Conversion of Acetaminophen to the Bioactive N-Acylphenolamine AM404 via Fatty Acid Amide Hydrolase-dependent Arachidonic Acid Conjugation in the Nervous System*

doi:10.1074/JBC.M501489200

Paper

Conversion of Acetaminophen to the Bioactive N-Acylphenolamine AM404 via Fatty Acid Amide Hydrolase-dependent Arachidonic Acid Conjugation in the Nervous System*

Published Sep 9, 2005 · E. Högestätt, B. Jönsson, A. Ermund

Journal of Biological Chemistry

Q1 SJR score

424

Citations

28

Influential Citations

Full textSemantic Scholar

Abstract

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.

Non-RCT

Animal Study

Highly Cited

Study Snapshot

Acetaminophen is converted to the bioactive N-arachidonoylphenolamine (AM404) in the nervous system, offering a novel pathway for drug metabolism and a potential analgesic effect.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

Sign up to use Study Snapshot

Consensus is limited without an account. Create an account or sign in to get more searches and use the Study Snapshot.

Create an account

Paper

Conversion of Acetaminophen to the Bioactive N-Acylphenolamine AM404 via Fatty Acid Amide Hydrolase-dependent Arachidonic Acid Conjugation in the Nervous System*

Sign up to use Study Snapshot

References

A role for the anandamide membrane transporter in TRPV1-mediated neurosecretion from trigeminal sensory neurons

Trigeminal sensory neurons possess an AMT-like mechanism, which is important for the pharmacological action of anandamide and NADA at native TRPV1 channels.

AM404, an inhibitor of anandamide reuptake decreases Fos-immunoreactivity in the spinal cord of neuropathic rats after non-noxious stimulation.

AM404, an inhibitor of anandamide reuptake, could potentially reduce neuropathic pain by affecting cannabinoid CB1 receptor, CB2 receptor, and vanilloid TRPV-1 receptor.

Expression of vanilloid receptor TRPV1 in the rat trigeminal sensory nuclei

The central projections of unmyelinated afferents sensitive to noxious heat and capsaicin are organized differently in the caudal trigeminal nucleus, potentially playing a role in hyperalgesia development.

Cyclooxygenase Isozymes: The Biology of Prostaglandin Synthesis and Inhibition

COX-1 and COX-2 enzymes play crucial roles in various physiological processes and may serve as targets for new drug therapies.

Anandamide transport is independent of fatty-acid amide hydrolase activity and is blocked by the hydrolysis-resistant inhibitor AM1172.

Anandamide internalization in mouse brain neurons is independent of fatty-acid amide hydrolase activity, and the hydrolysis-resistant inhibitor AM1172 may serve as a prototype for novel anandamide transport inhibitors with increased metabolic stability.

N-(4-Tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl)tetrahydropyrazine -1(2H)-carbox-amide (BCTC), a Novel, Orally Effective Vanilloid Receptor 1 Antagonist with Analgesic Properties: II. In Vivo Characterization in Rat Models of Inflammatory and Neuropathic Pain

BCTC effectively reduces acute, inflammatory, and neuropathic pain in rats, suggesting a role for VR1 in persistent and chronic pain arising from inflammation or nerve injury.

Comparative analysis of fatty acid amide hydrolase and cb1 cannabinoid receptor expression in the mouse brain: evidence of a widespread role for fatty acid amide hydrolase in regulation of endocannabinoid signaling

FAAH plays a widespread role in regulating endocannabinoid signaling in the mouse brain, with potential implications for understanding and treating neurodegenerative diseases.

A role for endocannabinoids in indomethacin-induced spinal antinociception.

Indomethacin-induced spinal antinociception involves a shift towards endocannabinoids synthesis and lowers nitric oxide levels, with endocannabinoids playing a role in pain modulation.

Citations

Identification of a Possible Endocannabinoid-Mediated Mechanism of Action of Cetylated Fatty Acids

Cetylated fatty acids' analgesic and anti-inflammatory properties may be partially due to their MAGL inhibition activities, resulting in a local increase in analgesic/anti-inflammatory endocannabinoids.

Structural, Electronic, Vibrational Properties and Molecular Docking of Paracetamol: a first-principle’s Study

Paracetamol shows a favorable binding affinity with the CYP2E1(1EQG) receptor, indicating a robust interaction and promising pharmacological importance.

Reactivity of acetaminophen toward the superoxide radical anion electrogenerated in N,N-dimethylformamide

Acetaminophen's superoxide-scavenging ability operates through a proton-coupled electron transfer mechanism, suggesting its metabolism in biological systems may occur via the NAPQI radical rather than the neutral NAPQI.

Prenatal Acetaminophen Exposure and its Associated Risk for Attention Deficit Hyperactivity Disorder.

Prenatal acetaminophen exposure is associated with an increased risk of developing neurodevelopmental disorders like ADHD in offspring, warranting a warning to pregnant patients.

Impaired brainstem auditory evoked potentials after in utero exposure to high dose paracetamol exposure

In utero exposure to high dose paracetamol can impair auditory brainstem function, potentially increasing the risk of neurodevelopmental disorders.

Evaluating the Role of Susceptibility Inducing Cofactors and of Acetaminophen in the Etiology of Autism Spectrum Disorder

Acetaminophen use is critical in the etiology of autism spectrum disorder, but its risks for neurodevelopment depend on underlying assumptions in multivariate analyses.

Cannabinoid Analgesia in Postoperative Pain Management: From Molecular Mechanisms to Clinical Reality

Cannabinoid compounds show potential in treating postoperative pain by modulating specific molecular mechanisms, but only two out of eleven clinical trials showed positive results.