Cyclooxygenase-1 (PTGS1)

evidence_span

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experimental_model

Lipopolysaccharide-challenged human whole blood with prostaglandin E2 and thromboxane B2 as isoform indices

exposure

Lipopolysaccharide induction of cyclooxygenase-2 with a single oral indomethacin dose ex vivo

limitations

Establishes the assay the other records rely on. Indomethacin rather than ibuprofen is the drug dosed here.

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

Human

plain_language

The first enzyme is always there and the second one appears when tissue is provoked; most of these drugs hit the first harder.

primary_references

[ibu-p8907587] A human whole blood assay for clinical evaluation of biochemical efficacy of cyclooxygenase inhibitors. (1996). https://pubmed.ncbi.nlm.nih.gov/8907587/ DOI: 10.1007/bf02265118

tissue_or_cell_type

Whole blood and mononuclear cells

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 357–368

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Lipopolysaccharide-challenged human whole blood with prostaglandin E2 and thromboxane B2 as isoform indices · source_derived_draft · unverified_draft

### ibu-most-nsaids-favour-cox1 Incubation of human mononuclear cells with lipopolysaccharide induced a time-dependent increase in cyclooxygenase-2 protein of more than a hundredfold at 24 hours with increased prostaglandin E2 production, while cyclooxygenase-1 protein was present at time zero and not induced, and most non-steroidal anti-inflammatory drugs are more potent at inhibiting cyclooxygenase-1 than cyclooxygenase-2, with five experimental compounds showing greater selectivity for cyclooxygenase-2. 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: The first enzyme is always there and the second one appears when tissue is provoked; most of these drugs hit the first harder. organism: Human tissue_or_cell_type: Whole blood and mononuclear cells experimental_model: Lipopolysaccharide-challenged human whole blood with prostaglandin E2 and thromboxane B2 as isoform indices limitations: Establishes the assay the other records rely on. Indomethacin rather than ibuprofen is the drug dosed here. exposure: Lipopolysaccharide induction of cyclooxygenase-2 with a single oral indomethacin dose ex vivo evidence_span: {"source_cache": "artifacts/ibuprofen-research/8907587.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "99f3a26e6399b5f81c18859b9f62eafcd7aa6fc4e483d97a39e8c35c060a9d75", "start_char": 0, "end_char": 1101, "text_sha256": "99f3a26e6399b5f81c18859b9f62eafcd7aa6fc4e483d97a39e8c35c060a9d75"} [ibu-p8907587] A human whole blood assay for clinical evaluation of biochemical efficacy of cyclooxygenase inhibitors. (1996). https://pubmed.ncbi.nlm.nih.gov/8907587/ DOI: 10.1007/bf02265118

evidence_span

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experimental_model

Ram seminal vesicle microsomal prostaglandin H synthase with product identification by cooxidation

exposure

Acetaminophen from 20 micromolar to above 10 millimolar, with glutathione, ascorbate and indomethacin

limitations

Shows that the drug both stimulates and inhibits the same enzyme depending on concentration, and that the enzyme makes NAPQI from it. A microsomal preparation at concentrations far above therapeutic.

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

Sheep

plain_language

The prostaglandin enzyme can itself turn the drug into the liver-damaging metabolite.

primary_references

[apap-p3124965] Acetaminophen and analogs as cosubstrates and inhibitors of prostaglandin H synthase. (1988). https://pubmed.ncbi.nlm.nih.gov/3124965/ DOI: 10.1016/0009-2797(88)90101-9

tissue_or_cell_type

Seminal vesicle microsomes

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 129–140

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Ram seminal vesicle microsomal prostaglandin H synthase with product identification by cooxidation · source_derived_draft · unverified_draft

### apap-the-enzyme-makes-napqi Using acetaminophen as a probe, at low concentrations it is converted in a cooxidation reaction with arachidonic acid to the dimer 4,4-dihydroxy-3,3-biacetanilide and other polymeric products, and the electrophilic metabolite N-acetyl-p-benzoquinone imine was detected directly and indirectly by its reaction with glutathione to form 3-S-glutathionylacetaminophen; the same products were formed by the synthase with hydrogen peroxide in reactions not inhibited by indomethacin, and formation of all products was inhibited by ascorbic acid and butylated hydroxyanisole. 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 prostaglandin enzyme can itself turn the drug into the liver-damaging metabolite. organism: Sheep tissue_or_cell_type: Seminal vesicle microsomes experimental_model: Ram seminal vesicle microsomal prostaglandin H synthase with product identification by cooxidation limitations: Shows that the drug both stimulates and inhibits the same enzyme depending on concentration, and that the enzyme makes NAPQI from it. A microsomal preparation at concentrations far above therapeutic. exposure: Acetaminophen from 20 micromolar to above 10 millimolar, with glutathione, ascorbate and indomethacin evidence_span: {"source_cache": "artifacts/paracetamol-research/3124965.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "dcc85a1ab66984973092042b5553f43fbbe5eb10b674614c9b1fa991b3969502", "start_char": 0, "end_char": 2236, "text_sha256": "dcc85a1ab66984973092042b5553f43fbbe5eb10b674614c9b1fa991b3969502"} [apap-p3124965] Acetaminophen and analogs as cosubstrates and inhibitors of prostaglandin H synthase. (1988). https://pubmed.ncbi.nlm.nih.gov/3124965/ DOI: 10.1016/0009-2797(88)90101-9

evidence_span

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experimental_model

Aspirin pharmacodynamics in MEG-01 and CHRF-288-11 human megakaryocytic cell lines with selective isoform inhibitors

exposure

Single and repeated aspirin exposures from 0.1 to 10 micromolar, with SC-560 and NS-398 as isoform probes

limitations

A surrogate for a tissue that cannot ethically be sampled repeatedly. Cell lines rather than primary megakaryocytes, which the authors state.

nutrient_topic

Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. · Aspirin / acetylsalicylic acid

organism

Human cells

plain_language

The precursor cell makes its thromboxane with the first enzyme, and has to build new enzyme to recover.

primary_references

[asa-p41265381] Aspirin inhibition and recovery of cyclooxygenase activity and thromboxane biosynthesis in human megakaryocytes: a translational surrogate model. (2025). https://pubmed.ncbi.nlm.nih.gov/41265381/ DOI: 10.1016/j.jpet.2025.103762

tissue_or_cell_type

Megakaryocytic cell lines

Aspirin: the serine it acetylates, the enzyme that acetylation creates, the dose that separates platelet from vessel wall, and the metabolite that is a different drug (2026-09-22) · lines 429–440

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Aspirin pharmacodynamics in MEG-01 and CHRF-288-11 human megakaryocytic cell lines with selective isoform inhibitors · source_derived_draft · unverified_draft

### asa-megakaryocyte-cox1 In human megakaryocytic cell lines a single 10 micromolar aspirin exposure suppressed thromboxane B2 by 90% and 85% respectively with full recovery within 48 to 72 hours, selective cyclooxygenase-1 inhibition by SC-560 reduced thromboxane B2 by more than 75% whereas cyclooxygenase-2 inhibition by NS-398 had minimal effect, and repeated exposure every 24 hours produced concentration- and time-dependent suppression reaching 89% by day 2 at 1 micromolar and 73% by day 4 at 0.1 micromolar, with delayed recovery likely reflecting de novo synthesis of cyclooxygenase-1 protein. Condition category: normal nutrient_topic: Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. plain_language: The precursor cell makes its thromboxane with the first enzyme, and has to build new enzyme to recover. organism: Human cells tissue_or_cell_type: Megakaryocytic cell lines experimental_model: Aspirin pharmacodynamics in MEG-01 and CHRF-288-11 human megakaryocytic cell lines with selective isoform inhibitors limitations: A surrogate for a tissue that cannot ethically be sampled repeatedly. Cell lines rather than primary megakaryocytes, which the authors state. exposure: Single and repeated aspirin exposures from 0.1 to 10 micromolar, with SC-560 and NS-398 as isoform probes evidence_span: {"source_cache": "artifacts/aspirin-research/41265381.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "88710110438cddd108a51822aeb63c5f0a8125192eecc85eeeaf1edf3c3d85cc", "start_char": 0, "end_char": 2110, "text_sha256": "88710110438cddd108a51822aeb63c5f0a8125192eecc85eeeaf1edf3c3d85cc"} [asa-p41265381] Aspirin inhibition and recovery of cyclooxygenase activity and thromboxane biosynthesis in human megakaryocytes: a translational surrogate model. (2025). https://pubmed.ncbi.nlm.nih.gov/41265381/ DOI: 10.1016/j.jpet.2025.103762

evidence_span

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experimental_model

Purified ovine cyclooxygenase-1 and human cyclooxygenase-2 assayed with and without a peroxide-removing system

exposure

Acetaminophen with and without glutathione peroxidase and glutathione

limitations

Adding a peroxide-removing system is the manipulation that reveals the mechanism, because it changes potency thirtyfold without changing the drug. Purified enzyme, so the concentrations are not tissue concentrations.

