{"id":"a42b7924-84e1-50f9-8666-152146975be2","stable_key":"7de430a5-1a36-5231-b931-35cc01d8f3bf:apap-the-enzyme-makes-napqi","predicate":"produces","statement":"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.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"positive","is_public":true,"mechanism_event_id":"fabd6e1b-eaa3-5517-8097-9f3245173271","mechanism_event_label":"The prostaglandin enzyme can itself turn the drug into the liver-damaging metabolite.","subject":{"id":"6284d26c-01e2-5e12-b192-ee391dd107e2","slug":"ptgs1","display_name":"Cyclooxygenase-1 (PTGS1)","entity_type_key":"protein"},"object":{"id":"43887d3e-e850-568f-9585-659c5561b3a7","slug":"napqi","display_name":"N-Acetyl-p-benzoquinone imine / NAPQI","entity_type_key":"small_molecule"},"evidence_count":1,"mechanism_event":{"id":"fabd6e1b-eaa3-5517-8097-9f3245173271","stable_key":"7de430a5-1a36-5231-b931-35cc01d8f3bf:apap-the-enzyme-makes-napqi-event","event_type":"biochemical_relationship","label":"The prostaglandin enzyme can itself turn the drug into the liver-damaging metabolite.","description":"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.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"a901be21-7915-543c-ac67-c39ef72b0d03","slug":"acetaminophen","display_name":"Paracetamol","entity_type_key":"drug"},"role":"oxidised_substrate","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"2a3845bf-b015-5c6f-aa3b-4c86b287b0b3","slug":"bi-apap","display_name":"4,4-dihydroxy-3,3-biacetanilide, the acetaminophen dimer","entity_type_key":"small_molecule"},"role":"co_product","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"57e2be21-5f4b-5755-8405-3b84904276ad","slug":"3-s-glutathionylacetaminophen","display_name":"3-S-Glutathionylacetaminophen","entity_type_key":"small_molecule"},"role":"trapped_adduct","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"b44c9e27-4bbb-52d3-a022-14cddded5073","slug":"glutathione","display_name":"GSH","entity_type_key":"small_molecule"},"role":"trapping_agent","stoichiometry":null,"state_label":"","sequence_order":3,"notes":""},{"entity":{"id":"38d0c4d9-53d1-5239-bfe3-c1b5e9b79085","slug":"ascorbate","display_name":"L-Ascorbate","entity_type_key":"small_molecule"},"role":"inhibiting_reductant","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":"subject","stoichiometry":null,"state_label":"","sequence_order":5,"notes":""},{"entity":{"id":"43887d3e-e850-568f-9585-659c5561b3a7","slug":"napqi","display_name":"N-Acetyl-p-benzoquinone imine / NAPQI","entity_type_key":"small_molecule"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":6,"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":"The prostaglandin enzyme can itself turn the drug into the liver-damaging metabolite.","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":"8567dfbb-b708-5962-9276-8d91b3bd6fa2","evidence_kind":"source_excerpt","locator":"Lines 129-140","start_line":129,"end_line":140,"excerpt":"### apap-the-enzyme-makes-napqi\nUsing 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.\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: The prostaglandin enzyme can itself turn the drug into the liver-damaging metabolite.\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. (1988). https://pubmed.ncbi.nlm.nih.gov/3124965/ DOI: 10.1016/0009-2797(88)90101-9","model_system":"Ram seminal vesicle microsomal prostaglandin H synthase with product identification by cooxidation","directness":"author_interpretation","verification_status":"source_derived_draft","notes":"Exact curation-document quotation, not publisher quotation. Study 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","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":[],"corrections":[],"research":null}