Fatty acid amide hydrolase / FAAH

evidence_span

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experimental_model

Review of fatty acid amide hydrolase structure and function

exposure

Hydrolysis of fatty acid amides including anandamide

limitations

A review, labelled as such, used for the enzymology. The structural claim is recorded from the crystal structure paper separately.

nutrient_topic

THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. · Delta-9-tetrahydrocannabinol / THC

organism

Mammalian enzyme

plain_language

One enzyme destroys the natural ligand within seconds of it being made.

primary_references

[thc-p15952893] Structure and function of fatty acid amide hydrolase. (2005). https://pubmed.ncbi.nlm.nih.gov/15952893/ DOI: 10.1146/annurev.biochem.74.082803.133450

tissue_or_cell_type

Membrane-bound enzyme

THC: the cannabinoid receptors, the endocannabinoid system it occupies, what the drug does, and the dietary fat it is built from (2026-09-21) · lines 361–372

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Review of fatty acid amide hydrolase structure and function · source_derived_draft · unverified_draft

### thc-faah-degrades-anandamide Fatty acid amide hydrolase is the principal enzyme hydrolysing fatty acid amides including anandamide, terminating their signalling. Condition category: normal nutrient_topic: THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. plain_language: One enzyme destroys the natural ligand within seconds of it being made. organism: Mammalian enzyme tissue_or_cell_type: Membrane-bound enzyme experimental_model: Review of fatty acid amide hydrolase structure and function limitations: A review, labelled as such, used for the enzymology. The structural claim is recorded from the crystal structure paper separately. exposure: Hydrolysis of fatty acid amides including anandamide evidence_span: {"source_cache": "artifacts/thc-research/15952893.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3213ef73e4fe6ef00bd2a0f1c09319ebc1e000f9cfd200ce3c1852f1e045c62c", "start_char": 0, "end_char": 724, "text_sha256": "3213ef73e4fe6ef00bd2a0f1c09319ebc1e000f9cfd200ce3c1852f1e045c62c"} [thc-p15952893] Structure and function of fatty acid amide hydrolase. (2005). https://pubmed.ncbi.nlm.nih.gov/15952893/ DOI: 10.1146/annurev.biochem.74.082803.133450

evidence_span

{"source_cache": "artifacts/thc-research/20493882.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c5acef9899dc5e90f996fb08c58b547c167bdbb2c879e1bd669a531fd10c3368", "start_char": 0, "end_char": 1382, "text_sha256": "c5acef9899dc5e90f996fb08c58b547c167bdbb2c879e1bd669a531fd10c3368"}

experimental_model

Crystal structure of fatty acid amide hydrolase bound to the carbamate inhibitor URB597

exposure

Inhibitor-bound structure

limitations

Identifies the water molecule that explains why the inhibitor is slowly reversible. Rat enzyme structure.

nutrient_topic

THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. · Delta-9-tetrahydrocannabinol / THC

organism

Rat enzyme

plain_language

The structure shows exactly how the enzyme is jammed, down to a single water molecule.

primary_references

[thc-p20493882] Crystal structure of fatty acid amide hydrolase bound to the carbamate inhibitor URB597: discovery of a deacylating water molecule and insight into enzyme inactivation. (2010). https://pubmed.ncbi.nlm.nih.gov/20493882/ DOI: 10.1016/j.jmb.2010.05.034

tissue_or_cell_type

Purified enzyme

THC: the cannabinoid receptors, the endocannabinoid system it occupies, what the drug does, and the dietary fat it is built from (2026-09-21) · lines 374–385

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Crystal structure of fatty acid amide hydrolase bound to the carbamate inhibitor URB597 · source_derived_draft · unverified_draft

### thc-faah-mechanism The crystal structure of fatty acid amide hydrolase bound to URB597 revealed a deacylating water molecule and gave insight into how the enzyme is inactivated by carbamate inhibitors. Condition category: normal nutrient_topic: THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. plain_language: The structure shows exactly how the enzyme is jammed, down to a single water molecule. organism: Rat enzyme tissue_or_cell_type: Purified enzyme experimental_model: Crystal structure of fatty acid amide hydrolase bound to the carbamate inhibitor URB597 limitations: Identifies the water molecule that explains why the inhibitor is slowly reversible. Rat enzyme structure. exposure: Inhibitor-bound structure evidence_span: {"source_cache": "artifacts/thc-research/20493882.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c5acef9899dc5e90f996fb08c58b547c167bdbb2c879e1bd669a531fd10c3368", "start_char": 0, "end_char": 1382, "text_sha256": "c5acef9899dc5e90f996fb08c58b547c167bdbb2c879e1bd669a531fd10c3368"} [thc-p20493882] Crystal structure of fatty acid amide hydrolase bound to the carbamate inhibitor URB597: discovery of a deacylating water molecule and insight into enzyme inactivation. (2010). https://pubmed.ncbi.nlm.nih.gov/20493882/ DOI: 10.1016/j.jmb.2010.05.034