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

Sheep and human enzyme

plain_language

Take the peroxide away and the same drug becomes thirty times stronger, which is the whole mechanism in one experiment.

primary_references

[apap-p11370851] Mechanism of acetaminophen inhibition of cyclooxygenase isoforms. (2001). https://pubmed.ncbi.nlm.nih.gov/11370851/ DOI: 10.1006/abbi.2000.2232

tissue_or_cell_type

Purified cyclooxygenase

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 77–88

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified ovine cyclooxygenase-1 and human cyclooxygenase-2 assayed with and without a peroxide-removing system · source_derived_draft · unverified_draft

### apap-potency-depends-on-peroxide The potency of acetaminophen against both purified ovine cyclooxygenase-1 and human cyclooxygenase-2 was increased approximately 30-fold by the presence of glutathione peroxidase and glutathione, giving half-maximal inhibitory concentrations of 33 and 980 micromolar respectively, acetaminophen was found to be a good reducing agent of both enzymes, and the results are consistent with a mechanism in which it reduces the active oxidized form of the enzyme to the resting form, so that inhibition would be more effective under conditions of low peroxide concentration, consistent with the known tissue selectivity. 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: Take the peroxide away and the same drug becomes thirty times stronger, which is the whole mechanism in one experiment. organism: Sheep and human enzyme tissue_or_cell_type: Purified cyclooxygenase experimental_model: Purified ovine cyclooxygenase-1 and human cyclooxygenase-2 assayed with and without a peroxide-removing system limitations: Adding a peroxide-removing system is the manipulation that reveals the mechanism, because it changes potency thirtyfold without changing the drug. Purified enzyme, so the concentrations are not tissue concentrations. exposure: Acetaminophen with and without glutathione peroxidase and glutathione evidence_span: {"source_cache": "artifacts/paracetamol-research/11370851.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "4eeda4b163828f2cc2a4341c4810df6bf6c683d6165eeb09479104f185e52ca4", "start_char": 0, "end_char": 1086, "text_sha256": "4eeda4b163828f2cc2a4341c4810df6bf6c683d6165eeb09479104f185e52ca4"} [apap-p11370851] Mechanism of acetaminophen inhibition of cyclooxygenase isoforms. (2001). https://pubmed.ncbi.nlm.nih.gov/11370851/ DOI: 10.1006/abbi.2000.2232

evidence_span

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experimental_model

Ram seminal vesicle microsomal prostaglandin H synthase with product identification by cooxidation

exposure

Acetaminophen from 20 micromolar to above 10 millimolar, with glutathione, ascorbate and indomethacin

limitations

Shows that the drug both stimulates and inhibits the same enzyme depending on concentration, and that the enzyme makes NAPQI from it. A microsomal preparation at concentrations far above therapeutic.

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

Sheep

plain_language

At low concentrations the drug feeds the enzyme and at high concentrations it stalls it, both by handing over electrons.

primary_references

[apap-p3124965] Acetaminophen and analogs as cosubstrates and inhibitors of prostaglandin H synthase. (1988). https://pubmed.ncbi.nlm.nih.gov/3124965/ DOI: 10.1016/0009-2797(88)90101-9

tissue_or_cell_type

Seminal vesicle microsomes

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 116–127

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Ram seminal vesicle microsomal prostaglandin H synthase with product identification by cooxidation · source_derived_draft · unverified_draft

### apap-stimulates-then-inhibits Relatively low concentrations of acetaminophen from 20 to 200 micromolar stimulate prostaglandin H synthase activity in ram seminal vesicle microsomes whereas concentrations above 10 millimolar inhibit the conversion of arachidonic acid to prostaglandin G2, both activities apparently involving reduction of oxidized complexes of the enzyme and roughly correlating with the electrochemical half-wave oxidation potentials of a series of hydroxyacetanilides, consistent with common intermediate enzyme forms for both cyclooxygenase and hydroperoxidase catalysed reactions of which one is reduced at low drug concentrations to stimulate and another at higher concentrations to inhibit. 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: At low concentrations the drug feeds the enzyme and at high concentrations it stalls it, both by handing over electrons. organism: Sheep tissue_or_cell_type: Seminal vesicle microsomes experimental_model: Ram seminal vesicle microsomal prostaglandin H synthase with product identification by cooxidation limitations: Shows that the drug both stimulates and inhibits the same enzyme depending on concentration, and that the enzyme makes NAPQI from it. A microsomal preparation at concentrations far above therapeutic. exposure: Acetaminophen from 20 micromolar to above 10 millimolar, with glutathione, ascorbate and indomethacin evidence_span: {"source_cache": "artifacts/paracetamol-research/3124965.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "dcc85a1ab66984973092042b5553f43fbbe5eb10b674614c9b1fa991b3969502", "start_char": 0, "end_char": 2236, "text_sha256": "dcc85a1ab66984973092042b5553f43fbbe5eb10b674614c9b1fa991b3969502"} [apap-p3124965] Acetaminophen and analogs as cosubstrates and inhibitors of prostaglandin H synthase. (1988). https://pubmed.ncbi.nlm.nih.gov/3124965/ DOI: 10.1016/0009-2797(88)90101-9

cross_nutrient

false

experimental_model

Recombinant human COX enzyme assay; PGF2alpha readout after chemical reduction

exposure

10 min compound preincubation; arachidonic acid 5 µM for 2 min; stannous chloride converted PG intermediates to PGF2alpha for ELISA.

limitations

This assay differs from older ovine COX-1/oxygen-electrode work; species and substrate differences preclude labeling every potency discrepancy as a contradiction.

nutrient_topic

Vitamin E research collection; topical membership is not evidence of a direct dietary effect. · Vitamin E

organism

Homo sapiens

plain_language

Gamma-tocopherol reduced activity of purified human COX-1 under these assay conditions.

primary_references

[park2022] Different forms of vitamin E and metabolite 13'-carboxychromanols inhibit cyclooxygenase-1 and its catalyzed thromboxane in platelets, and tocotrienols and 13'-carboxychromanols are competitive inhibitors of 5-lipoxygenase. (2022). https://pubmed.ncbi.nlm.nih.gov/34710615/ DOI: 10.1016/j.jnutbio.2021.108884

tissue_or_cell_type

Cell-free enzyme

Vitamin E: transport, membrane protection and nutrient interactions (2026-09-17) · lines 1089–1100

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human COX enzyme assay; PGF2alpha readout after chemical reduction · source_derived_draft · unverified_draft

### e-sig-gamma-human-cox1 Gamma-tocopherol inhibited human recombinant COX-1 in a prostaglandin-product assay, with the tested non-alpha vitamin E forms showing IC50 values of 1–2.5 µM. Parent vitamin E forms did not significantly inhibit COX-2 in the same system. Condition category: normal nutrient_topic: Vitamin E research collection; topical membership is not evidence of a direct dietary effect. plain_language: Gamma-tocopherol reduced activity of purified human COX-1 under these assay conditions. organism: Homo sapiens tissue_or_cell_type: Cell-free enzyme experimental_model: Recombinant human COX enzyme assay; PGF2alpha readout after chemical reduction limitations: This assay differs from older ovine COX-1/oxygen-electrode work; species and substrate differences preclude labeling every potency discrepancy as a contradiction. exposure: 10 min compound preincubation; arachidonic acid 5 µM for 2 min; stannous chloride converted PG intermediates to PGF2alpha for ELISA. cross_nutrient: false [park2022] Different forms of vitamin E and metabolite 13'-carboxychromanols inhibit cyclooxygenase-1 and its catalyzed thromboxane in platelets, and tocotrienols and 13'-carboxychromanols are competitive inhibitors of 5-lipoxygenase. (2022). https://pubmed.ncbi.nlm.nih.gov/34710615/ DOI: 10.1016/j.jnutbio.2021.108884

evidence_span

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experimental_model

Eight acyl salicylates tested against human cyclooxygenase-1 and -2 expressed transiently in cos-1 cells, with the S530A mutant as a control

exposure

Valeryl salicylate and related esters compared with acetylsalicylate

limitations

Uses the acetylation chemistry as a design principle and confirms the serine requirement with a mutant. Recombinant enzyme and a murine fibroblast line, not human tissue.

nutrient_topic

Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. · Aspirin / acetylsalicylic acid

organism

Human and sheep enzyme

plain_language

Swap aspirin’s acetyl group for a bigger one and you get a drug that hits only the first enzyme.

primary_references

[asa-p7872783] Selective inhibition of prostaglandin endoperoxide synthase-1 (cyclooxygenase-1) by valerylsalicylic acid. (1995). https://pubmed.ncbi.nlm.nih.gov/7872783/ DOI: 10.1006/abbi.1995.1130

tissue_or_cell_type

Recombinant cyclooxygenase

Aspirin: the serine it acetylates, the enzyme that acetylation creates, the dose that separates platelet from vessel wall, and the metabolite that is a different drug (2026-09-22) · lines 182–193

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Eight acyl salicylates tested against human cyclooxygenase-1 and -2 expressed transiently in cos-1 cells, with the S530A mutant as a control · source_derived_draft · unverified_draft

