{"id":"1aa9beca-29fc-5a6d-9e58-f018738caa0c","stable_key":"7de430a5-1a36-5231-b931-35cc01d8f3bf:apap-four-hundred-fold-cell-difference","predicate":"inhibits","statement":"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.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"negative","is_public":true,"mechanism_event_id":"508dce9c-052e-5c14-8265-0a20e149fe05","mechanism_event_label":"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.","subject":{"id":"a901be21-7915-543c-ac67-c39ef72b0d03","slug":"acetaminophen","display_name":"Paracetamol","entity_type_key":"drug"},"object":{"id":"168a23a4-0a61-5467-9f5f-75ebe322eeb3","slug":"cellular-selectivity","display_name":"Selectivity of a drug between cell types rather than between enzyme isoforms","entity_type_key":"cellular_process"},"evidence_count":1,"mechanism_event":{"id":"508dce9c-052e-5c14-8265-0a20e149fe05","stable_key":"7de430a5-1a36-5231-b931-35cc01d8f3bf:apap-four-hundred-fold-cell-difference-event","event_type":"biochemical_relationship","label":"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.","description":"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.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"abbaa45c-a788-5217-b530-490380609d47","slug":"huvec","display_name":"Human umbilical vein endothelial cell","entity_type_key":"cell_type"},"role":"sensitive_cell","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"3cc7ab30-e6f8-51b9-8979-70f0ea692dc8","slug":"platelet","display_name":"Blood platelet","entity_type_key":"cell_type"},"role":"resistant_cell","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"6284d26c-01e2-5e12-b192-ee391dd107e2","slug":"ptgs1","display_name":"Cyclooxygenase-1 (PTGS1)","entity_type_key":"protein"},"role":"equally_inhibited_isoform","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"c8a31ed4-f2ca-5d43-8352-e9935129a785","slug":"ptgs2","display_name":"Cyclooxygenase-2 (PTGS2)","entity_type_key":"protein"},"role":"equally_inhibited_isoform","stoichiometry":null,"state_label":"","sequence_order":3,"notes":""},{"entity":{"id":"a901be21-7915-543c-ac67-c39ef72b0d03","slug":"acetaminophen","display_name":"Paracetamol","entity_type_key":"drug"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":4,"notes":""},{"entity":{"id":"168a23a4-0a61-5467-9f5f-75ebe322eeb3","slug":"cellular-selectivity","display_name":"Selectivity of a drug between cell types rather than between enzyme isoforms","entity_type_key":"cellular_process"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":5,"notes":""}]},"contexts":[{"dimension":"availability_state","value_text":"biomarker_context","comparator":null,"unit":null,"notes":"Imported condition classification; 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topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404.","comparator":null,"unit":null,"notes":"","entity":{"slug":"acetaminophen","display_name":"Paracetamol","entity_type_key":"drug"}},{"dimension":"organism","value_text":"Human","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"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.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[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","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Endothelium and platelets","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"trigger_kind","value_text":"biomarker_context","comparator":null,"unit":null,"notes":"Imported condition classification; unverified.","entity":null}],"evidence":[{"id":"d39b6411-db1a-54b8-9f8f-cc693762642e","evidence_kind":"source_excerpt","locator":"Lines 90-101","start_line":90,"end_line":101,"excerpt":"### apap-four-hundred-fold-cell-difference\nAcetaminophen 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.\nCondition category: biomarker_context\nnutrient_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.\nplain_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.\norganism: Human\ntissue_or_cell_type: Endothelium and platelets\nexperimental_model: Interleukin-1-alpha-stimulated human endothelial cells and human platelets compared, with hydroperoxide addition\nlimitations: 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.