{"id":"4e564f7e-7e4d-5f6c-984a-96efab006abf","stable_key":"3238e4f0-8d45-5c72-8624-6e9a8b20527c:ibu-different-cytochromes","predicate":"is_metabolised_by","statement":"Complementary-DNA-expressed CYP2C9 favoured formation of S-2- and S-3-hydroxyibuprofen while CYP2C8 favoured R-2-hydroxyibuprofen formation, high-affinity Km values for S-ibuprofen hydroxylation were 38 and 21 micromolar against 47 and 29 micromolar for R-ibuprofen, sulfaphenazole competitively inhibited all four hydroxylations with submicromolar Ki values, and the regio- and stereoselectivities observed in vitro were consistent with those noted in vivo.","claim_class":"observational","status":"source_derived_draft","evidence_grade":"ungraded","direction":"context_dependent","is_public":true,"mechanism_event_id":"ff669a7f-3129-5e7f-9ab9-3d5f84571a29","mechanism_event_label":"The body uses two different clearance enzymes for the two hands of the same molecule.","subject":{"id":"eb6d83d8-65fd-5cb0-a8e2-b0bb74506200","slug":"cyp2c8","display_name":"Human cytochrome P450 2C8","entity_type_key":"protein"},"object":{"id":"07a563b8-3005-5217-9cc9-b76365f062c7","slug":"r-ibuprofen","display_name":"R(-)-ibuprofen","entity_type_key":"small_molecule"},"evidence_count":1,"mechanism_event":{"id":"ff669a7f-3129-5e7f-9ab9-3d5f84571a29","stable_key":"3238e4f0-8d45-5c72-8624-6e9a8b20527c:ibu-different-cytochromes-event","event_type":"observed_intervention","label":"The body uses two different clearance enzymes for the two hands of the same molecule.","description":"Complementary-DNA-expressed CYP2C9 favoured formation of S-2- and S-3-hydroxyibuprofen while CYP2C8 favoured R-2-hydroxyibuprofen formation, high-affinity Km values for S-ibuprofen hydroxylation were 38 and 21 micromolar against 47 and 29 micromolar for R-ibuprofen, sulfaphenazole competitively inhibited all four hydroxylations with submicromolar Ki values, and the regio- and stereoselectivities observed in vitro were consistent with those noted in vivo.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"c96f78f4-5bca-5867-9ac1-652891d40aa0","slug":"cyp2c9","display_name":"Human cytochrome P450 2C9","entity_type_key":"protein"},"role":"other_enzyme","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"04282f17-56c4-54a9-aa33-37bc4c537c87","slug":"s-ibuprofen","display_name":"S(+)-ibuprofen","entity_type_key":"small_molecule"},"role":"other_substrate","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"bf976254-5a57-5ad2-9b8f-a99d970e52da","slug":"hydroxyibuprofen","display_name":"2- and 3-hydroxyibuprofen","entity_type_key":"small_molecule"},"role":"product","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"4df605f3-91b3-50d4-a7e7-220d680b3d03","slug":"sulfaphenazole","display_name":"Sulfaphenazole, a CYP2C9 inhibitor","entity_type_key":"chemical_species"},"role":"inhibitor_used","stoichiometry":null,"state_label":"","sequence_order":3,"notes":""},{"entity":{"id":"eb6d83d8-65fd-5cb0-a8e2-b0bb74506200","slug":"cyp2c8","display_name":"Human cytochrome P450 2C8","entity_type_key":"protein"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":4,"notes":""},{"entity":{"id":"07a563b8-3005-5217-9cc9-b76365f062c7","slug":"r-ibuprofen","display_name":"R(-)-ibuprofen","entity_type_key":"small_molecule"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":5,"notes":""}]},"contexts":[{"dimension":"evidence_span","value_text":"{\"source_cache\": \"artifacts/ibuprofen-research/9296349.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"19179a5f8220c1d4037113812f8968e2730ecf07c6ad94997d2661d7c6c75afb\", \"start_char\": 0, \"end_char\": 2012, \"text_sha256\": \"19179a5f8220c1d4037113812f8968e2730ecf07c6ad94997d2661d7c6c75afb\"}","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Human liver microsomes and complementary-DNA-expressed cytochromes with a bank of fourteen microsomal preparations","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"Both enantiomers of ibuprofen assayed for 2- and 3-hydroxylation, with sulfaphenazole, retinol and arachidonic acid as inhibitors","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"Assigns each enantiomer to a different cytochrome by direct comparison in the same system. 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In vitro microsomes, though the authors note the selectivities matched those seen in vivo.\nexposure: Both enantiomers of ibuprofen assayed for 2- and 3-hydroxylation, with sulfaphenazole, retinol and arachidonic acid as inhibitors\nevidence_span: {\"source_cache\": \"artifacts/ibuprofen-research/9296349.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"19179a5f8220c1d4037113812f8968e2730ecf07c6ad94997d2661d7c6c75afb\", \"start_char\": 0, \"end_char\": 2012, \"text_sha256\": \"19179a5f8220c1d4037113812f8968e2730ecf07c6ad94997d2661d7c6c75afb\"}\n[ibu-p9296349] Regioselective and stereoselective metabolism of ibuprofen by human cytochrome P450 2C. 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