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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Visualization of Binding and Transcytosis of Botulinum Toxin by Human Intestinal Epithelial Cells

Departments of Medicine (C.R.A., A.B.M., L.L.S.), Pathology (G.H.), and Biochemistry and Molecular Pharmacology (L.L.S.), Jefferson Medical College, Philadelphia, Pennsylvania

Botulinum toxin is an unusually potent oral poison, which means that the toxin must have an efficient mechanism for escaping the lumen of the gut to reach the general circulation. Previous work involving iodination of toxin and analysis of its movement demonstrated a specific process of transepithelial transport. In the present study, botulinum toxin labeled with Alexa Fluor 488 was used to visualize the discrete steps of binding, internalization, transcytosis, and release. The data revealed that binding sites for the toxin were distributed across the apical surface of epithelial cells, and there was no evidence of significant clustering. The amount of toxin bound to receptors at saturation was too large to be accommodated in a single wave of endocytosis. Toxin that entered epithelial cells did not remain in the vicinity of the endocytosing membrane, which is in striking contrast to events in neuronal cells. Instead, the toxin began to spread across the length of cells, eventually being released on the basolateral surface. Migration of toxin through epithelial cells required redistribution to the cell periphery. This migration pattern could be attributed to the large and centrally located nucleus, which physically displaced transport vesicles. Transcytosed toxin began to reach the contralateral surface within ca. 5 min, and transcytosis was essentially complete within 20 to 30 min.

Address correspondence to: Dr. Lance L. Simpson, Jefferson Medical College, Room 314-JAH, 1020 Locust Street, Philadelphia, PA 19107. E-mail: Lance.Simpson{at}jefferson.edu

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