evidence_span

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experimental_model

Rat cerebellar membrane preparations assayed by time-dependent loss of anandamide potency and by direct amidase assay

exposure

Ibuprofen compared against acetylsalicylic acid, sulindac, acetaminophen, ketoprofen and naproxen

limitations

The comparator set is what distinguishes this from a class effect: five other drugs failed. The concentration required is high, and the authors relate it to peak plasma levels rather than measuring them.

nutrient_topic

Ibuprofen research collection; topical membership is not evidence of a direct clinical effect, and the racemate is recorded separately from each of its two enantiomers. · Ibuprofen

organism

Rat

plain_language

Ibuprofen, and not the other painkillers tested, slows the destruction of the body’s own cannabis-like signal.

primary_references

[ibu-p9060042] Ibuprofen inhibits the metabolism of the endogenous cannabimimetic agent anandamide. (1997). https://pubmed.ncbi.nlm.nih.gov/9060042/ DOI: 10.1111/j.1600-0773.1997.tb00291.x

tissue_or_cell_type

Cerebellar membranes

Ibuprofen: the enantiomer that works, the one that was called inactive, the one-way chemistry that turns one into the other, and the targets that are not cyclooxygenase (2026-09-22) · lines 448–459

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat cerebellar membrane preparations assayed by time-dependent loss of anandamide potency and by direct amidase assay · source_derived_draft · unverified_draft

### ibu-blocks-anandamide-breakdown The time-dependent reduction in potency of anandamide toward inhibition of cannabinoid agonist binding in rat cerebellar membranes was blocked by ibuprofen but not by acetylsalicylic acid, sulindac, acetaminophen or to any significant extent by ketoprofen and naproxen, a direct assay of anandamide amidase gave a half-maximal inhibitory concentration for ibuprofen of approximately 400 micromolar, and that potency was of the same order as required for inhibition of cyclooxygenase-2 in cell-free systems and as the peak plasma concentrations following a two times 200 milligram dose regimen, so following therapeutic doses the metabolism of anandamide may be affected. Condition category: normal nutrient_topic: Ibuprofen research collection; topical membership is not evidence of a direct clinical effect, and the racemate is recorded separately from each of its two enantiomers. plain_language: Ibuprofen, and not the other painkillers tested, slows the destruction of the body’s own cannabis-like signal. organism: Rat tissue_or_cell_type: Cerebellar membranes experimental_model: Rat cerebellar membrane preparations assayed by time-dependent loss of anandamide potency and by direct amidase assay limitations: The comparator set is what distinguishes this from a class effect: five other drugs failed. The concentration required is high, and the authors relate it to peak plasma levels rather than measuring them. exposure: Ibuprofen compared against acetylsalicylic acid, sulindac, acetaminophen, ketoprofen and naproxen evidence_span: {"source_cache": "artifacts/ibuprofen-research/9060042.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2c89a26f3812060e97e7bb481126a90840282d64348fc8d4ae9d1dcc7f0a4543", "start_char": 0, "end_char": 1394, "text_sha256": "2c89a26f3812060e97e7bb481126a90840282d64348fc8d4ae9d1dcc7f0a4543"} [ibu-p9060042] Ibuprofen inhibits the metabolism of the endogenous cannabimimetic agent anandamide. (1997). https://pubmed.ncbi.nlm.nih.gov/9060042/ DOI: 10.1111/j.1600-0773.1997.tb00291.x

evidence_span

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experimental_model

Jurkat T cells stimulated through the T-cell receptor with transcription factor reporter assays

exposure

AM404 applied to CD3 and CD28-stimulated cells, with fatty acid amide hydrolase independence tested

limitations

Identifies a target of the metabolite that has nothing to do with pain. Cell line work at concentrations that are not related here to those reached in a person.

