Pure botulinum neurotoxin is absorbed from the stomach and small intestine and produces peripheral neuromuscular blockade
Pure botulinum neurotoxin is absorbed from the stomach and small intestine and produces peripheral neuromuscular blockade
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DOI：
10.1128/iai.67.9.4708-4712.1999
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发表时间：
1999-09-01
影响因子：
3.1
通讯作者：
Simpson, LL
中科院分区：
文献类型：
--
作者：
Maksymowych, AB;Reinhard, M;Simpson, LL
A 血清型肉毒梭菌产生一种神经毒素，由通过二硫键连接的 100 kDa 重链和 50 kDa 轻链组成。 900 kDa 复合物，由单个非毒素、非血凝素亚基和血凝蛋白家族非共价结合形成。先前的研究表明，虽然从未最终证明，但如果没有复合物中辅助蛋白的参与，神经毒素本身就无法通过胃存活和/或无法从肠道吸收。因此，本研究比较了三种神经毒素制剂在体内小鼠模型中的相对吸收和毒性，通过手术将等摩尔量的血清A型血凝素复合物、不含血凝素的复合物和纯化的神经毒素引入胃或小肠。在一些实验中，神经毒素从给药部位的移动受到幽门结扎的限制，相对毒性的比较表明，在足够的剂量下，含血凝素的复合物、不含血凝素的复合物和纯神经毒素均可从胃吸收，复合物中的神经毒素的效力大于纯神经毒素的效力，但这种差异的幅度随着神经毒素剂量的增加而减小。当将含有血凝素的复合物、不含血凝素的复合物和纯神经毒素直接放入肠道时，获得了定性相似的结果。这项工作证实，纯 A 型肉毒杆菌神经毒素口服时具有毒性。这意味着纯神经毒素不需要血凝素或其他辅助蛋白质即可从胃肠系统吸收到全身循环中。
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.