{"id":"62f13f6a-3ebe-531d-bdec-15553fe470ff","stable_key":"7de430a5-1a36-5231-b931-35cc01d8f3bf:apap-salicylate-is-not-a-cosubstrate","predicate":"reported_comparison","statement":"Salicylate inhibits prostaglandin H synthase-1 and -2 with a potency inversely related to ambient hydroperoxide concentrations and its inhibition of synthase-1 was prevented by 12-hydroperoxyeicosatetraenoic acid, but unlike typical phenolic inhibitors such as acetaminophen, salicylate was ineffective as a reducing cosubstrate for the peroxidase activity, implicating the cyclooxygenase site as its target; 12-HPETE does not prevent inhibition of the manganese-reconstituted enzyme by salicylate, indicating that reversal by hydroperoxides depends on electron transfer between the cyclooxygenase and peroxidase active sites.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"context_dependent","is_public":true,"mechanism_event_id":"ecaf3327-f933-5282-9c9c-dc61fe3a1a52","mechanism_event_label":"Two drugs that both stop working when peroxide is high, reaching that point by different routes.","subject":{"id":"5739797a-3699-591b-95fd-f8b80e612713","slug":"salicylate","display_name":"Salicylate / salicylic acid","entity_type_key":"small_molecule"},"object":{"id":"a901be21-7915-543c-ac67-c39ef72b0d03","slug":"acetaminophen","display_name":"Paracetamol","entity_type_key":"drug"},"evidence_count":1,"mechanism_event":{"id":"ecaf3327-f933-5282-9c9c-dc61fe3a1a52","stable_key":"7de430a5-1a36-5231-b931-35cc01d8f3bf:apap-salicylate-is-not-a-cosubstrate-event","event_type":"biochemical_relationship","label":"Two drugs that both stop working when peroxide is high, reaching that point by different routes.","description":"Salicylate inhibits prostaglandin H synthase-1 and -2 with a potency inversely related to ambient hydroperoxide concentrations and its inhibition of synthase-1 was prevented by 12-hydroperoxyeicosatetraenoic acid, but unlike typical phenolic inhibitors such as acetaminophen, salicylate was ineffective as a reducing cosubstrate for the peroxidase activity, implicating the cyclooxygenase site as its target; 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zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"23bbb8a6c280cfcae85e304695c2a93f2c748c804befc1e006f415f4f8dfaed0\", \"start_char\": 0, \"end_char\": 1592, \"text_sha256\": \"23bbb8a6c280cfcae85e304695c2a93f2c748c804befc1e006f415f4f8dfaed0\"}","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Prostaglandin H synthase inhibition by salicylate compared with phenolic inhibitors, using manganese-reconstituted enzyme","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"Salicylate and benzoic acid analogues, with 12-hydroperoxyeicosatetraenoic acid and prostaglandin G2","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"Recorded here because it separates paracetamol from salicylate mechanistically while showing both are peroxide-sensitive. The work is on salicylate, which is stated on the claim.","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":"Enzyme","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"Two drugs that both stop working when peroxide is high, reaching that point by different routes.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[apap-p12538810] Inhibition of prostaglandin H2 synthases by salicylate is dependent on the oxidative state of the enzymes. (2003). https://pubmed.ncbi.nlm.nih.gov/12538810/ DOI: 10.1124/jpet.102.042853","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Prostaglandin H synthase","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"bc1515aa-bf67-58d7-b302-6d9cd4ae489f","evidence_kind":"source_excerpt","locator":"Lines 168-179","start_line":168,"end_line":179,"excerpt":"### apap-salicylate-is-not-a-cosubstrate\nSalicylate inhibits prostaglandin H synthase-1 and -2 with a potency inversely related to ambient hydroperoxide concentrations and its inhibition of synthase-1 was prevented by 12-hydroperoxyeicosatetraenoic acid, but unlike typical phenolic inhibitors such as acetaminophen, salicylate was ineffective as a reducing cosubstrate for the peroxidase activity, implicating the cyclooxygenase site as its target; 12-HPETE does not prevent inhibition of the manganese-reconstituted enzyme by salicylate, indicating that reversal by hydroperoxides depends on electron transfer between the cyclooxygenase and peroxidase active sites.\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: Two drugs that both stop working when peroxide is high, reaching that point by different routes.\norganism: Enzyme\ntissue_or_cell_type: Prostaglandin H synthase\nexperimental_model: Prostaglandin H synthase inhibition by salicylate compared with phenolic inhibitors, using manganese-reconstituted enzyme\nlimitations: Recorded here because it separates paracetamol from salicylate mechanistically while showing both are peroxide-sensitive. The work is on salicylate, which is stated on the claim.\nexposure: Salicylate and benzoic acid analogues, with 12-hydroperoxyeicosatetraenoic acid and prostaglandin G2\nevidence_span: {\"source_cache\": \"artifacts/paracetamol-research/12538810.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"23bbb8a6c280cfcae85e304695c2a93f2c748c804befc1e006f415f4f8dfaed0\", \"start_char\": 0, \"end_char\": 1592, \"text_sha256\": \"23bbb8a6c280cfcae85e304695c2a93f2c748c804befc1e006f415f4f8dfaed0\"}\n[apap-p12538810] Inhibition of prostaglandin H2 synthases by salicylate is dependent on the oxidative state of the enzymes. 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