nutrient_topic

Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. · Paracetamol

organism

Human cells

plain_language

The metabolite also switches off a transcription factor that immune cells use, by a route unrelated to the enzyme that made it.

primary_references

[apap-p17196940] The acetaminophen-derived bioactive N-acylphenolamine AM404 inhibits NFAT by targeting nuclear regulatory events. (2007). https://pubmed.ncbi.nlm.nih.gov/17196940/ DOI: 10.1016/j.bcp.2006.12.001

tissue_or_cell_type

T lymphocytes

Paracetamol: the enzyme it reduces rather than blocks, the isoform that turned out not to exist, the metabolite that carries the analgesia, and the metabolite that destroys the liver (2026-09-22) · lines 389–400

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Jurkat T cells stimulated through the T-cell receptor with transcription factor reporter assays · source_derived_draft · unverified_draft

### apap-am404-blocks-nfat AM404 was a potent inhibitor of T-cell-receptor-mediated T-cell activation, specifically inhibiting interleukin-2 and tumour necrosis factor alpha gene transcription and tumour necrosis factor alpha synthesis in stimulated Jurkat T cells in a fatty acid amide hydrolase independent way, inhibiting both the binding to DNA and the transcriptional activity of endogenous nuclear factor of activated T cells without affecting early steps such as calcium mobilization or dephosphorylation, and without interfering with the pathways leading to AP-1 or nuclear factor kappa B activation. Condition category: normal nutrient_topic: Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. plain_language: The metabolite also switches off a transcription factor that immune cells use, by a route unrelated to the enzyme that made it. organism: Human cells tissue_or_cell_type: T lymphocytes experimental_model: Jurkat T cells stimulated through the T-cell receptor with transcription factor reporter assays limitations: Identifies a target of the metabolite that has nothing to do with pain. Cell line work at concentrations that are not related here to those reached in a person. exposure: AM404 applied to CD3 and CD28-stimulated cells, with fatty acid amide hydrolase independence tested evidence_span: {"source_cache": "artifacts/paracetamol-research/17196940.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "adb730eafbac5bf2eeb05418523f3f943b2b4f0ffb83e8e80cdc97c6f0ce27e9", "start_char": 0, "end_char": 1544, "text_sha256": "adb730eafbac5bf2eeb05418523f3f943b2b4f0ffb83e8e80cdc97c6f0ce27e9"} [apap-p17196940] The acetaminophen-derived bioactive N-acylphenolamine AM404 inhibits NFAT by targeting nuclear regulatory events. (2007). https://pubmed.ncbi.nlm.nih.gov/17196940/ DOI: 10.1016/j.bcp.2006.12.001

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

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experimental_model

Formalin, tail immersion and von Frey tests in fatty acid amide hydrolase and TRPV1 knockout mice with intracerebroventricular injection

exposure

Oral acetaminophen at a dose lacking hypolocomotor activity, with intracerebroventricular AM404 and capsazepine

limitations

Two separate knockouts and a central antagonist all point the same way, and the dose was chosen to avoid sedation confounding the pain tests. Brain prostaglandin E2 was unchanged at that dose, which is a notable negative.

nutrient_topic

Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. · Paracetamol

organism

Mouse

plain_language

Remove the channel and the painkiller stops working, while putting the metabolite straight into the brain works.

primary_references

[apap-p20862299] TRPV1 in brain is involved in acetaminophen-induced antinociception. (2010). https://pubmed.ncbi.nlm.nih.gov/20862299/ DOI: 10.1371/journal.pone.0012748

tissue_or_cell_type

Brain

trigger_kind

machinery_impairment Imported condition classification; unverified.

Paracetamol: the enzyme it reduces rather than blocks, the isoform that turned out not to exist, the metabolite that carries the analgesia, and the metabolite that destroys the liver (2026-09-22) · lines 311–322

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Formalin, tail immersion and von Frey tests in fatty acid amide hydrolase and TRPV1 knockout mice with intracerebroventricular injection · source_derived_draft · unverified_draft