### asa-bigger-acyl-group-selective Valeryl (pentanoyl) salicylate was the only compound of eight acyl salicylates to show isozyme selectivity and inhibited human cyclooxygenase-1 much more effectively than cyclooxygenase-2 in a time-dependent manner, inhibited ovine cyclooxygenase-1 but did not inhibit the S530A mutant of ovine cyclooxygenase-1 which is also refractory to acetylsalicylate, so valeryl salicylate acylates the active site serine. Condition category: normal nutrient_topic: Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. plain_language: Swap aspirin’s acetyl group for a bigger one and you get a drug that hits only the first enzyme. organism: Human and sheep enzyme tissue_or_cell_type: Recombinant cyclooxygenase experimental_model: Eight acyl salicylates tested against human cyclooxygenase-1 and -2 expressed transiently in cos-1 cells, with the S530A mutant as a control limitations: Uses the acetylation chemistry as a design principle and confirms the serine requirement with a mutant. Recombinant enzyme and a murine fibroblast line, not human tissue. exposure: Valeryl salicylate and related esters compared with acetylsalicylate evidence_span: {"source_cache": "artifacts/aspirin-research/7872783.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f7e8a07a2704cb600938505ec51355671355769c01868ed0966731382901425b", "start_char": 0, "end_char": 1756, "text_sha256": "f7e8a07a2704cb600938505ec51355671355769c01868ed0966731382901425b"} [asa-p7872783] Selective inhibition of prostaglandin endoperoxide synthase-1 (cyclooxygenase-1) by valerylsalicylic acid. (1995). https://pubmed.ncbi.nlm.nih.gov/7872783/ DOI: 10.1006/abbi.1995.1130

availability_state

biomarker_context Imported condition classification; unverified.

evidence_span

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experimental_model

Clinical case report of an adverse reaction in an aspirin-sensitive asthmatic

exposure

A single 400 milligram ibuprofen tablet in a 53-year-old aspirin-sensitive asthmatic with nasal polyps

limitations

A single case, but it identifies the basis of the reaction as shared pharmacology rather than immunology, which is what determines whether a substitute drug is safe.

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

Human

plain_language

The reaction is not an allergy to the drug but to what the drug does, so any drug that does the same thing will do it too.

primary_references

[ibu-p696734] Cross-reactivity between aspirin and ibuprofen in an asthmatic--a case report. (1978). https://pubmed.ncbi.nlm.nih.gov/696734/ DOI: 10.1093/ajhp/35.10.1245

tissue_or_cell_type

Airway and skin

trigger_kind

biomarker_context Imported condition classification; unverified.

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 539–550

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Clinical case report of an adverse reaction in an aspirin-sensitive asthmatic · source_derived_draft · unverified_draft

### ibu-cross-reacts-pharmacologically A 53-year-old aspirin-sensitive asthmatic man with nasal polyps developed an urticarial rash, laboured breathing, laryngeal oedema and chest tightness after a 400 milligram ibuprofen tablet, requiring isoproterenol, subcutaneous epinephrine, intramuscular diphenhydramine and intravenous hydrocortisone; the reaction was not mediated immunologically but resulted from the prostaglandin synthetase inhibitor activity shared by aspirin, ibuprofen and other analgesics, so selection of an analgesic for an aspirin-sensitive patient should be based on that activity. Condition category: biomarker_context 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: The reaction is not an allergy to the drug but to what the drug does, so any drug that does the same thing will do it too. organism: Human tissue_or_cell_type: Airway and skin experimental_model: Clinical case report of an adverse reaction in an aspirin-sensitive asthmatic limitations: A single case, but it identifies the basis of the reaction as shared pharmacology rather than immunology, which is what determines whether a substitute drug is safe. exposure: A single 400 milligram ibuprofen tablet in a 53-year-old aspirin-sensitive asthmatic with nasal polyps evidence_span: {"source_cache": "artifacts/ibuprofen-research/696734.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ca9f025b68310a2b49def4e15ad6f25fb14fc900284de8d68cd80aa6a7f47139", "start_char": 0, "end_char": 949, "text_sha256": "ca9f025b68310a2b49def4e15ad6f25fb14fc900284de8d68cd80aa6a7f47139"} [ibu-p696734] Cross-reactivity between aspirin and ibuprofen in an asthmatic--a case report. (1978). https://pubmed.ncbi.nlm.nih.gov/696734/ DOI: 10.1093/ajhp/35.10.1245

evidence_span

{"source_cache": "artifacts/ibuprofen-research/3088675.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ee49ae775f6c268fd63afc816cda206f0bdab5efe9ce86b4f97fd8ee6bda3a1a", "start_char": 0, "end_char": 1400, "text_sha256": "ee49ae775f6c268fd63afc816cda206f0bdab5efe9ce86b4f97fd8ee6bda3a1a"}

experimental_model

Kinetics of recovery of platelet thromboxane production after single doses, with platelets resuspended in drug-free plasma

exposure

Indomethacin and ibuprofen compared, with isolated platelets and platelet microsomes

limitations

The resuspension experiment is what separates a reversible inhibitor from a slowly reversible one. It uses indomethacin as the contrast and reports ibuprofen as the reference reversible drug.

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

Human

plain_language

Wash the drug away and the platelet enzyme is working again at once, which is the opposite of what aspirin does.

primary_references

[ibu-p3088675] Time-dependent inhibition of platelet cyclooxygenase by indomethacin is slowly reversible. (1986). https://pubmed.ncbi.nlm.nih.gov/3088675/ DOI: 10.1016/0090-6980(86)90170-x

tissue_or_cell_type

Platelets

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 279–290

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Kinetics of recovery of platelet thromboxane production after single doses, with platelets resuspended in drug-free plasma · source_derived_draft · unverified_draft

### ibu-ibuprofen-washes-straight-out When platelets were isolated and resuspended in homologous drug-free plasma, slow recovery of thromboxane production was seen after indomethacin with 50% of control activity regained in 100 minutes, whereas ibuprofen-treated platelets, exposed to a competitive inhibitor of cyclooxygenase, recovered nearly completely immediately on being resuspended in drug-free plasma. 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: Wash the drug away and the platelet enzyme is working again at once, which is the opposite of what aspirin does. organism: Human tissue_or_cell_type: Platelets experimental_model: Kinetics of recovery of platelet thromboxane production after single doses, with platelets resuspended in drug-free plasma limitations: The resuspension experiment is what separates a reversible inhibitor from a slowly reversible one. It uses indomethacin as the contrast and reports ibuprofen as the reference reversible drug. exposure: Indomethacin and ibuprofen compared, with isolated platelets and platelet microsomes evidence_span: {"source_cache": "artifacts/ibuprofen-research/3088675.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ee49ae775f6c268fd63afc816cda206f0bdab5efe9ce86b4f97fd8ee6bda3a1a", "start_char": 0, "end_char": 1400, "text_sha256": "ee49ae775f6c268fd63afc816cda206f0bdab5efe9ce86b4f97fd8ee6bda3a1a"} [ibu-p3088675] Time-dependent inhibition of platelet cyclooxygenase by indomethacin is slowly reversible. (1986). https://pubmed.ncbi.nlm.nih.gov/3088675/ DOI: 10.1016/0090-6980(86)90170-x

evidence_span

{"source_cache": "artifacts/ibuprofen-research/8831731.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d3161aac692f44c874cafb498e9606f0382b380662ccb58cd1683139f1c1df99", "start_char": 0, "end_char": 1993, "text_sha256": "d3161aac692f44c874cafb498e9606f0382b380662ccb58cd1683139f1c1df99"}

experimental_model

Chinese hamster ovary cell lines stably expressing each human cyclooxygenase isoform, with cell-free comparison

exposure

Ibuprofen, indomethacin, NS-398 and DuP-697 across intact cells and microsomal preparations

limitations

Shows that the selectivity numbers depend on the assay, which bears on every potency ratio quoted for this drug class. A heterologous expression system.

