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1 Department of Pediatrics and 2 Department of Cell Biology, Medical University of South Carolina, Charleston, South Carolina 29425
Acetaldehyde-induced
cytotoxicity is an important factor in pathogenesis of alcohol-related
diseases; however, the mechanism of this toxicity is unknown. We
recently showed that acetaldehyde increases epithelial paracellular
permeability. We asked whether protein tyrosine phosphorylation via
modulation of tyrosine kinases and/or PTPases is a mechanism involved
in acetaldehyde-induced disruption of the tight junctions in the Caco-2
cell monolayer. Immunofluorescence localization of occludin and ZO-1
showed disruption of the tight junctions in acetaldehyde-treated cell
monolayer. Administration of genistein prevented acetaldehyde-induced
permeability. Acetaldehyde increased tyrosine phosphorylation of three
clusters of proteins with molecular masses of 30-50, 60-90,
and 110-150 kDa; three of these proteins were ZO-1, E-cadherin,
and 
-catenin. Acetaldehyde reduced PTPase activity in plasma
membrane and soluble fractions, whereas tyrosine kinase activity
remained unaffected. Treatment with acetaldehyde resulted in a 97%
loss of protein tyrosine phosphatase (PTP)1B activity and a partial
reduction of PTP1C and PTP1D activities. These results strongly suggest that acetaldehyde inhibits PTPases to increase protein tyrosine phosphorylation, which may result in disruption of the tight junctions.
tyrosine kinase; occludin; ZO-1; alcoholic liver disease
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