### apap-analgesia-needs-trpv1 The antinociceptive effect of acetaminophen at an oral dose lacking hypolocomotor activity was absent in fatty acid amide hydrolase and TRPV1 knockout mice in the formalin, tail immersion and von Frey tests, that dose did not affect global brain contents of prostaglandin E2 or endocannabinoids, intracerebroventricular injection of AM404 produced a TRPV1-mediated antinociceptive effect in the formalin test, and pharmacological inhibition of brain TRPV1 by intracerebroventricular capsazepine abolished the antinociceptive effect of oral acetaminophen. Condition category: machinery_impairment nutrient_topic: Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. plain_language: Remove the channel and the painkiller stops working, while putting the metabolite straight into the brain works. organism: Mouse tissue_or_cell_type: Brain experimental_model: Formalin, tail immersion and von Frey tests in fatty acid amide hydrolase and TRPV1 knockout mice with intracerebroventricular injection limitations: Two separate knockouts and a central antagonist all point the same way, and the dose was chosen to avoid sedation confounding the pain tests. Brain prostaglandin E2 was unchanged at that dose, which is a notable negative. exposure: Oral acetaminophen at a dose lacking hypolocomotor activity, with intracerebroventricular AM404 and capsazepine evidence_span: {"source_cache": "artifacts/paracetamol-research/20862299.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2cb3934d80d1a7a6632c49f2007cb6e203b3851706a4ffeb43fda2bb655fa8f2", "start_char": 0, "end_char": 1701, "text_sha256": "2cb3934d80d1a7a6632c49f2007cb6e203b3851706a4ffeb43fda2bb655fa8f2"} [apap-p20862299] TRPV1 in brain is involved in acetaminophen-induced antinociception. (2010). https://pubmed.ncbi.nlm.nih.gov/20862299/ DOI: 10.1371/journal.pone.0012748

evidence_span

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experimental_model

Thermal, mechanical and chemical pain tests in cannabinoid receptor 1 knockout mice with receptor binding and pathway lesions

exposure

Acetaminophen with AM-251, cannabinoid receptor 1 deletion, fatty acid amide hydrolase inhibition and serotonergic pathway lesion

limitations

The binding experiment is what makes the receptor involvement indirect rather than direct, which is the substantive point. The proposed sequence is the authors’ synthesis.

nutrient_topic

Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. · Paracetamol

organism

Mouse

plain_language

The drug needs the cannabinoid receptor but never touches it, which is what a metabolite doing the work looks like.

primary_references

[apap-p18485596] Endocannabinoid and serotonergic systems are needed for acetaminophen-induced analgesia. (2008). https://pubmed.ncbi.nlm.nih.gov/18485596/ DOI: 10.1016/j.pain.2008.03.030

tissue_or_cell_type

Brain and spinal cord

Paracetamol: the enzyme it reduces rather than blocks, the isoform that turned out not to exist, the metabolite that carries the analgesia, and the metabolite that destroys the liver (2026-09-22) · lines 337–348

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Thermal, mechanical and chemical pain tests in cannabinoid receptor 1 knockout mice with receptor binding and pathway lesions · source_derived_draft · unverified_draft

### apap-cb1-needed-but-not-bound In thermal, mechanical and chemical pain tests the specific cannabinoid receptor 1 antagonist AM-251 abolished the analgesic action of acetaminophen, which was also lost in cannabinoid receptor 1 knockout mice, yet acetaminophen was shown unable to bind to those receptors demonstrating an indirect involvement, inhibition of fatty acid amide hydrolase suppressed the effect, and the antinociceptive activity of a cannabinoid receptor 1 agonist was itself inhibited by lesion of bulbospinal serotonergic pathways and by spinal 5-HT receptor antagonists, leading the authors to propose a sequence of metabolism to AM404, indirect cannabinoid receptor involvement, reinforcement of serotonergic bulbospinal pathways and action at spinal serotonergic receptors. Condition category: normal nutrient_topic: Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. plain_language: The drug needs the cannabinoid receptor but never touches it, which is what a metabolite doing the work looks like. organism: Mouse tissue_or_cell_type: Brain and spinal cord experimental_model: Thermal, mechanical and chemical pain tests in cannabinoid receptor 1 knockout mice with receptor binding and pathway lesions limitations: The binding experiment is what makes the receptor involvement indirect rather than direct, which is the substantive point. The proposed sequence is the authors’ synthesis. exposure: Acetaminophen with AM-251, cannabinoid receptor 1 deletion, fatty acid amide hydrolase inhibition and serotonergic pathway lesion evidence_span: {"source_cache": "artifacts/paracetamol-research/18485596.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9bd927cbceffd6cf3a23e34bb0a6ce1584f989173a383745a97b82222f89798f", "start_char": 0, "end_char": 1545, "text_sha256": "9bd927cbceffd6cf3a23e34bb0a6ce1584f989173a383745a97b82222f89798f"} [apap-p18485596] Endocannabinoid and serotonergic systems are needed for acetaminophen-induced analgesia. (2008). https://pubmed.ncbi.nlm.nih.gov/18485596/ DOI: 10.1016/j.pain.2008.03.030

