{"id":"6bbd14b4-0bcd-5ed5-8fc7-780dfafea536","stable_key":"f2ec2007-88ff-5a96-a73b-8b5085e9cea9:mbz-selectivity-only-twofold","predicate":"reported_comparison","statement":"Mebendazole inhibited colchicine binding to partially purified Ascaris suum intestinal tubulin competitively with an inhibition constant of 4.22 x 10-6 molar and inhibited colchicine binding to porcine brain tubulin competitively with an inhibition constant of 8.0 x 10-6 molar, so that in view of the small difference in drug binding abilities it remains unclear whether the selective toxicity can be solely explained by interference with the parasite microtubular system, and the authors suggest that differential pharmacokinetic behaviour between parasite and host may be the essential basis for the difference in susceptibility.","claim_class":"observational","status":"source_derived_draft","evidence_grade":"ungraded","direction":"neutral","is_public":true,"mechanism_event_id":"67ec206c-3c31-5f51-a4ac-5a268274baeb","mechanism_event_label":"Measured in the worm’s gut rather than its embryos, the drug is only about twice as selective, which is not enough to explain its safety.","subject":{"id":"f8582a13-fc2e-5127-a61f-5b0594e54069","slug":"mebendazole","display_name":"Mebendazole","entity_type_key":"drug"},"object":{"id":"bd64884e-6ee7-55df-9993-c2887f5a50df","slug":"nematode-beta-tubulin","display_name":"Nematode beta-tubulin","entity_type_key":"protein"},"evidence_count":1,"mechanism_event":{"id":"67ec206c-3c31-5f51-a4ac-5a268274baeb","stable_key":"f2ec2007-88ff-5a96-a73b-8b5085e9cea9:mbz-selectivity-only-twofold-event","event_type":"observed_intervention","label":"Measured in the worm’s gut rather than its embryos, the drug is only about twice as selective, which is not enough to explain its safety.","description":"Mebendazole inhibited colchicine binding to partially purified Ascaris suum intestinal tubulin competitively with an inhibition constant of 4.22 x 10-6 molar and inhibited colchicine binding to porcine brain tubulin competitively with an inhibition constant of 8.0 x 10-6 molar, so that in view of the small difference in drug binding abilities it remains unclear whether the selective toxicity can be solely explained by interference with the parasite microtubular system, and the authors suggest that differential pharmacokinetic behaviour between parasite and host may be the essential basis for the difference in susceptibility.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"3394b04b-6dc0-528b-8e94-0644d5d33f45","slug":"mammalian-brain-tubulin","display_name":"Mammalian brain tubulin","entity_type_key":"protein"},"role":"comparator_protein","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"c42f1791-ecdc-584a-b45d-99dc23ededff","slug":"oral-bioavailability","display_name":"Oral bioavailability","entity_type_key":"cellular_process"},"role":"proposed_alternative","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"f8582a13-fc2e-5127-a61f-5b0594e54069","slug":"mebendazole","display_name":"Mebendazole","entity_type_key":"drug"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"bd64884e-6ee7-55df-9993-c2887f5a50df","slug":"nematode-beta-tubulin","display_name":"Nematode beta-tubulin","entity_type_key":"protein"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":3,"notes":""}]},"contexts":[{"dimension":"evidence_span","value_text":"{\"source_cache\": \"artifacts/mebendazole-research/7335116.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"358adb37f881bf9fc64cf4cea24ce690792e958df702a705b2addda3295ad144\", \"start_char\": 0, \"end_char\": 1621, \"text_sha256\": \"358adb37f881bf9fc64cf4cea24ce690792e958df702a705b2addda3295ad144\"}","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Colchicine and tritiated mebendazole binding to partially purified tubulin from Ascaris suum intestine and porcine brain","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"In vitro incubation of Ascaris suum with 10 micromolar mebendazole, with tubulin partially purified from the intestine","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"Measures the tissue mebendazole actually damages rather than embryonic tissue, and reaches the opposite conclusion about selectivity. Solubility prevented a precise association constant for mebendazole itself.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"Mebendazole research collection; topical membership is not evidence of a direct clinical effect, and mebendazole is recorded separately from albendazole, from the benzimidazole class and from its own crystal forms.","comparator":null,"unit":null,"notes":"","entity":{"slug":"mebendazole","display_name":"Mebendazole","entity_type_key":"drug"}},{"dimension":"organism","value_text":"Nematode and pig","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"Measured in the worm’s gut rather than its embryos, the drug is only about twice as selective, which is not enough to explain its safety.