{"id":"3c23cbba-2144-5ab0-bd9e-20ae568e92d5","stable_key":"7de430a5-1a36-5231-b931-35cc01d8f3bf:apap-stimulates-then-inhibits","predicate":"modulates","statement":"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.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"context_dependent","is_public":true,"mechanism_event_id":"308488e2-3b8b-5622-9087-b689f99a0bdc","mechanism_event_label":"At low concentrations the drug feeds the enzyme and at high concentrations it stalls it, both by handing over electrons.","subject":{"id":"a901be21-7915-543c-ac67-c39ef72b0d03","slug":"acetaminophen","display_name":"Paracetamol","entity_type_key":"drug"},"object":{"id":"6284d26c-01e2-5e12-b192-ee391dd107e2","slug":"ptgs1","display_name":"Cyclooxygenase-1 (PTGS1)","entity_type_key":"protein"},"evidence_count":1,"mechanism_event":{"id":"308488e2-3b8b-5622-9087-b689f99a0bdc","stable_key":"7de430a5-1a36-5231-b931-35cc01d8f3bf:apap-stimulates-then-inhibits-event","event_type":"biochemical_relationship","label":"At low concentrations the drug feeds the enzyme and at high concentrations it stalls it, both by handing over electrons.","description":"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.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"c0fa302a-92e8-5be9-afc8-a386ac026b21","slug":"pghs-compound-i","display_name":"Prostaglandin H synthase compound I","entity_type_key":"protein_state"},"role":"reduced_intermediate","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"e43c3122-fa3d-5d7e-9714-9707230d414c","slug":"pghs-compound-ii","display_name":"Prostaglandin H synthase compound II","entity_type_key":"protein_state"},"role":"reduced_intermediate","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"db2a1421-bdbf-5d98-9292-0b308f88cdfc","slug":"reducing-cosubstrate","display_name":"A reducing cosubstrate of the peroxidase","entity_type_key":"cellular_process"},"role":"mechanism","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"39f9446f-52a6-502d-b507-91137726f82c","slug":"arachidonic-acid","display_name":"AA","entity_type_key":"small_molecule"},"role":"substrate","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":"6284d26c-01e2-5e12-b192-ee391dd107e2","slug":"ptgs1","display_name":"Cyclooxygenase-1 (PTGS1)","entity_type_key":"protein"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":5,"notes":""}]},"contexts":[{"dimension":"evidence_span","value_text":"{\"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\"}","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Ram seminal vesicle microsomal prostaglandin H synthase with product identification by cooxidation","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"Acetaminophen from 20 micromolar to above 10 millimolar, with glutathione, ascorbate and indomethacin","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"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.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"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.","comparator":null,"unit":null,"notes":"","entity":{"slug":"acetaminophen","display_name":"Paracetamol","entity_type_key":"drug"}},{"dimension":"organism","value_text":"Sheep","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"At low concentrations the drug feeds the enzyme and at high concentrations it stalls it, both by handing over electrons.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[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","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Seminal vesicle microsomes","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"8c024d7e-ca3c-5d7e-accb-16bb166c9698","evidence_kind":"source_excerpt","locator":"Lines 116-127","start_line":116,"end_line":127,"excerpt":"### apap-stimulates-then-inhibits\nRelatively 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.\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: At low concentrations the drug feeds the enzyme and at high concentrations it stalls it, both by handing over electrons.\norganism: Sheep\ntissue_or_cell_type: Seminal vesicle microsomes\nexperimental_model: Ram seminal vesicle microsomal prostaglandin H synthase with product identification by cooxidation\nlimitations: 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.\nexposure: Acetaminophen from 20 micromolar to above 10 millimolar, with glutathione, ascorbate and indomethacin\nevidence_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\"}\n[apap-p3124965] Acetaminophen and analogs as cosubstrates and inhibitors of prostaglandin H synthase. 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