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

Human enzyme in hamster cells

plain_language

Against both enzymes it is a reversible blocker, and the numbers you get depend on which assay you use.

primary_references

[ibu-p8831731] Mechanism of selective inhibition of human prostaglandin G/H synthase-1 and -2 in intact cells. (1996). https://pubmed.ncbi.nlm.nih.gov/8831731/ DOI: 10.1016/0006-2952(96)00462-5

tissue_or_cell_type

Intact cells and cell-free preparations

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 292–303

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Chinese hamster ovary cell lines stably expressing each human cyclooxygenase isoform, with cell-free comparison · source_derived_draft · unverified_draft

### ibu-reversible-against-both-isoforms Reversible inhibition of both cellular cyclooxygenase-1 and cyclooxygenase-2 was observed with the nonselective drugs ibuprofen and indomethacin, whereas the selective inhibitor DuP-697 was reversible against cyclooxygenase-1 but irreversible against cyclooxygenase-2, and indomethacin displayed time-dependent inhibition of both cellular isoforms; the selectivities and potencies of inhibitors determined using intact cells are affected by substrate concentration and differ from those determined in cell-free microsomal or purified enzyme preparations. 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: Against both enzymes it is a reversible blocker, and the numbers you get depend on which assay you use. organism: Human enzyme in hamster cells tissue_or_cell_type: Intact cells and cell-free preparations experimental_model: Chinese hamster ovary cell lines stably expressing each human cyclooxygenase isoform, with cell-free comparison limitations: Shows that the selectivity numbers depend on the assay, which bears on every potency ratio quoted for this drug class. A heterologous expression system. exposure: Ibuprofen, indomethacin, NS-398 and DuP-697 across intact cells and microsomal preparations evidence_span: {"source_cache": "artifacts/ibuprofen-research/8831731.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d3161aac692f44c874cafb498e9606f0382b380662ccb58cd1683139f1c1df99", "start_char": 0, "end_char": 1993, "text_sha256": "d3161aac692f44c874cafb498e9606f0382b380662ccb58cd1683139f1c1df99"} [ibu-p8831731] Mechanism of selective inhibition of human prostaglandin G/H synthase-1 and -2 in intact cells. (1996). https://pubmed.ncbi.nlm.nih.gov/8831731/ DOI: 10.1016/0006-2952(96)00462-5

evidence_span

{"source_cache": "artifacts/ibuprofen-research/14741265.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "244b7634bca0e2a090e86f49257289d02d19637b2c540260e94662dcdaa4111a", "start_char": 0, "end_char": 405, "text_sha256": "244b7634bca0e2a090e86f49257289d02d19637b2c540260e94662dcdaa4111a"}

experimental_model

Chemical modification of flurbiprofen and ibuprofen to alter cyclooxygenase-1 binding kinetics

exposure

Halogenated and carboxylate-modified analogues tested for slow tight-binding behaviour

limitations

A structure-activity result on the kinetic class of inhibition rather than on potency. It does not report the potencies themselves.

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

Enzyme

plain_language

Cap the acid group and the drug can no longer settle into the slow, tenacious kind of binding.

primary_references

[ibu-p14741265] Manipulation of kinetic profiles in 2-aryl propionic acid cyclooxygenase inhibitors. (2004). https://pubmed.ncbi.nlm.nih.gov/14741265/ DOI: 10.1016/j.bmcl.2003.11.034

tissue_or_cell_type

Cyclooxygenase-1

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 266–277

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Chemical modification of flurbiprofen and ibuprofen to alter cyclooxygenase-1 binding kinetics · source_derived_draft · unverified_draft

### ibu-the-free-acid-is-required Conversion of the carboxylate moiety of flurbiprofen to an ester or amide abolishes slow tight-binding behaviour regardless of halogenation state, and contrary to prior predictions a halogen substituent is not sufficient to confer slow tight-binding behaviour. 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: Cap the acid group and the drug can no longer settle into the slow, tenacious kind of binding. organism: Enzyme tissue_or_cell_type: Cyclooxygenase-1 experimental_model: Chemical modification of flurbiprofen and ibuprofen to alter cyclooxygenase-1 binding kinetics limitations: A structure-activity result on the kinetic class of inhibition rather than on potency. It does not report the potencies themselves. exposure: Halogenated and carboxylate-modified analogues tested for slow tight-binding behaviour evidence_span: {"source_cache": "artifacts/ibuprofen-research/14741265.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "244b7634bca0e2a090e86f49257289d02d19637b2c540260e94662dcdaa4111a", "start_char": 0, "end_char": 405, "text_sha256": "244b7634bca0e2a090e86f49257289d02d19637b2c540260e94662dcdaa4111a"} [ibu-p14741265] Manipulation of kinetic profiles in 2-aryl propionic acid cyclooxygenase inhibitors. (2004). https://pubmed.ncbi.nlm.nih.gov/14741265/ DOI: 10.1016/j.bmcl.2003.11.034

evidence_span

{"source_cache": "artifacts/ibuprofen-research/11755111.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1dd77f4a1eebd7777285c424b1731f4744d0fa593e62cfbde0a92dbb6242b239", "start_char": 0, "end_char": 2074, "text_sha256": "1dd77f4a1eebd7777285c424b1731f4744d0fa593e62cfbde0a92dbb6242b239"}

experimental_model

Reporter and enzyme assays comparing ibuprofen isomers against naproxen and indomethacin across four readouts

exposure

S(+)- and R(-)-ibuprofen compared directly on cyclooxygenase-1 and -2, platelet function and nuclear receptor activation

limitations

The only record here that measures both enantiomers on the same panel, which is what makes the fold-differences meaningful. Several different assay systems are combined.

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, human and sheep systems

plain_language

At the first enzyme one hand is thirty to ninety times stronger; at the second enzyme the two hands are indistinguishable.

primary_references

[ibu-p11755111] Activation of peroxisome proliferator-activated receptor isoforms and inhibition of prostaglandin H(2) synthases by ibuprofen, naproxen, and indomethacin. (2001). https://pubmed.ncbi.nlm.nih.gov/11755111/ DOI: 10.1016/s0006-2952(01)00822-x

tissue_or_cell_type

Transfected cells, hepatoma cells, platelets and purified enzyme

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 318–329

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Reporter and enzyme assays comparing ibuprofen isomers against naproxen and indomethacin across four readouts · source_derived_draft · unverified_draft

### ibu-thirty-two-fold-at-cox1 The S(+) isomer of ibuprofen was 32-, 41- and 96-fold more potent than the R(-) isomer for inhibition of prostaglandin endoperoxide H synthase-1 activity, human platelet aggregation and serotonin secretion respectively, while on prostaglandin endoperoxide H synthase-2 the ibuprofen isomers showed no selectivity, and indomethacin, S(+)-ibuprofen and S(+)-naproxen were 6-, 27- and 5-fold more potent as inhibitors of synthase-1 than of synthase-2. 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: At the first enzyme one hand is thirty to ninety times stronger; at the second enzyme the two hands are indistinguishable. organism: Rat, human and sheep systems tissue_or_cell_type: Transfected cells, hepatoma cells, platelets and purified enzyme experimental_model: Reporter and enzyme assays comparing ibuprofen isomers against naproxen and indomethacin across four readouts limitations: The only record here that measures both enantiomers on the same panel, which is what makes the fold-differences meaningful. Several different assay systems are combined. exposure: S(+)- and R(-)-ibuprofen compared directly on cyclooxygenase-1 and -2, platelet function and nuclear receptor activation evidence_span: {"source_cache": "artifacts/ibuprofen-research/11755111.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1dd77f4a1eebd7777285c424b1731f4744d0fa593e62cfbde0a92dbb6242b239", "start_char": 0, "end_char": 2074, "text_sha256": "1dd77f4a1eebd7777285c424b1731f4744d0fa593e62cfbde0a92dbb6242b239"} [ibu-p11755111] Activation of peroxisome proliferator-activated receptor isoforms and inhibition of prostaglandin H(2) synthases by ibuprofen, naproxen, and indomethacin. (2001). https://pubmed.ncbi.nlm.nih.gov/11755111/ DOI: 10.1016/s0006-2952(01)00822-x

evidence_span

{"source_cache": "artifacts/ibuprofen-research/8567676.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "773dc61cda18ae93ea7dfaf128870c2c5926fb828d7a1563f413e97e29893eda", "start_char": 0, "end_char": 2200, "text_sha256": "773dc61cda18ae93ea7dfaf128870c2c5926fb828d7a1563f413e97e29893eda"}

experimental_model

Site-directed mutants of ovine cyclooxygenase-1 at Arg120, Glu524 and Tyr355 expressed in COS-1 cells

exposure

D- and L-ibuprofen and flurbiprofen tested against the mutant panel

limitations

Identifies which residue does the stereochemical discrimination by changing it and watching the discrimination collapse. Ovine recombinant enzyme.

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

Sheep enzyme

plain_language

One tyrosine is what lets the enzyme tell the two hands of the drug apart; remove it and the difference mostly goes.

primary_references

[ibu-p8567676] Involvement of arginine 120, glutamate 524, and tyrosine 355 in the binding of arachidonate and 2-phenylpropionic acid inhibitors to the cyclooxygenase active site of ovine prostaglandin endoperoxide H synthase-1. (1996). https://pubmed.ncbi.nlm.nih.gov/8567676/ DOI: 10.1074/jbc.271.4.2179

tissue_or_cell_type

Recombinant cyclooxygenase-1

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 240–251

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Site-directed mutants of ovine cyclooxygenase-1 at Arg120, Glu524 and Tyr355 expressed in COS-1 cells · source_derived_draft · unverified_draft