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

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experimental_model

Brain and spinal cord metabolite identification in wild-type and fatty acid amide hydrolase knockout mice

exposure

Acetaminophen, with the conjugation step tested by genetic deletion of the conjugating enzyme

limitations

Identifies a previously unknown route of drug metabolism and proves the enzyme by knockout. The downstream activities are measured on purified enzyme and cell lines rather than in the treated animal.

nutrient_topic

Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. · Paracetamol

organism

Mouse

plain_language

The brain takes the drug apart and builds the pieces into something new, and that something is what acts.

primary_references

[apap-p15987694] Conversion of acetaminophen to the bioactive N-acylphenolamine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system. (2005). https://pubmed.ncbi.nlm.nih.gov/15987694/ DOI: 10.1074/jbc.m501489200

tissue_or_cell_type

Brain and spinal cord

trigger_kind

machinery_impairment Imported condition classification; unverified.

Paracetamol: the enzyme it reduces rather than blocks, the isoform that turned out not to exist, the metabolite that carries the analgesia, and the metabolite that destroys the liver (2026-09-22) · lines 298–309

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Brain and spinal cord metabolite identification in wild-type and fatty acid amide hydrolase knockout mice · source_derived_draft · unverified_draft

### apap-faah-builds-am404 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, and this conjugation is absent in mice lacking the enzyme fatty acid amide hydrolase; AM404 also inhibits purified cyclooxygenase-1 and -2 and prostaglandin synthesis in lipopolysaccharide-stimulated macrophages and acts on the endogenous cannabinoid system, identifying fatty acid conjugation as a novel pathway for drug metabolism. Condition category: machinery_impairment nutrient_topic: Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. plain_language: The brain takes the drug apart and builds the pieces into something new, and that something is what acts. organism: Mouse tissue_or_cell_type: Brain and spinal cord experimental_model: Brain and spinal cord metabolite identification in wild-type and fatty acid amide hydrolase knockout mice limitations: Identifies a previously unknown route of drug metabolism and proves the enzyme by knockout. The downstream activities are measured on purified enzyme and cell lines rather than in the treated animal. exposure: Acetaminophen, with the conjugation step tested by genetic deletion of the conjugating enzyme evidence_span: {"source_cache": "artifacts/paracetamol-research/15987694.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8da7599ee6674ced34346ae03fae0e421bcc5c1f53b0cb879145d7a511502001", "start_char": 0, "end_char": 1093, "text_sha256": "8da7599ee6674ced34346ae03fae0e421bcc5c1f53b0cb879145d7a511502001"} [apap-p15987694] Conversion of acetaminophen to the bioactive N-acylphenolamine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system. (2005). https://pubmed.ncbi.nlm.nih.gov/15987694/ DOI: 10.1074/jbc.m501489200

evidence_span

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experimental_model

Body temperature after paracetamol in cannabinoid receptor 1 and TRPV1 knockout mice with antagonists and fatty acid amide hydrolase manipulation

exposure

300 milligrams per kilogram paracetamol in knockouts and after AM251 or SB366791, with AM404 given directly

limitations

Applies the same knockout logic used for analgesia to a different endpoint and gets the opposite answer, which is why both are recorded. Hypothermia below normal is not the same endpoint as antipyresis in fever.

nutrient_topic

Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. · Paracetamol

organism

Mouse

plain_language

The same knockouts that abolish the painkilling leave the temperature drop completely untouched.

primary_references

[apap-p21628499] Paracetamol-induced hypothermia is independent of cannabinoids and transient receptor potential vanilloid-1 and is not mediated by AM404. (2011). https://pubmed.ncbi.nlm.nih.gov/21628499/ DOI: 10.1124/dmd.111.038638

tissue_or_cell_type

Whole body temperature

Paracetamol: the enzyme it reduces rather than blocks, the isoform that turned out not to exist, the metabolite that carries the analgesia, and the metabolite that destroys the liver (2026-09-22) · lines 376–387

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Body temperature after paracetamol in cannabinoid receptor 1 and TRPV1 knockout mice with antagonists and fatty acid amide hydrolase manipulation · source_derived_draft · unverified_draft

