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J Biol Chem, Vol. 273, Issue 34, 21950-21957, August 21, 1998
From the Departments of Medicine and of Biochemistry and Molecular
Pharmacology, Jefferson Medical College,
Philadelphia, Pennsylvania 19107
T-84 and Caco-2 human colon carcinoma cells and
Madin-Darby canine kidney (MDCK) cells were used to study binding and
transcytosis of iodinated Clostridium botulinum neurotoxin
serotypes A, B, and C, as well as tetanus toxin. Specific binding and
transcytosis were demonstrated for serotypes A and B in intestinal
cells. Using serotype A as an example, the rate of transcytosis by T-84
cells was determined in both apical to basolateral (11.34 fmol/h/cm2) as well as basolateral to apical (8.98 fmol/h/cm2) directions, and by Caco-2 cells in the apical
to basolateral (8.42 fmol/h/cm2) direction. Serotype A
retained intact di-chain structure during transit through T-84 or
Caco-2 cells, and when released on the basolateral side was toxic
in vivo to mice and in vitro on mouse phrenic
nerve-hemidiaphragm preparations. Serotype C and tetanus toxin did not
bind effectively to T-84 cells, nor were they efficiently transcytosed
(8-10% of serotype A). MDCK cells did not bind or efficiently
transcytose (0.32 fmol/h/cm2) botulinum toxin. Further
characterization demonstrated that the rate of transcytosis for
serotype A in T-84 cells was increased 66% when vesicle sorting was
disrupted by 5 µM brefeldin A, decreased 42% when
microtubules were disrupted by 10 µM nocodazole, and decreased 74% at 18 °C. Drugs that antagonize toxin action at the
nerve terminal, such as bafilomycin A1 (which prevents
acidification of endosomes) and methylamine HCl (which neutralizes
acidification of endosomes), produced only a modest inhibitory effect
on the rate of transcytosis (17-22%). These results may provide an
explanation for the mechanism by which botulinum toxin escapes the
human gastrointestinal tract, and they may also explain why specific
serotypes cause human disease and others do not.
Binding and Transcytosis of Botulinum Neurotoxin by Polarized
Human Colon Carcinoma Cells
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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