Component

COX-3 / COX-1b, a cyclooxygenase-1 transcript retaining intron 1

COX-3 / COX-1b, a cyclooxygenase-1 transcript retaining intron 1. Species, exposure and limitations are retained in each linked claim.

5 recorded relationships. Experimental role, claim status and evidence remain attached to each record.

Read recorded mechanisms Open recursive mind map

How nutrients influence it

Every nutrient with a recorded effect on this component, credited to the nutrient that acted rather than the chapter that recorded it. Open a nutrient to see the findings and the conditions they were measured under.

How nutrients reach it in more than one step

Chains of two or more recorded steps that end here, grouped by the nutrient they start from. Each step is a separate finding, so a chain is a route a mechanism could take, not proof that it does.

Tracing routes…

What it does

Every recorded relationship this component is part of, grouped by its role. Plain wording comes first; the technical statement follows.

Recorded relationships

What it acts on

  1. 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.

    COX-3 / COX-1b, a cyclooxygenase-1 transcript retaining intron 1 → Antinociception in thermal, mechanical and chemical pain tests source_derived_draftungraded
    Experimental context and source evidence
    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
    Complete structured claim and evidence

  2. 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.

    COX-3 / COX-1b, a cyclooxygenase-1 transcript retaining intron 1 → Reduction of a raised body temperature source_derived_draftungraded
    Experimental context and source evidence
    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
    Complete structured claim and evidence

What acts on it

  1. A third distinct cyclooxygenase isozyme, COX-3, made from the cyclooxygenase-1 gene but retaining intron 1 in its messenger RNA, was described as expressed in canine cerebral cortex and as an approximately 5.2 kilobase transcript most abundant in human cerebral cortex and heart, the retained intron introducing an insertion of 30 to 34 amino acids into the hydrophobic signal peptide; canine COX-3 expressed in insect cells possessed glycosylation-dependent cyclooxygenase activity and was selectively inhibited by analgesic and antipyretic drugs such as acetaminophen, phenacetin, antipyrine and dipyrone, so that inhibition of COX-3 could represent a primary central mechanism by which these drugs decrease pain and possibly fever.

    Paracetamol → COX-3 / COX-1b, a cyclooxygenase-1 transcript retaining intron 1 source_derived_draftungraded
    Experimental context and source evidence
    evidence_span
    {"source_cache": "artifacts/paracetamol-research/12242329.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0c00962f9e58da9af386335ac3312d5c260d637270d80481a6f55d0ebec67a78", "start_char": 0, "end_char": 1711, "text_sha256": "0c00962f9e58da9af386335ac3312d5c260d637270d80481a6f55d0ebec67a78"}
    experimental_model
    Cloning and expression of cyclooxygenase-1-derived transcripts from canine cerebral cortex in insect cells
    exposure
    Canine COX-3 compared with murine cyclooxygenase-1 and -2 against acetaminophen, phenacetin, antipyrine and dipyrone
    limitations
    The paper that proposed the answer. Its activity data are for the canine protein expressed in insect cells; the human claim is about messenger RNA abundance, not about an active protein.
    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 and human
    plain_language
    A third form of the enzyme was reported in dog brain, and it was the one this drug blocked.
    primary_references
    [apap-p12242329] COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. (2002). https://pubmed.ncbi.nlm.nih.gov/12242329/ DOI: 10.1073/pnas.162468699
    tissue_or_cell_type
    Cerebral cortex

    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 194–205

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cloning and expression of cyclooxygenase-1-derived transcripts from canine cerebral cortex in insect cells · source_derived_draft · unverified_draft

    ### apap-cox3-proposed A third distinct cyclooxygenase isozyme, COX-3, made from the cyclooxygenase-1 gene but retaining intron 1 in its messenger RNA, was described as expressed in canine cerebral cortex and as an approximately 5.2 kilobase transcript most abundant in human cerebral cortex and heart, the retained intron introducing an insertion of 30 to 34 amino acids into the hydrophobic signal peptide; canine COX-3 expressed in insect cells possessed glycosylation-dependent cyclooxygenase activity and was selectively inhibited by analgesic and antipyretic drugs such as acetaminophen, phenacetin, antipyrine and dipyrone, so that inhibition of COX-3 could represent a primary central mechanism by which these drugs decrease pain and possibly fever. 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: A third form of the enzyme was reported in dog brain, and it was the one this drug blocked. organism: Dog and human tissue_or_cell_type: Cerebral cortex experimental_model: Cloning and expression of cyclooxygenase-1-derived transcripts from canine cerebral cortex in insect cells limitations: The paper that proposed the answer. Its activity data are for the canine protein expressed in insect cells; the human claim is about messenger RNA abundance, not about an active protein. exposure: Canine COX-3 compared with murine cyclooxygenase-1 and -2 against acetaminophen, phenacetin, antipyrine and dipyrone evidence_span: {"source_cache": "artifacts/paracetamol-research/12242329.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0c00962f9e58da9af386335ac3312d5c260d637270d80481a6f55d0ebec67a78", "start_char": 0, "end_char": 1711, "text_sha256": "0c00962f9e58da9af386335ac3312d5c260d637270d80481a6f55d0ebec67a78"} [apap-p12242329] COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. (2002). https://pubmed.ncbi.nlm.nih.gov/12242329/ DOI: 10.1073/pnas.162468699
    Complete structured claim and evidence

Where it participates (unsigned role)

  1. 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.

    Intron 1 of the cyclooxygenase-1 gene → A frameshift arising from retention of an unprocessed intron source_derived_draftungraded
    Experimental context and source evidence
    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
    Complete structured claim and evidence

  2. 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.

    Paracetamol → Platelet thromboxane A2 production in vitro source_derived_draftungraded
    Experimental context and source evidence
    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
    Complete structured claim and evidence

In the sources

Preserved passages that mention this component, quoted exactly. Open one to read it in context.

    This is a research prototype built from draft material. It is not medical advice, and its statements still await verification against the original studies.

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