### apap-hypothermia-is-a-different-mechanism Paracetamol induced hypothermia to the same extent in cannabinoid receptor 1 and TRPV1 knockout mice as in wild-type mice and to the same extent in mice pretreated with the antagonists AM251 or SB366791 as in controls, AM404 failed to induce hypothermia at pharmacological doses, inhibition of fatty acid amide hydrolase did not prevent the development of hypothermia and paracetamol induced hypothermia in fatty acid amide hydrolase knockout mice to the same extent as in wild-type mice, so paracetamol induces hypothermia independent of cannabinoids and TRPV1 and AM404 does not mediate this response. Condition category: normal nutrient_topic: Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. plain_language: The same knockouts that abolish the painkilling leave the temperature drop completely untouched. organism: Mouse tissue_or_cell_type: Whole body temperature experimental_model: Body temperature after paracetamol in cannabinoid receptor 1 and TRPV1 knockout mice with antagonists and fatty acid amide hydrolase manipulation limitations: Applies the same knockout logic used for analgesia to a different endpoint and gets the opposite answer, which is why both are recorded. Hypothermia below normal is not the same endpoint as antipyresis in fever. exposure: 300 milligrams per kilogram paracetamol in knockouts and after AM251 or SB366791, with AM404 given directly evidence_span: {"source_cache": "artifacts/paracetamol-research/21628499.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "784e57af3594f8d46b3b9fa70cdbc69451f9c2d424253c3b69b216d7cc541613", "start_char": 0, "end_char": 1809, "text_sha256": "784e57af3594f8d46b3b9fa70cdbc69451f9c2d424253c3b69b216d7cc541613"} [apap-p21628499] Paracetamol-induced hypothermia is independent of cannabinoids and transient receptor potential vanilloid-1 and is not mediated by AM404. (2011). https://pubmed.ncbi.nlm.nih.gov/21628499/ DOI: 10.1124/dmd.111.038638

evidence_span

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experimental_model

Human HepG2 cells and mice given acute and repeated doses, with PPAR-alpha-deficient animals and a human case

exposure

0.5 to 20 millimolar in cells and 750 milligrams per kilogram in mice, acute and repeated over four days

limitations

Follows a lipid signalling system across cells, mice, knockouts and one human case. The biphasic time course is the informative part and complicates any single-timepoint reading.

nutrient_topic

Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. · Paracetamol

organism

Human cells, mouse and human

plain_language

The same lipid system that makes the painkilling metabolite is knocked down by an overdose and then rebounds, and animals lacking it fare worse.

primary_references

[apap-p29056914] Acetaminophen-Induced Liver Injury Alters the Acyl Ethanolamine-Based Anti-Inflammatory Signaling System in Liver. (2017). https://pubmed.ncbi.nlm.nih.gov/29056914/ DOI: 10.3389/fphar.2017.00705

tissue_or_cell_type

Liver

Paracetamol: the enzyme it reduces rather than blocks, the isoform that turned out not to exist, the metabolite that carries the analgesia, and the metabolite that destroys the liver (2026-09-22) · lines 441–452

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human HepG2 cells and mice given acute and repeated doses, with PPAR-alpha-deficient animals and a human case · source_derived_draft · unverified_draft

### apap-the-lipid-brake-fails-then-rebounds Acetaminophen produced a biphasic response in the N-acyl ethanolamide and PPAR alpha system, with decreased PPAR alpha expression after 6 hours followed by a generalised increase of system components including PPAR alpha, NAPE-PLD and fatty acid amide hydrolase and of the N-acyl ethanolamides after 24 hours, confirmed in mice where gene expression of PPAR alpha and fatty acid amide hydrolase fell at 6 hours and rose by 24 hours, repeated administration decreased both and increased liver N-acyl ethanolamides with complete restoration after 15 days of rest, immunohistochemistry in a human case of acetaminophen hepatotoxicity confirmed the decrements, and damage-related alterations after repeated administration were aggravated in PPAR alpha-deficient mice. Condition category: normal nutrient_topic: Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. plain_language: The same lipid system that makes the painkilling metabolite is knocked down by an overdose and then rebounds, and animals lacking it fare worse. organism: Human cells, mouse and human tissue_or_cell_type: Liver experimental_model: Human HepG2 cells and mice given acute and repeated doses, with PPAR-alpha-deficient animals and a human case limitations: Follows a lipid signalling system across cells, mice, knockouts and one human case. The biphasic time course is the informative part and complicates any single-timepoint reading. exposure: 0.5 to 20 millimolar in cells and 750 milligrams per kilogram in mice, acute and repeated over four days evidence_span: {"source_cache": "artifacts/paracetamol-research/29056914.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2ca7517052bab3c774f315af85f3aa8cdf810e43dc44444724bff46e2f1bdab3", "start_char": 0, "end_char": 2081, "text_sha256": "2ca7517052bab3c774f315af85f3aa8cdf810e43dc44444724bff46e2f1bdab3"} [apap-p29056914] Acetaminophen-Induced Liver Injury Alters the Acyl Ethanolamine-Based Anti-Inflammatory Signaling System in Liver. (2017). https://pubmed.ncbi.nlm.nih.gov/29056914/ DOI: 10.3389/fphar.2017.00705