### ibu-tyr355-reads-the-handedness Ratios of half-maximal inhibitory concentrations for cyclooxygenase inhibition by D- and L-ibuprofen were 32 for native cyclooxygenase-1, 67 for the R120Q mutant and 7.1 for the Y355F mutant, and the decreased stereochemical specificity of the Y355F mutant suggests that Tyr355 is a determinant of the stereospecificity of the enzyme toward inhibitors of the 2-phenylpropionic acid class. 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: One tyrosine is what lets the enzyme tell the two hands of the drug apart; remove it and the difference mostly goes. organism: Sheep enzyme tissue_or_cell_type: Recombinant cyclooxygenase-1 experimental_model: Site-directed mutants of ovine cyclooxygenase-1 at Arg120, Glu524 and Tyr355 expressed in COS-1 cells limitations: Identifies which residue does the stereochemical discrimination by changing it and watching the discrimination collapse. Ovine recombinant enzyme. exposure: D- and L-ibuprofen and flurbiprofen tested against the mutant panel evidence_span: {"source_cache": "artifacts/ibuprofen-research/8567676.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "773dc61cda18ae93ea7dfaf128870c2c5926fb828d7a1563f413e97e29893eda", "start_char": 0, "end_char": 2200, "text_sha256": "773dc61cda18ae93ea7dfaf128870c2c5926fb828d7a1563f413e97e29893eda"} [ibu-p8567676] Involvement of arginine 120, glutamate 524, and tyrosine 355 in the binding of arachidonate and 2-phenylpropionic acid inhibitors to the cyclooxygenase active site of ovine prostaglandin endoperoxide H synthase-1. (1996). https://pubmed.ncbi.nlm.nih.gov/8567676/ DOI: 10.1074/jbc.271.4.2179

availability_state

biomarker_context Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/paracetamol-research/2666482.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9c731e77d65955b683aa03e7df1252729e11b1fb8bed714b9138f22c725eac2b", "start_char": 0, "end_char": 1081, "text_sha256": "9c731e77d65955b683aa03e7df1252729e11b1fb8bed714b9138f22c725eac2b"}

experimental_model

Double-blind placebo-controlled oral challenge and desensitisation in three aspirin-sensitive asthmatic subjects

exposure

1000 to 2000 milligram acetaminophen challenges, with aspirin desensitisation and acetaminophen desensitisation

limitations

Three subjects, selected for a history of reacting, so the frequency of cross-reactivity cannot be read from it. The cross-desensitisation result is what identifies the shared mechanism.

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

plain_language

Desensitise the patient to aspirin and they stop reacting to paracetamol, so it is the same mechanism at work.

primary_references

[apap-p2666482] Cross sensitivity with acetaminophen in aspirin-sensitive subjects with asthma. (1989). https://pubmed.ncbi.nlm.nih.gov/2666482/ DOI: 10.1016/0091-6749(89)90174-7

tissue_or_cell_type

Airway

trigger_kind

biomarker_context 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 454–465

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-blind placebo-controlled oral challenge and desensitisation in three aspirin-sensitive asthmatic subjects · source_derived_draft · unverified_draft

### apap-cross-desensitisation-shows-shared-mechanism Three aspirin-sensitive asthmatic subjects with a history of reactions underwent double-blind placebo-controlled challenges and reacted to 1000 milligrams of acetaminophen with a greater than 20% fall in forced expiratory volume in one second, two were desensitized to aspirin and then rechallenged with 1000 milligrams of acetaminophen without reaction, and two were desensitized to acetaminophen achieving refractoriness to 1500 but not 2000 milligrams, so cross sensitivity was documented at large challenge doses and the cross desensitization suggests similar mechanisms are responsible for reactions to aspirin, non-steroidal anti-inflammatory drugs and acetaminophen. Condition category: biomarker_context 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: Desensitise the patient to aspirin and they stop reacting to paracetamol, so it is the same mechanism at work. organism: Human tissue_or_cell_type: Airway experimental_model: Double-blind placebo-controlled oral challenge and desensitisation in three aspirin-sensitive asthmatic subjects limitations: Three subjects, selected for a history of reacting, so the frequency of cross-reactivity cannot be read from it. The cross-desensitisation result is what identifies the shared mechanism. exposure: 1000 to 2000 milligram acetaminophen challenges, with aspirin desensitisation and acetaminophen desensitisation evidence_span: {"source_cache": "artifacts/paracetamol-research/2666482.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9c731e77d65955b683aa03e7df1252729e11b1fb8bed714b9138f22c725eac2b", "start_char": 0, "end_char": 1081, "text_sha256": "9c731e77d65955b683aa03e7df1252729e11b1fb8bed714b9138f22c725eac2b"} [apap-p2666482] Cross sensitivity with acetaminophen in aspirin-sensitive subjects with asthma. (1989). https://pubmed.ncbi.nlm.nih.gov/2666482/ DOI: 10.1016/0091-6749(89)90174-7

evidence_span

{"source_cache": "artifacts/paracetamol-research/17884974.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e2856e9fc1c319219fd3d3cb145f70bb1157f7ca0baa0221594c9583cf7ddc23", "start_char": 0, "end_char": 1857, "text_sha256": "e2856e9fc1c319219fd3d3cb145f70bb1157f7ca0baa0221594c9583cf7ddc23"}

experimental_model

Ex vivo and in vitro human whole blood cyclooxygenase assays in five volunteers given a single oral dose

exposure

1000 milligrams oral acetaminophen, with coagulation-induced thromboxane B2 and lipopolysaccharide-induced prostaglandin E2 as isoform indices

limitations

Measures both isoform indices in dosed people and relates them to plasma concentration. Five volunteers and a single dose.

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

plain_language

In people it blocks the second enzyme as hard as a proper anti-inflammatory does, and never blocks the first enough to touch platelets.

primary_references

[apap-p17884974] Acetaminophen (paracetamol) is a selective cyclooxygenase-2 inhibitor in man. (2008). https://pubmed.ncbi.nlm.nih.gov/17884974/ DOI: 10.1096/fj.07-8506com

tissue_or_cell_type

Whole blood

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 259–270

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Ex vivo and in vitro human whole blood cyclooxygenase assays in five volunteers given a single oral dose · source_derived_draft · unverified_draft

### apap-four-fold-cox2-selective-in-man In vitro acetaminophen elicited a 4.4-fold selectivity toward cyclooxygenase-2 inhibition with half-maximal inhibitory concentrations of 113.7 micromolar for cyclooxygenase-1 and 25.8 micromolar for cyclooxygenase-2, following a single oral 1000 milligram dose maximal ex vivo inhibitions were 56% for cyclooxygenase-1 and 83% for cyclooxygenase-2, plasma concentrations remained above the in vitro cyclooxygenase-2 value for at least 5 hours, and ex vivo values compared favourably with in vitro ones; acetaminophen inhibited cyclooxygenase-2 by more than 80%, comparable to non-steroidal anti-inflammatory drugs and selective inhibitors, but the greater than 95% cyclooxygenase-1 blockade relevant for suppression of platelet function was not achieved, and in view of its substantial cyclooxygenase-2 inhibition the cardiovascular warnings defined for selective inhibitors should also be considered. 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: In people it blocks the second enzyme as hard as a proper anti-inflammatory does, and never blocks the first enough to touch platelets. organism: Human tissue_or_cell_type: Whole blood experimental_model: Ex vivo and in vitro human whole blood cyclooxygenase assays in five volunteers given a single oral dose limitations: Measures both isoform indices in dosed people and relates them to plasma concentration. Five volunteers and a single dose. exposure: 1000 milligrams oral acetaminophen, with coagulation-induced thromboxane B2 and lipopolysaccharide-induced prostaglandin E2 as isoform indices evidence_span: {"source_cache": "artifacts/paracetamol-research/17884974.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e2856e9fc1c319219fd3d3cb145f70bb1157f7ca0baa0221594c9583cf7ddc23", "start_char": 0, "end_char": 1857, "text_sha256": "e2856e9fc1c319219fd3d3cb145f70bb1157f7ca0baa0221594c9583cf7ddc23"} [apap-p17884974] Acetaminophen (paracetamol) is a selective cyclooxygenase-2 inhibitor in man. (2008). https://pubmed.ncbi.nlm.nih.gov/17884974/ DOI: 10.1096/fj.07-8506com

availability_state

biomarker_context Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/paracetamol-research/12011469.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7e599890f658a63c52471fbc7e6853d7db6a5ecbe892241a39c8a633b3ab2d0d", "start_char": 0, "end_char": 1561, "text_sha256": "7e599890f658a63c52471fbc7e6853d7db6a5ecbe892241a39c8a633b3ab2d0d"}

experimental_model

Interleukin-1-alpha-stimulated human endothelial cells and human platelets compared, with hydroperoxide addition

exposure

Acetaminophen with 2 micromolar arachidonic acid, and with prostaglandin G2, 12-hydroperoxyeicosatetraenoic acid or tert-butyl hydroperoxide added back

limitations

The decisive record of the chapter: it measures a 435-fold difference between two human cell types, shows it is not isoform selectivity, and reverses it by adding the peroxide back.