\nexposure: Acetaminophen with 2 micromolar arachidonic acid, and with prostaglandin G2, 12-hydroperoxyeicosatetraenoic acid or tert-butyl hydroperoxide added back\nevidence_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\"}\n[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","model_system":"Interleukin-1-alpha-stimulated human endothelial cells and human platelets compared, with hydroperoxide addition","directness":"author_interpretation","verification_status":"source_derived_draft","notes":"Exact curation-document quotation, not publisher quotation. Study 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","relationship":"supports","weight":1.0,"link_notes":"","source":{"id":"9ee11177-f860-5877-bb82-f4ee4acdc538","stable_key":"import-7de430a5-1a36-5231-b931-35cc01d8f3bf","title":"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)","document_type":"imported_text","citation_label":"AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text.","file_path":"","sha256":"9c145887aa10fa7b85f54712e0b41fd9e04fb9544d3182793dd84414dbf8c2ae","revision_id":"c3e7827a-4f10-55e0-97b9-5782b044f7cc","review_status":"unverified_draft","notes":""}}],"relations":[],"conflicts":[{"id":"33791ef9-6384-582a-a2f4-a477b417cb70","title":"Is paracetamol a selective cyclooxygenase-2 inhibitor?","kind":"context_difference","status":"open","why":"Human whole blood gives a clear answer: 4.4-fold selectivity in vitro, and after a single gram, 83% inhibition of the cyclooxygenase-2 index against 56% of the cyclooxygenase-1 index, with those authors concluding the drug functions as a selective cyclooxygenase-2 inhibitor and that the cardiovascular warnings for that class should apply to it. Against that, on purified enzyme the two isoforms are inhibited equally, and the 435-fold difference between endothelial cells and platelets was shown to be cellular rather than isoform selectivity, abolished by adding hydroperoxide back. A third record offers a reconciliation: at the low arachidonate concentrations of intact cells, cyclooxygenase-2 carries the lower flux and so generates less of the hydroperoxide that reverses the drug, which would produce apparent isoform selectivity from a mechanism that has nothing to do with isoform binding. That reconciliation is a proposal rather than a measurement, and the records disagree about what the observed selectivity means even where they agree on what was measured.","resolution":"Unresolved; needs review.","created_at":"2026-09-22 17:05:56","record_type":"conflict","display_label":"Recorded conflict","record_url":"/conflicts/33791ef9-6384-582a-a2f4-a477b417cb70","sides":[{"conflict_id":"33791ef9-6384-582a-a2f4-a477b417cb70","ordinal":0,"label":"In people it blocks the second enzyme as hard as a proper anti-inflammatory does, and never blocks the first enough to touch platelets.","revision_id":"c3e7827a-4f10-55e0-97b9-5782b044f7cc","start_line":259,"end_line":270,"quote":"### apap-four-fold-cox2-selective-in-man\nIn 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.\nCondition category: normal\nnutrient_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.\nplain_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.\norganism: Human\ntissue_or_cell_type: Whole blood\nexperimental_model: Ex vivo and in vitro human whole blood cyclooxygenase assays in five volunteers given a single oral dose\nlimitations: Measures both isoform indices in dosed people and relates them to plasma concentration. Five volunteers and a single dose.\nexposure: 1000 milligrams oral acetaminophen, with coagulation-induced thromboxane B2 and lipopolysaccharide-induced prostaglandin E2 as isoform indices\nevidence_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\"}\n[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","source_key":"import-7de430a5-1a36-5231-b931-35cc01d8f3bf","source_title":"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)","claim_ids":["78bee281-d708-5c0a-beee-513a2133b6a2"]},{"conflict_id":"33791ef9-6384-582a-a2f4-a477b417cb70","ordinal":1,"label":"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.","revision_id":"c3e7827a-4f10-55e0-97b9-5782b044f7cc","start_line":90,"end_line":101,"quote":"### apap-four-hundred-fold-cell-difference\nAcetaminophen 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.\nCondition category: biomarker_context\nnutrient_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.\nplain_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.\norganism: Human\ntissue_or_cell_type: Endothelium and platelets\nexperimental_model: Interleukin-1-alpha-stimulated human endothelial cells and human platelets compared, with hydroperoxide addition\nlimitations: 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.\nexposure: Acetaminophen with 2 micromolar arachidonic acid, and with prostaglandin G2, 12-hydroperoxyeicosatetraenoic acid or tert-butyl hydroperoxide added back\nevidence_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\"}\n[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","source_key":"import-7de430a5-1a36-5231-b931-35cc01d8f3bf","source_title":"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)","claim_ids":["1aa9beca-29fc-5a6d-9e58-f018738caa0c"]}]}],"corrections":[],"research":null}