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[mbz-p7335116] Intestinal tubulin as possible target for the chemotherapeutic action of mebendazole in parasitic nematodes. (1981). https://pubmed.ncbi.nlm.nih.gov/7335116/ DOI: 10.1016/0166-6851(81)90064-5","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Nematode intestinal tubulin and porcine brain tubulin","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"77865c72-d8b4-599c-a214-e047dda23b13","evidence_kind":"source_excerpt","locator":"Lines 134-145","start_line":134,"end_line":145,"excerpt":"### mbz-selectivity-only-twofold\nMebendazole inhibited colchicine binding to partially purified Ascaris suum intestinal tubulin competitively with an inhibition constant of 4.22 x 10-6 molar and inhibited colchicine binding to porcine brain tubulin competitively with an inhibition constant of 8.0 x 10-6 molar, so that in view of the small difference in drug binding abilities it remains unclear whether the selective toxicity can be solely explained by interference with the parasite microtubular system, and the authors suggest that differential pharmacokinetic behaviour between parasite and host may be the essential basis for the difference in susceptibility.\nCondition category: normal\nnutrient_topic: Mebendazole research collection; topical membership is not evidence of a direct clinical effect, and mebendazole is recorded separately from albendazole, from the benzimidazole class and from its own crystal forms.\nplain_language: Measured in the worm’s gut rather than its embryos, the drug is only about twice as selective, which is not enough to explain its safety.\norganism: Nematode and pig\ntissue_or_cell_type: Nematode intestinal tubulin and porcine brain tubulin\nexperimental_model: Colchicine and tritiated mebendazole binding to partially purified tubulin from Ascaris suum intestine and porcine brain\nlimitations: Measures the tissue mebendazole actually damages rather than embryonic tissue, and reaches the opposite conclusion about selectivity. Solubility prevented a precise association constant for mebendazole itself.\nexposure: In vitro incubation of Ascaris suum with 10 micromolar mebendazole, with tubulin partially purified from the intestine\nevidence_span: {\"source_cache\": \"artifacts/mebendazole-research/7335116.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"358adb37f881bf9fc64cf4cea24ce690792e958df702a705b2addda3295ad144\", \"start_char\": 0, \"end_char\": 1621, \"text_sha256\": \"358adb37f881bf9fc64cf4cea24ce690792e958df702a705b2addda3295ad144\"}\n[mbz-p7335116] Intestinal tubulin as possible target for the chemotherapeutic action of mebendazole in parasitic nematodes. (1981). https://pubmed.ncbi.nlm.nih.gov/7335116/ DOI: 10.1016/0166-6851(81)90064-5","model_system":"Colchicine and tritiated mebendazole binding to partially purified tubulin from Ascaris suum intestine and porcine brain","directness":"author_interpretation","verification_status":"source_derived_draft","notes":"Exact curation-document quotation, not publisher quotation. Study references: [mbz-p7335116] Intestinal tubulin as possible target for the chemotherapeutic action of mebendazole in parasitic nematodes. (1981). https://pubmed.ncbi.nlm.nih.gov/7335116/ DOI: 10.1016/0166-6851(81)90064-5","relationship":"supports","weight":1.0,"link_notes":"","source":{"id":"06104773-03d0-5e5c-b9da-eb484e7be657","stable_key":"import-f2ec2007-88ff-5a96-a73b-8b5085e9cea9","title":"Mebendazole: the tubulin it binds, why that is selective, the crystal form that decides whether any of it works, and the off-target that became an oncology programme (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":"58b652636677e5033fd1dd555744485fcef18f21a97dcf68723fe072b656f413","revision_id":"a2cd9c22-0549-52ca-a653-8a0c2362ec85","review_status":"unverified_draft","notes":""}}],"relations":[],"conflicts":[{"id":"812dac77-6cf9-5e7e-a9cd-412b20ed8d72","title":"Does tighter binding to parasite tubulin explain why mebendazole spares the host?","kind":"contradiction","status":"open","why":"Measured against Ascaris suum embryonic tubulin, mebendazole bound 250 to 400 times more tightly than to bovine brain tubulin, and that ratio is the standard explanation for the drug being safe in the host. Measured against tubulin purified from the Ascaris intestine, the tissue the drug visibly destroys, the difference against porcine brain tubulin was about twofold, and those authors concluded that interference with the parasite microtubular system cannot on its own explain selective toxicity, proposing differential pharmacokinetics instead. The two studies used different parasite tissues, different mammalian sources and different purification, and one reports mebendazole as noncompetitive with colchicine on nematode tubulin while the other reports it as competitive on intestinal tubulin. Two later records in this collection offer a third answer, that the selectivity is kinetic and temperature dependent rather than a matter of equilibrium affinity. Which reading is correct is not settled here.","resolution":"Unresolved; needs review.","created_at":"2026-09-22 05:04:17","record_type":"conflict","display_label":"Recorded conflict","record_url":"/conflicts/812dac77-6cf9-5e7e-a9cd-412b20ed8d72","sides":[{"conflict_id":"812dac77-6cf9-5e7e-a9cd-412b20ed8d72","ordinal":0,"label":"The drug grips worm tubulin hundreds of times more tightly than ours, which is the usual explanation for why it is safe.","revision_id":"a2cd9c22-0549-52ca-a653-8a0c2362ec85","start_line":95,"end_line":106,"quote":"### mbz-selectivity-250-fold\nThe inhibition constants of mebendazole and fenbendazole for Ascaris suum embryonic tubulin were 1.9 x 10-8 and 6.5 x 10-8 molar while those for bovine brain tubulin were 7.3 x 10-6 and 1.7 x 10-5 molar, values 250 to 400 times greater, so that differential binding affinities between nematode and mammalian tubulin may explain the selective toxicity.