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

plain_language

The same drug is four hundred times weaker in a platelet than in an inflamed blood vessel, and it is not because the enzymes differ.

primary_references

[apap-p12011469] Determinants of the cellular specificity of acetaminophen as an inhibitor of prostaglandin H(2) synthases. (2002). https://pubmed.ncbi.nlm.nih.gov/12011469/ DOI: 10.1073/pnas.102588199

tissue_or_cell_type

Endothelium and platelets

trigger_kind

biomarker_context 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 90–101

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Interleukin-1-alpha-stimulated human endothelial cells and human platelets compared, with hydroperoxide addition · source_derived_draft · unverified_draft

### apap-four-hundred-fold-cell-difference Acetaminophen inhibited prostaglandin H synthase activity with a half-maximal inhibitory concentration of 4.3 micromolar in interleukin-1-alpha-stimulated human umbilical vein endothelial cells against 1,870 micromolar in the platelet with 2 micromolar arachidonic acid as substrate, and this difference is not caused by isoform selectivity because acetaminophen inhibits purified ovine prostaglandin H synthase-1 and murine recombinant synthase-2 equally. Condition category: biomarker_context 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 drug is four hundred times weaker in a platelet than in an inflamed blood vessel, and it is not because the enzymes differ. organism: Human tissue_or_cell_type: Endothelium and platelets experimental_model: Interleukin-1-alpha-stimulated human endothelial cells and human platelets compared, with hydroperoxide addition limitations: The decisive record of the chapter: it measures a 435-fold difference between two human cell types, shows it is not isoform selectivity, and reverses it by adding the peroxide back. exposure: Acetaminophen with 2 micromolar arachidonic acid, and with prostaglandin G2, 12-hydroperoxyeicosatetraenoic acid or tert-butyl hydroperoxide added back evidence_span: {"source_cache": "artifacts/paracetamol-research/12011469.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7e599890f658a63c52471fbc7e6853d7db6a5ecbe892241a39c8a633b3ab2d0d", "start_char": 0, "end_char": 1561, "text_sha256": "7e599890f658a63c52471fbc7e6853d7db6a5ecbe892241a39c8a633b3ab2d0d"} [apap-p12011469] Determinants of the cellular specificity of acetaminophen as an inhibitor of prostaglandin H(2) synthases. (2002). https://pubmed.ncbi.nlm.nih.gov/12011469/ DOI: 10.1073/pnas.102588199

evidence_span

{"source_cache": "artifacts/paracetamol-research/15650114.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1661f4d2b21244e0fc16b9a3b947cf4d09d39be35367ed263cce441f43a60563", "start_char": 0, "end_char": 1473, "text_sha256": "1661f4d2b21244e0fc16b9a3b947cf4d09d39be35367ed263cce441f43a60563"}

experimental_model

Cloning and sequencing of rat COX-1b from cerebral endothelial cells with transfection and antibody generation

exposure

Rat COX-1b complementary DNA transfected into COS-7 cells, assayed for activity and for effect on acetaminophen inhibition

limitations

Tests the proposal in a second species by building the protein and asking whether it works. The protein is detected in rat tissue, so the finding is that it exists and is not a cyclooxygenase.

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

Rat

plain_language

In the rat the retained intron shifts the reading frame, so what is made is a different protein altogether and not an enzyme.

primary_references

[apap-p15650114] Cloning and characterization of cyclooxygenase-1b (putative cyclooxygenase-3) in rat. (2005). https://pubmed.ncbi.nlm.nih.gov/15650114/ DOI: 10.1124/jpet.104.079533

tissue_or_cell_type

Cerebral endothelial cells

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 220–231

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cloning and sequencing of rat COX-1b from cerebral endothelial cells with transfection and antibody generation · source_derived_draft · unverified_draft

### apap-frameshift-makes-a-different-protein The 98 base pair intron 1 of the cyclooxygenase-1 gene remains unprocessed in rat COX-1b messenger RNA, causing a frameshift mutation and a 127 amino acid open reading frame with no sequence similarity with known cyclooxygenases, and transfection of COS-7 cells produced a protein of the expected size which was also detected in rat tissues with highest expression in heart, kidney and neuronal tissue, but rat COX-1b does not have cyclooxygenase activity and does not have any effect on the inhibition of prostaglandin production by acetaminophen, leading the authors to propose the name cyclooxygenase variant protein instead. 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: In the rat the retained intron shifts the reading frame, so what is made is a different protein altogether and not an enzyme. organism: Rat tissue_or_cell_type: Cerebral endothelial cells experimental_model: Cloning and sequencing of rat COX-1b from cerebral endothelial cells with transfection and antibody generation limitations: Tests the proposal in a second species by building the protein and asking whether it works. The protein is detected in rat tissue, so the finding is that it exists and is not a cyclooxygenase. exposure: Rat COX-1b complementary DNA transfected into COS-7 cells, assayed for activity and for effect on acetaminophen inhibition evidence_span: {"source_cache": "artifacts/paracetamol-research/15650114.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1661f4d2b21244e0fc16b9a3b947cf4d09d39be35367ed263cce441f43a60563", "start_char": 0, "end_char": 1473, "text_sha256": "1661f4d2b21244e0fc16b9a3b947cf4d09d39be35367ed263cce441f43a60563"} [apap-p15650114] Cloning and characterization of cyclooxygenase-1b (putative cyclooxygenase-3) in rat. (2005). https://pubmed.ncbi.nlm.nih.gov/15650114/ DOI: 10.1124/jpet.104.079533

evidence_span

{"source_cache": "artifacts/paracetamol-research/15148345.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6ca43f39a9bb4cbc398f4f7f6e3401854f6c100b72fb7fdf952ee49486438d3c", "start_char": 0, "end_char": 1940, "text_sha256": "6ca43f39a9bb4cbc398f4f7f6e3401854f6c100b72fb7fdf952ee49486438d3c"}

experimental_model

Comparison of acetaminophen, rofecoxib, naproxen and SC560 across rat aorta, heart, lung, brain, cerebellum and whole blood

exposure

Four drugs of differing isoform selectivity, with transcript and protein detection including an anti-canine-COX-3 antibody

limitations

Tests the proposal functionally across tissues and looks for the protein directly. A rat study, and a negative Western blot is weaker evidence than a positive one.

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

Rat

plain_language

Nobody could find the protein, and in brain the drug showed no special selectivity at all.

primary_references

[apap-p15148345] Cyclooxygenases 1, 2, and 3 and the production of prostaglandin I2: investigating the activities of acetaminophen and cyclooxygenase-2-selective inhibitors in rat tissues. (2004). https://pubmed.ncbi.nlm.nih.gov/15148345/ DOI: 10.1124/jpet.103.063875

tissue_or_cell_type

Multiple tissues

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 233–244

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Comparison of acetaminophen, rofecoxib, naproxen and SC560 across rat aorta, heart, lung, brain, cerebellum and whole blood · source_derived_draft · unverified_draft

### apap-no-cox3-protein-found Prostanoid production by rat aorta, heart, lung and whole blood was inhibited by all drugs tested with the order of potency SC560 greater than naproxen greater than acetaminophen greater than or equal to rofecoxib while in brain and cerebellum no differences among drug potencies were found, Western blotting using a commercially available antibody raised against canine COX-3 failed to detect any immunoreactive proteins, and the authors conclude that cyclooxygenase-1 and -2 are the functional forms present in the rat tissues tested, that acetaminophen is not a selective inhibitor of cyclooxygenase activities in the central nervous system, and that expression of an active cyclooxygenase protein from COX-3 messenger RNA in the rat is apparently impossible. 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: Nobody could find the protein, and in brain the drug showed no special selectivity at all. organism: Rat tissue_or_cell_type: Multiple tissues experimental_model: Comparison of acetaminophen, rofecoxib, naproxen and SC560 across rat aorta, heart, lung, brain, cerebellum and whole blood limitations: Tests the proposal functionally across tissues and looks for the protein directly. A rat study, and a negative Western blot is weaker evidence than a positive one. exposure: Four drugs of differing isoform selectivity, with transcript and protein detection including an anti-canine-COX-3 antibody evidence_span: {"source_cache": "artifacts/paracetamol-research/15148345.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6ca43f39a9bb4cbc398f4f7f6e3401854f6c100b72fb7fdf952ee49486438d3c", "start_char": 0, "end_char": 1940, "text_sha256": "6ca43f39a9bb4cbc398f4f7f6e3401854f6c100b72fb7fdf952ee49486438d3c"} [apap-p15148345] Cyclooxygenases 1, 2, and 3 and the production of prostaglandin I2: investigating the activities of acetaminophen and cyclooxygenase-2-selective inhibitors in rat tissues. (2004). https://pubmed.ncbi.nlm.nih.gov/15148345/ DOI: 10.1124/jpet.103.063875

evidence_span

{"source_cache": "artifacts/paracetamol-research/11113024.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f3d9785240d2bc30e79775035576d3b017471500c110d627653e6fd80e820eee", "start_char": 0, "end_char": 1012, "text_sha256": "f3d9785240d2bc30e79775035576d3b017471500c110d627653e6fd80e820eee"}

experimental_model

Review of the evidence for an unidentified cyclooxygenase form, written before COX-3 was cloned

exposure

Acetaminophen compared against its effects on urinary prostaglandin metabolites and on platelet and gastric prostaglandin synthesis

limitations

A review that states the puzzle precisely before an answer existed. The human observations it collects are the clinical signature any mechanism has to explain.