evidence_span

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experimental_model

Metabolite formation and antinociception for 4-aminophenol and a vanillylamine analogue across knockouts and pharmacological blockade

exposure

Systemic 4-aminophenol and 4-hydroxy-3-methoxybenzylamine, with fatty acid amide hydrolase, TRPV1, cannabinoid and serotonergic manipulations

limitations

The broadest test of the route: it reconstructs the whole chain from metabolite formation to descending pathway, and shows the profile of the metabolite matches that of the parent drug.

nutrient_topic

Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. · Paracetamol

organism

Mouse and rat

plain_language

Every step of the proposed chain was cut in turn, and cutting any of them stopped the painkilling.

primary_references

[apap-p23940628] Fatty acid amide hydrolase-dependent generation of antinociceptive drug metabolites acting on TRPV1 in the brain. (2013). https://pubmed.ncbi.nlm.nih.gov/23940628/ DOI: 10.1371/journal.pone.0070690

tissue_or_cell_type

Brain and spinal cord

Paracetamol: the enzyme it reduces rather than blocks, the isoform that turned out not to exist, the metabolite that carries the analgesia, and the metabolite that destroys the liver (2026-09-22) · lines 324–335

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Metabolite formation and antinociception for 4-aminophenol and a vanillylamine analogue across knockouts and pharmacological blockade · source_derived_draft · unverified_draft

### apap-the-whole-chain Systemic 4-aminophenol and 4-hydroxy-3-methoxybenzylamine led to dose-dependent formation of AM404 and of arvanil and olvanil respectively in the mouse brain, the order of potency of these lipid metabolites as TRPV1 activators being arvanil equal to olvanil much greater than AM404, both parent amines displayed antinociceptive activity in rodent pain tests, formation of these metabolites and the antinociceptive effects were substantially reduced or disappeared in fatty acid amide hydrolase null mice, activity was lost in TRPV1 null mice, intracerebroventricular capsazepine eliminated the effects, and in the rat, inhibition of fatty acid amide hydrolase, TRPV1, cannabinoid CB1 receptors and spinal 5-HT3 or 5-HT1A receptors and chemical deletion of bulbospinal serotonergic pathways all prevented the action, giving a pharmacological profile identical to that previously reported for paracetamol. Condition category: normal nutrient_topic: Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. plain_language: Every step of the proposed chain was cut in turn, and cutting any of them stopped the painkilling. organism: Mouse and rat tissue_or_cell_type: Brain and spinal cord experimental_model: Metabolite formation and antinociception for 4-aminophenol and a vanillylamine analogue across knockouts and pharmacological blockade limitations: The broadest test of the route: it reconstructs the whole chain from metabolite formation to descending pathway, and shows the profile of the metabolite matches that of the parent drug. exposure: Systemic 4-aminophenol and 4-hydroxy-3-methoxybenzylamine, with fatty acid amide hydrolase, TRPV1, cannabinoid and serotonergic manipulations evidence_span: {"source_cache": "artifacts/paracetamol-research/23940628.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "cc9d85547497bfdf88095aaeccf5a11cb9198140ebb35523d5da1b85f76e0a44", "start_char": 0, "end_char": 2208, "text_sha256": "cc9d85547497bfdf88095aaeccf5a11cb9198140ebb35523d5da1b85f76e0a44"} [apap-p23940628] Fatty acid amide hydrolase-dependent generation of antinociceptive drug metabolites acting on TRPV1 in the brain. (2013). https://pubmed.ncbi.nlm.nih.gov/23940628/ DOI: 10.1371/journal.pone.0070690