\nCondition category: normal\nnutrient_topic: Mebendazole research collection; topical membership is not evidence of a direct clinical effect, and mebendazole is recorded separately from albendazole, from the benzimidazole class and from its own crystal forms.\nplain_language: The drug grips worm tubulin hundreds of times more tightly than ours, which is the usual explanation for why it is safe.\norganism: Nematode and cattle\ntissue_or_cell_type: Embryonic nematode tubulin and bovine brain tubulin\nexperimental_model: Inhibition of tritiated colchicine binding to cytosolic tubulin from 8-day Ascaris suum embryos and from bovine brain\nlimitations: The founding selectivity result. It measures embryonic tubulin; the study in this collection that measured intestinal tubulin found a far smaller difference.\nexposure: Mebendazole and fenbendazole compared on the two tubulins in the same assay\nevidence_span: {\"source_cache\": \"artifacts/mebendazole-research/7388055.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"5613d7fb281b4fd39b17bfdbafaf0ea823fb63b928048a9dd112fb71bf4cd2b7\", \"start_char\": 0, \"end_char\": 1209, \"text_sha256\": \"5613d7fb281b4fd39b17bfdbafaf0ea823fb63b928048a9dd112fb71bf4cd2b7\"}\n[mbz-p7388055] Interaction of anthelmintic benzimidazoles with Ascaris suum embryonic tubulin. (1980). https://pubmed.ncbi.nlm.nih.gov/7388055/ DOI: 10.1016/0304-4165(80)90431-6","source_key":"import-f2ec2007-88ff-5a96-a73b-8b5085e9cea9","source_title":"Mebendazole: the tubulin it binds, why that is selective, the crystal form that decides whether any of it works, and the off-target that became an oncology programme (2026-09-22)","claim_ids":["cd993756-73c3-5f3e-bef0-2333ec27f3a5"]},{"conflict_id":"812dac77-6cf9-5e7e-a9cd-412b20ed8d72","ordinal":1,"label":"Measured in the worm’s gut rather than its embryos, the drug is only about twice as selective, which is not enough to explain its safety.","revision_id":"a2cd9c22-0549-52ca-a653-8a0c2362ec85","start_line":134,"end_line":145,"quote":"### mbz-selectivity-only-twofold\nMebendazole inhibited colchicine binding to partially purified Ascaris suum intestinal tubulin competitively with an inhibition constant of 4.22 x 10-6 molar and inhibited colchicine binding to porcine brain tubulin competitively with an inhibition constant of 8.0 x 10-6 molar, so that in view of the small difference in drug binding abilities it remains unclear whether the selective toxicity can be solely explained by interference with the parasite microtubular system, and the authors suggest that differential pharmacokinetic behaviour between parasite and host may be the essential basis for the difference in susceptibility.\nCondition category: normal\nnutrient_topic: Mebendazole research collection; topical membership is not evidence of a direct clinical effect, and mebendazole is recorded separately from albendazole, from the benzimidazole class and from its own crystal forms.\nplain_language: Measured in the worm’s gut rather than its embryos, the drug is only about twice as selective, which is not enough to explain its safety.\norganism: Nematode and pig\ntissue_or_cell_type: Nematode intestinal tubulin and porcine brain tubulin\nexperimental_model: Colchicine and tritiated mebendazole binding to partially purified tubulin from Ascaris suum intestine and porcine brain\nlimitations: Measures the tissue mebendazole actually damages rather than embryonic tissue, and reaches the opposite conclusion about selectivity. Solubility prevented a precise association constant for mebendazole itself.\nexposure: In vitro incubation of Ascaris suum with 10 micromolar mebendazole, with tubulin partially purified from the intestine\nevidence_span: {\"source_cache\": \"artifacts/mebendazole-research/7335116.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"358adb37f881bf9fc64cf4cea24ce690792e958df702a705b2addda3295ad144\", \"start_char\": 0, \"end_char\": 1621, \"text_sha256\": \"358adb37f881bf9fc64cf4cea24ce690792e958df702a705b2addda3295ad144\"}\n[mbz-p7335116] Intestinal tubulin as possible target for the chemotherapeutic action of mebendazole in parasitic nematodes. (1981). https://pubmed.ncbi.nlm.nih.gov/7335116/ DOI: 10.1016/0166-6851(81)90064-5","source_key":"import-f2ec2007-88ff-5a96-a73b-8b5085e9cea9","source_title":"Mebendazole: the tubulin it binds, why that is selective, the crystal form that decides whether any of it works, and the off-target that became an oncology programme (2026-09-22)","claim_ids":["6bbd14b4-0bcd-5ed5-8fc7-780dfafea536"]}]}],"corrections":[],"research":null}