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 and animal

plain_language

It lowers prostaglandins measured in urine while leaving the platelet and the stomach alone, and that is the puzzle every account has to solve.

primary_references

[apap-p11113024] Mechanism of action of acetaminophen: is there a cyclooxygenase 3? (2000). https://pubmed.ncbi.nlm.nih.gov/11113024/ DOI: 10.1086/317520

tissue_or_cell_type

Platelets, gastric mucosa and tissue homogenates

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 207–218

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Review of the evidence for an unidentified cyclooxygenase form, written before COX-3 was cloned · source_derived_draft · unverified_draft

### apap-the-puzzle-stated Acetaminophen has potent antipyretic and analgesic actions but very weak anti-inflammatory activity, and when administered to humans it reduces levels of prostaglandin metabolites in urine but does not reduce synthesis of prostaglandins by blood platelets or by the stomach mucosa; because it is a weak inhibitor in vitro of both cyclooxygenase-1 and -2 the possibility exists that it inhibits a so far unidentified form, and in animal studies cyclooxygenase in homogenates of different tissues varies in sensitivity to its inhibitory action, which may be evidence that there are more than two isoforms. 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: It lowers prostaglandins measured in urine while leaving the platelet and the stomach alone, and that is the puzzle every account has to solve. organism: Human and animal tissue_or_cell_type: Platelets, gastric mucosa and tissue homogenates experimental_model: Review of the evidence for an unidentified cyclooxygenase form, written before COX-3 was cloned limitations: A review that states the puzzle precisely before an answer existed. The human observations it collects are the clinical signature any mechanism has to explain. exposure: Acetaminophen compared against its effects on urinary prostaglandin metabolites and on platelet and gastric prostaglandin synthesis evidence_span: {"source_cache": "artifacts/paracetamol-research/11113024.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f3d9785240d2bc30e79775035576d3b017471500c110d627653e6fd80e820eee", "start_char": 0, "end_char": 1012, "text_sha256": "f3d9785240d2bc30e79775035576d3b017471500c110d627653e6fd80e820eee"} [apap-p11113024] Mechanism of action of acetaminophen: is there a cyclooxygenase 3? (2000). https://pubmed.ncbi.nlm.nih.gov/11113024/ DOI: 10.1086/317520

evidence_span

{"source_cache": "artifacts/paracetamol-research/15879007.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "857ae81119eac4c47a63027afa15fde1b0099c377c0d444e13da087ea71dec86", "start_char": 0, "end_char": 807, "text_sha256": "857ae81119eac4c47a63027afa15fde1b0099c377c0d444e13da087ea71dec86"}

experimental_model

Critical review of the COX-3 literature

exposure

Evaluation of the expression levels, kinetics and species differences of the proposed isoform

limitations

A review rather than new data. It states the species-specific reason the proposal fails and the reason it would not matter even where the protein is active.

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

Dog, rodent and human

plain_language

Even in the dog the amounts are too small to matter, and in people the protein is not an enzyme.

primary_references

[apap-p15879007] Acetaminophen and the cyclooxygenase-3 puzzle: sorting out facts, fictions, and uncertainties. (2005). https://pubmed.ncbi.nlm.nih.gov/15879007/ DOI: 10.1124/jpet.105.085431

tissue_or_cell_type

Cyclooxygenase variants

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 246–257

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Critical review of the COX-3 literature · source_derived_draft · unverified_draft

### apap-unlikely-in-any-species Although COX-3 might have cyclooxygenase activity in canines and that activity might be inhibited by acetaminophen, its low expression level and the kinetics indicate unlikely clinical relevance, and in rodents and humans COX-3 encodes proteins with completely different amino acid sequences than cyclooxygenase-1 or -2 and without cyclooxygenase activity, so it is improbable that it plays a role in prostaglandin-mediated fever and pain in these species. 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: Even in the dog the amounts are too small to matter, and in people the protein is not an enzyme. organism: Dog, rodent and human tissue_or_cell_type: Cyclooxygenase variants experimental_model: Critical review of the COX-3 literature limitations: A review rather than new data. It states the species-specific reason the proposal fails and the reason it would not matter even where the protein is active. exposure: Evaluation of the expression levels, kinetics and species differences of the proposed isoform evidence_span: {"source_cache": "artifacts/paracetamol-research/15879007.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "857ae81119eac4c47a63027afa15fde1b0099c377c0d444e13da087ea71dec86", "start_char": 0, "end_char": 807, "text_sha256": "857ae81119eac4c47a63027afa15fde1b0099c377c0d444e13da087ea71dec86"} [apap-p15879007] Acetaminophen and the cyclooxygenase-3 puzzle: sorting out facts, fictions, and uncertainties. (2005). https://pubmed.ncbi.nlm.nih.gov/15879007/ DOI: 10.1124/jpet.105.085431

availability_state

biomarker_context Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/aspirin-research/6411052.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a685344a88574182dbad6f8d70308dce88384a63ed0c561ccaec4d522000b132", "start_char": 0, "end_char": 1551, "text_sha256": "a685344a88574182dbad6f8d70308dce88384a63ed0c561ccaec4d522000b132"}

experimental_model

Platelet aggregation and cyclooxygenase activity in subjects given ibuprofen before aspirin, in vitro and in vivo

exposure

Ibuprofen ingestion followed by 650 milligrams of aspirin, with recovery followed to 26 hours

limitations

The observation is clean and has been confirmed since. The authors’ inference from it, that aspirin must act on the heme group rather than by acetylating the protein, is contradicted by the mutant and crystallographic records in this collection and is not adopted here.

nutrient_topic

Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. · Aspirin / acetylsalicylic acid

organism

Human

plain_language

Take ibuprofen first and aspirin never gets its chance; the protection wears off in a day like ibuprofen, not like aspirin.

primary_references

[asa-p6411052] Ibuprofen protects platelet cyclooxygenase from irreversible inhibition by aspirin. (1983). https://pubmed.ncbi.nlm.nih.gov/6411052/ DOI: 10.1161/01.atv.3.4.383

tissue_or_cell_type

Platelets

trigger_kind

biomarker_context Imported condition classification; unverified.

Aspirin: the serine it acetylates, the enzyme that acetylation creates, the dose that separates platelet from vessel wall, and the metabolite that is a different drug (2026-09-22) · lines 442–453

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Platelet aggregation and cyclooxygenase activity in subjects given ibuprofen before aspirin, in vitro and in vivo · source_derived_draft · unverified_draft

### asa-ibuprofen-blocks-aspirin Platelet function and prostaglandin synthesis recovered completely 26 hours after ingestion of ibuprofen but remained compromised 26 hours after taking aspirin, and when 650 milligrams of aspirin was administered after ibuprofen, platelet function and cyclooxygenase activity recovered as completely at 26 hours as in platelets exposed to ibuprofen alone, so prior exposure to ibuprofen in vivo completely protected cyclooxygenase from the irreversible effects of aspirin. Condition category: biomarker_context nutrient_topic: Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. plain_language: Take ibuprofen first and aspirin never gets its chance; the protection wears off in a day like ibuprofen, not like aspirin. organism: Human tissue_or_cell_type: Platelets experimental_model: Platelet aggregation and cyclooxygenase activity in subjects given ibuprofen before aspirin, in vitro and in vivo limitations: The observation is clean and has been confirmed since. The authors’ inference from it, that aspirin must act on the heme group rather than by acetylating the protein, is contradicted by the mutant and crystallographic records in this collection and is not adopted here. exposure: Ibuprofen ingestion followed by 650 milligrams of aspirin, with recovery followed to 26 hours evidence_span: {"source_cache": "artifacts/aspirin-research/6411052.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a685344a88574182dbad6f8d70308dce88384a63ed0c561ccaec4d522000b132", "start_char": 0, "end_char": 1551, "text_sha256": "a685344a88574182dbad6f8d70308dce88384a63ed0c561ccaec4d522000b132"} [asa-p6411052] Ibuprofen protects platelet cyclooxygenase from irreversible inhibition by aspirin. (1983). https://pubmed.ncbi.nlm.nih.gov/6411052/ DOI: 10.1161/01.atv.3.4.383

evidence_span

{"source_cache": "artifacts/aspirin-research/7552725.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "dd61431f20eb312313942bc8a89f970d5d2e33600b32abe692f20d9d5c57d7b1", "start_char": 0, "end_char": 751, "text_sha256": "dd61431f20eb312313942bc8a89f970d5d2e33600b32abe692f20d9d5c57d7b1"}

experimental_model

X-ray crystal structure at 3.4 angstrom of prostaglandin H2 synthase-1 inactivated by a potent aspirin analogue

exposure

2-bromoacetoxy-benzoic acid acetylation, with salicylic acid soaked into the structure

limitations

Direct structural evidence rather than inference from mutants, though at modest resolution and using an analogue rather than aspirin itself.

nutrient_topic

Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. · Aspirin / acetylsalicylic acid

organism

Enzyme

plain_language

The breakdown product sits in the same place the drug needs to reach, and gets in its way.

