology, Department of Laboratory Medicine, Lund University, SE-221 85 Lund, Sweden.
Jönsson
Bo A G
BA
Ermund
Anna
A
Andersson
David A
DA
Björk
Henrik
H
Alexander
Jessica P
JP
Cravatt
Benjamin F
BF
Basbaum
Allan I
AI
Zygmunt
Peter M
PM
D000082:Acetaminophen / Q000378:metabolism* / Q000493:pharmacokinetics; D000581:Amidohydrolases / Q000235:genetics / Q000502:physiology*; D000627:Aminophenols / Q000378:metabolism / Q000493:pharmacokinetics; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D001095:Arachidonic Acids / Q000378:metabolism* / Q000494:pharmacology; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D002490:Central Nervous System / Q000378:metabolism*; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis; D005260:Female; D005727:Ganglia, Spinal / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D000099252:Fatty Acid Amide Hydrolases
D000082:Acetaminophen; D000581:Amidohydrolases; D000627:Aminophenols; D016718:Arachidonic Acid; D001095:Arachidonic Acids; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases; D000099252:Fatty Acid Amide Hydrolases; C496512:Ptgs1 protein, mouse; C496513:Ptgs1 protein, rat; C107594:N-(4-hydroxyphenyl)arachidonylamide