{"id":"63d29f3c-b278-5cda-b665-ad309ad7f0de","stable_key":"3238e4f0-8d45-5c72-8624-6e9a8b20527c:ibu-reversible-against-both-isoforms","predicate":"inhibits","statement":"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.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"negative","is_public":true,"mechanism_event_id":"c89e5770-a0e5-53ef-b6a0-be7f188d4b26","mechanism_event_label":"Against both enzymes it is a reversible blocker, and the numbers you get depend on which assay you use.","subject":{"id":"b429f269-1d01-59f4-881a-868de0849d0d","slug":"ibuprofen","display_name":"Ibuprofen","entity_type_key":"drug"},"object":{"id":"c8a31ed4-f2ca-5d43-8352-e9935129a785","slug":"ptgs2","display_name":"Cyclooxygenase-2 (PTGS2)","entity_type_key":"protein"},"evidence_count":1,"mechanism_event":{"id":"c89e5770-a0e5-53ef-b6a0-be7f188d4b26","stable_key":"3238e4f0-8d45-5c72-8624-6e9a8b20527c:ibu-reversible-against-both-isoforms-event","event_type":"biochemical_relationship","label":"Against both enzymes it is a reversible blocker, and the numbers you get depend on which assay you use.","description":"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.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"6284d26c-01e2-5e12-b192-ee391dd107e2","slug":"ptgs1","display_name":"Cyclooxygenase-1 (PTGS1)","entity_type_key":"protein"},"role":"co_inhibited_isoform","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"3a693286-2f97-5bfc-a1d6-986ec4694029","slug":"reversible-cox-inhibition","display_name":"Reversible, competitive inhibition of cyclooxygenase","entity_type_key":"cellular_process"},"role":"mechanism","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"52a2d1bd-f96d-5a87-84de-682aa1db8672","slug":"cox-selectivity-ratio","display_name":"The ratio of cyclooxygenase-1 to cyclooxygenase-2 inhibitory potency","entity_type_key":"cellular_process"},"role":"assay_dependent_measure","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"b4ad67ed-ff1f-5c41-a6a4-040205a3bdf3","slug":"indomethacin","display_name":"Indomethacin","entity_type_key":"small_molecule"},"role":"comparator","stoichiometry":null,"state_label":"","sequence_order":3,"notes":""},{"entity":{"id":"b429f269-1d01-59f4-881a-868de0849d0d","slug":"ibuprofen","display_name":"Ibuprofen","entity_type_key":"drug"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":4,"notes":""},{"entity":{"id":"c8a31ed4-f2ca-5d43-8352-e9935129a785","slug":"ptgs2","display_name":"Cyclooxygenase-2 (PTGS2)","entity_type_key":"protein"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":5,"notes":""}]},"contexts":[{"dimension":"evidence_span","value_text":"{\"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\"}","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Chinese hamster ovary cell lines stably expressing each human cyclooxygenase isoform, with cell-free comparison","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"Ibuprofen, indomethacin, NS-398 and DuP-697 across intact cells and microsomal preparations","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"Shows that the selectivity numbers depend on the assay, which bears on every potency ratio quoted for this drug class. 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A heterologous expression system.\nexposure: Ibuprofen, indomethacin, NS-398 and DuP-697 across intact cells and microsomal preparations\nevidence_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\"}\n[ibu-p8831731] Mechanism of selective inhibition of human prostaglandin G/H synthase-1 and -2 in intact cells. 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