primary_references

[asa-p7552725] The structural basis of aspirin activity inferred from the crystal structure of inactivated prostaglandin H2 synthase. (1995). https://pubmed.ncbi.nlm.nih.gov/7552725/ DOI: 10.1038/nsb0895-637

tissue_or_cell_type

Crystallised prostaglandin H2 synthase-1

Aspirin: the serine it acetylates, the enzyme that acetylation creates, the dose that separates platelet from vessel wall, and the metabolite that is a different drug (2026-09-22) · lines 143–154

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · X-ray crystal structure at 3.4 angstrom of prostaglandin H2 synthase-1 inactivated by a potent aspirin analogue · source_derived_draft · unverified_draft

### asa-salicylate-antagonises-at-the-site In the crystal structure of the inactivated enzyme the product salicylic acid was observed binding at a site consistent with its antagonistic effect on aspirin activity. Condition category: normal nutrient_topic: Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. plain_language: The breakdown product sits in the same place the drug needs to reach, and gets in its way. organism: Enzyme tissue_or_cell_type: Crystallised prostaglandin H2 synthase-1 experimental_model: X-ray crystal structure at 3.4 angstrom of prostaglandin H2 synthase-1 inactivated by a potent aspirin analogue limitations: Direct structural evidence rather than inference from mutants, though at modest resolution and using an analogue rather than aspirin itself. exposure: 2-bromoacetoxy-benzoic acid acetylation, with salicylic acid soaked into the structure evidence_span: {"source_cache": "artifacts/aspirin-research/7552725.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "dd61431f20eb312313942bc8a89f970d5d2e33600b32abe692f20d9d5c57d7b1", "start_char": 0, "end_char": 751, "text_sha256": "dd61431f20eb312313942bc8a89f970d5d2e33600b32abe692f20d9d5c57d7b1"} [asa-p7552725] The structural basis of aspirin activity inferred from the crystal structure of inactivated prostaglandin H2 synthase. (1995). https://pubmed.ncbi.nlm.nih.gov/7552725/ DOI: 10.1038/nsb0895-637

evidence_span

{"source_cache": "artifacts/aspirin-research/2108169.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c7b11508521a3854b432f3836de6e92ba9863c8edb244d747bb1c37634c0bb50", "start_char": 0, "end_char": 2076, "text_sha256": "c7b11508521a3854b432f3836de6e92ba9863c8edb244d747bb1c37634c0bb50"}

experimental_model

Site-directed mutagenesis of sheep prostaglandin endoperoxide synthase expressed in Cos-1 cells

exposure

Serine 530 replaced with alanine, compared with the native enzyme against aspirin and reversible inhibitors

limitations

The decisive experiment for the mechanism: it separates what the serine does for catalysis from what acetylating it does. Recombinant sheep enzyme, not human enzyme in a tissue.

nutrient_topic

Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. · Aspirin / acetylsalicylic acid

organism

Sheep and mouse enzyme

plain_language

Remove the serine and the enzyme still works; it is there to be acetylated, not to do the chemistry.

primary_references

[asa-p2108169] The aspirin and heme-binding sites of ovine and murine prostaglandin endoperoxide synthases. (1990). https://pubmed.ncbi.nlm.nih.gov/2108169/ DOI: 10.1016/s0021-9258(19)34105-5

tissue_or_cell_type

Recombinant enzyme in Cos-1 cells

Aspirin: the serine it acetylates, the enzyme that acetylation creates, the dose that separates platelet from vessel wall, and the metabolite that is a different drug (2026-09-22) · lines 78–89

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Site-directed mutagenesis of sheep prostaglandin endoperoxide synthase expressed in Cos-1 cells · source_derived_draft · unverified_draft

### asa-serine-is-not-catalytic Cos-1 cells transfected with native or Ser-530-to-alanine mutant sheep prostaglandin endoperoxide synthase expressed comparable cyclooxygenase and hydroperoxidase activities, with the same Km for arachidonate of 8 micromolar and the same ID50 values for reversible inhibition by flurbiprofen at 5 micromolar, flufenamate at 20 micromolar and aspirin at 20 millimolar; however only the native enzyme was irreversibly inactivated by aspirin, so the active site Ser-530 is not essential for catalysis or substrate binding. Condition category: normal nutrient_topic: Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. plain_language: Remove the serine and the enzyme still works; it is there to be acetylated, not to do the chemistry. organism: Sheep and mouse enzyme tissue_or_cell_type: Recombinant enzyme in Cos-1 cells experimental_model: Site-directed mutagenesis of sheep prostaglandin endoperoxide synthase expressed in Cos-1 cells limitations: The decisive experiment for the mechanism: it separates what the serine does for catalysis from what acetylating it does. Recombinant sheep enzyme, not human enzyme in a tissue. exposure: Serine 530 replaced with alanine, compared with the native enzyme against aspirin and reversible inhibitors evidence_span: {"source_cache": "artifacts/aspirin-research/2108169.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c7b11508521a3854b432f3836de6e92ba9863c8edb244d747bb1c37634c0bb50", "start_char": 0, "end_char": 2076, "text_sha256": "c7b11508521a3854b432f3836de6e92ba9863c8edb244d747bb1c37634c0bb50"} [asa-p2108169] The aspirin and heme-binding sites of ovine and murine prostaglandin endoperoxide synthases. (1990). https://pubmed.ncbi.nlm.nih.gov/2108169/ DOI: 10.1016/s0021-9258(19)34105-5

evidence_span

{"source_cache": "artifacts/aspirin-research/10692466.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9da1ede1fbf95d6f42d4bb15dc08b5d1869549a7cd94cbfa9da9f9865fd780ff", "start_char": 0, "end_char": 2055, "text_sha256": "9da1ede1fbf95d6f42d4bb15dc08b5d1869549a7cd94cbfa9da9f9865fd780ff"}

experimental_model

Site-directed mutagenesis of mouse COX-2 residues predicted from comparison of the two isoform crystal structures

exposure

Val-434, Arg-513, Val-523, Val-228 and Gly-533 mutated towards their cyclooxygenase-1 equivalents, then acetylated

limitations

Explains the isoform difference residue by residue. Murine enzyme, and the L-shaped substrate configuration is an inference from the mutant product profiles.

nutrient_topic

Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. · Aspirin / acetylsalicylic acid

organism

Mouse enzyme

plain_language

Three amino acids are the whole difference between an enzyme aspirin kills and one aspirin repurposes.

primary_references

[asa-p10692466] Spatial requirements for 15-(R)-hydroxy-5Z,8Z,11Z, 13E-eicosatetraenoic acid synthesis within the cyclooxygenase active site of murine COX-2. Why acetylated COX-1 does not synthesize 15-(R)-hete. (2000). https://pubmed.ncbi.nlm.nih.gov/10692466/ DOI: 10.1074/jbc.275.9.6586

tissue_or_cell_type

Cyclooxygenase-2

Aspirin: the serine it acetylates, the enzyme that acetylation creates, the dose that separates platelet from vessel wall, and the metabolite that is a different drug (2026-09-22) · lines 247–258

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Site-directed mutagenesis of mouse COX-2 residues predicted from comparison of the two isoform crystal structures · source_derived_draft · unverified_draft

### asa-three-residues-decide Acetylated cyclooxygenase-2 is essentially a lipoxygenase making 15(R)- and 11(R)-hydroxyeicosatetraenoic acid whereas acetylated cyclooxygenase-1 is unable to oxidise arachidonic acid to any products, and site-directed mutagenesis of Val-434, Arg-513 and Val-523 in mouse cyclooxygenase-2 to their cyclooxygenase-1 equivalents abrogated 11- and 15-HETE production after aspirin treatment, confirming these residues as the major isoform selectivity determinants; V228F and G533A produced wild-type-like profiles but on acetylation neither could make HETE products, suggesting arachidonic acid orientates in an L-shaped binding configuration. Condition category: normal nutrient_topic: Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. plain_language: Three amino acids are the whole difference between an enzyme aspirin kills and one aspirin repurposes. organism: Mouse enzyme tissue_or_cell_type: Cyclooxygenase-2 experimental_model: Site-directed mutagenesis of mouse COX-2 residues predicted from comparison of the two isoform crystal structures limitations: Explains the isoform difference residue by residue. Murine enzyme, and the L-shaped substrate configuration is an inference from the mutant product profiles. exposure: Val-434, Arg-513, Val-523, Val-228 and Gly-533 mutated towards their cyclooxygenase-1 equivalents, then acetylated evidence_span: {"source_cache": "artifacts/aspirin-research/10692466.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9da1ede1fbf95d6f42d4bb15dc08b5d1869549a7cd94cbfa9da9f9865fd780ff", "start_char": 0, "end_char": 2055, "text_sha256": "9da1ede1fbf95d6f42d4bb15dc08b5d1869549a7cd94cbfa9da9f9865fd780ff"} [asa-p10692466] Spatial requirements for 15-(R)-hydroxy-5Z,8Z,11Z, 13E-eicosatetraenoic acid synthesis within the cyclooxygenase active site of murine COX-2. Why acetylated COX-1 does not synthesize 15-(R)-hete. (2000). https://pubmed.ncbi.nlm.nih.gov/10692466/ DOI: 10.1074/jbc.275.9.6586