title: Pure botulinum neurotoxin is absorbed from the stomach and small intestine and produces peripheral neuromuscular blockade.
abstract: Clostridium botulinum serotype A produces a neurotoxin composed of a 100-kDa heavy chain and a 50-kDa light chain linked by a disulfide bond. This neurotoxin is part of a ca. 900-kDa complex, formed by noncovalent association with a single nontoxin, nonhemagglutinin subunit and a family of hemagglutinating proteins. Previous work has suggested, although never conclusively demonstrated, that neurotoxin alone cannot survive passage through the stomach and/or cannot be absorbed from the gut without the involvement of auxiliary proteins in the complex. Therefore, this study compared the relative absorption and toxicity of three preparations of neurotoxin in an in vivo mouse model. Equimolar amounts of serotype A complex with hemagglutinins, complex without hemagglutinins, and purified neurotoxin were surgically introduced into the stomach or into the small intestine. In some experiments, movement of neurotoxin from the site of administration was restricted by ligation of the pylorus. Comparison of relative toxicities demonstrated that at adequate doses, complex with hemagglutinins, complex without hemagglutinins, and pure neurotoxin can be absorbed from the stomach. The potency of neurotoxin in complex was greater than that of pure neurotoxin, but the magnitude of this difference diminished as the dosage of neurotoxin increased. Qualitatively similar results were obtained when complex with hemagglutinins, complex without hemagglutinins, and pure neurotoxin were placed directly into the intestine. This work establishes that pure botulinum neurotoxin serotype A is toxic when administered orally. This means that pure neurotoxin does not require hemagglutinins or other auxiliary proteins for absorption from the gastrointestinal system into the general circulation.
authors.affiliation: Departments of Medicine and of Biochemistry and Molecular Pharmacology, Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA.
authors.forename: A B
authors.initials: AB
authors.lastname: Maksymowych
authors.forename: M
authors.initials: M
authors.lastname: Reinhard
authors.forename: C J
authors.initials: CJ
authors.lastname: Malizio
authors.forename: M C
authors.initials: MC
authors.lastname: Goodnough
authors.forename: E A
authors.initials: EA
authors.lastname: Johnson
authors.forename: L L
authors.initials: LL
authors.lastname: Simpson
mesh_terms: D000042:Absorption; D000818:Animals; D019274:Botulinum Toxins, Type A / Q000493:pharmacokinetics* / Q000633:toxicity; D003014:Clostridium botulinum; D004305:Dose-Response Relationship, Drug; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism*; D006388:Hemagglutinins / Q000378:metabolism / Q000633:toxicity; D007408:Intestinal Absorption; D007421:Intestine, Small / Q000378:metabolism*; D051379:Mice; D009465:Neuromuscular Agents / Q000493:pharmacokinetics* / Q000633:toxicity
chemical_list: D006388:Hemagglutinins; D009465:Neuromuscular Agents; D019274:Botulinum Toxins, Type A