{"id":"ff112171-a581-5802-a6c9-bbc7af457e40","stable_key":"8b3cf083-ea9c-54f5-b42b-bf1fef5b2978:metformin-environment-sensitivity","predicate":"depends_on","statement":"Dependency on complex I, and therefore sensitivity to metformin, was dictated by other pathways affecting NAD+ regeneration and aspartate levels, so sensitivity was not an intrinsic property of the cells.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"context_dependent","is_public":true,"mechanism_event_id":"0136ac13-35b8-5a96-a186-8a2c81b6b5b2","mechanism_event_label":"The same drug dose does different things depending on what else the cell can use.","subject":{"id":"519971b1-5aef-5ad7-8022-840144855cd0","slug":"metformin","display_name":"Metformin","entity_type_key":"drug"},"object":{"id":"6fe789f0-efb9-5d2c-b43a-9d705a5da004","slug":"cellular-nad-ratio","display_name":"Cellular NAD+/NADH ratio","entity_type_key":"cellular_process"},"evidence_count":1,"mechanism_event":{"id":"0136ac13-35b8-5a96-a186-8a2c81b6b5b2","stable_key":"8b3cf083-ea9c-54f5-b42b-bf1fef5b2978:metformin-environment-sensitivity-event","event_type":"biochemical_relationship","label":"The same drug dose does different things depending on what else the cell can use.","description":"Dependency on complex I, and therefore sensitivity to metformin, was dictated by other pathways affecting NAD+ regeneration and aspartate levels, so sensitivity was not an intrinsic property of the cells.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"5cd08cb7-cf10-5a19-a745-9008423a7908","slug":"cellular-complex-i-activity","display_name":"Mitochondrial complex I (NADH dehydrogenase) activity","entity_type_key":"cellular_process"},"role":"context_process","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"519971b1-5aef-5ad7-8022-840144855cd0","slug":"metformin","display_name":"Metformin","entity_type_key":"drug"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"6fe789f0-efb9-5d2c-b43a-9d705a5da004","slug":"cellular-nad-ratio","display_name":"Cellular NAD+/NADH ratio","entity_type_key":"cellular_process"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""}]},"contexts":[{"dimension":"evidence_span","value_text":"{\"source_cache\": \"artifacts/metformin-research/27746050.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"661b69cac488b8ac530cc9385bff10b367b48327d01fe1c29c75bee56ee4f6b3\", \"start_char\": 0, \"end_char\": 1079, \"text_sha256\": \"661b69cac488b8ac530cc9385bff10b367b48327d01fe1c29c75bee56ee4f6b3\"}","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Cancer cells in varied culture environments with complex I inhibitors","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"Metformin and other complex I inhibitors across environments differing in NAD+ regeneration and aspartate supply","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"Establishes that sensitivity is environment-dependent; it argues against reading a culture concentration as a fixed drug property.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake.","comparator":null,"unit":null,"notes":"","entity":{"slug":"metformin","display_name":"Metformin","entity_type_key":"drug"}},{"dimension":"organism","value_text":"Human and mouse cancer cells","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"The same drug dose does different things depending on what else the cell can use.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[metformin-p27746050] Environment Dictates Dependence on Mitochondrial Complex I for NAD+ and Aspartate Production and Determines Cancer Cell Sensitivity to Metformin. (2016). https://pubmed.ncbi.nlm.nih.gov/27746050/ DOI: 10.1016/j.cmet.2016.09.006","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Cancer cells in culture and in vivo","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"0c409993-ec9d-5bc6-8966-2ae7ecf86c5d","evidence_kind":"source_excerpt","locator":"Lines 723-734","start_line":723,"end_line":734,"excerpt":"### metformin-environment-sensitivity\nDependency on complex I, and therefore sensitivity to metformin, was dictated by other pathways affecting NAD+ regeneration and aspartate levels, so sensitivity was not an intrinsic property of the cells.\nCondition category: normal\nnutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake.\nplain_language: The same drug dose does different things depending on what else the cell can use.\norganism: Human and mouse cancer cells\ntissue_or_cell_type: Cancer cells in culture and in vivo\nexperimental_model: Cancer cells in varied culture environments with complex I inhibitors\nlimitations: Establishes that sensitivity is environment-dependent; it argues against reading a culture concentration as a fixed drug property.\nexposure: Metformin and other complex I inhibitors across environments differing in NAD+ regeneration and aspartate supply\nevidence_span: {\"source_cache\": \"artifacts/metformin-research/27746050.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"661b69cac488b8ac530cc9385bff10b367b48327d01fe1c29c75bee56ee4f6b3\", \"start_char\": 0, \"end_char\": 1079, \"text_sha256\": \"661b69cac488b8ac530cc9385bff10b367b48327d01fe1c29c75bee56ee4f6b3\"}\n[metformin-p27746050] Environment Dictates Dependence on Mitochondrial Complex I for NAD+ and Aspartate Production and Determines Cancer Cell Sensitivity to Metformin. 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