Copper treatment alters the permeability of tight junctions in cultured human intestinal Caco-2 cells

Am J Physiol. 1999 Dec;277(6):G1138-48. doi: 10.1152/ajpgi.1999.277.6.G1138.


The effects of copper on tight-junction permeability were investigated in human intestinal Caco-2 cells, monitoring transepithelial electrical resistance and transepithelial passage of mannitol. Apical treatment of Caco-2 cells with 10-100 microM CuCl(2) (up to 3 h) produced a time- and concentration-dependent increase in tight-junction permeability, reversible after 24 h in complete medium in the absence of added copper. These effects were not observed in cells treated with copper complexed to L-histidine [Cu(His)(2)]. The copper-induced increase in tight-junction permeability was affected by the pH of the apical medium, as was the apical uptake of (64)CuCl(2), both exhibiting a maximum at pH 6.0. Treatment with CuCl(2) produced a concentration-dependent reduction in the staining of F actin but not of the junctional proteins zonula occludens-1, occludin, and E-cadherin and produced ultrastructural alterations to microvilli and tight junctions that were not observed after treatment with up to 200 microM Cu(His)(2) for 3 h. Overall, these data point to an intracellular effect of copper on tight junctions, mediated by perturbations of the F actin cytoskeleton.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / physiology
  • Biological Transport / drug effects
  • Caco-2 Cells
  • Copper / pharmacokinetics*
  • Cycloheximide / pharmacology
  • Electric Impedance
  • Fluorescent Antibody Technique
  • Fluorescent Dyes
  • Histidine / pharmacokinetics
  • Humans
  • Hydrogen-Ion Concentration
  • Microscopy, Confocal
  • Microscopy, Electron
  • Microvilli / drug effects
  • Microvilli / metabolism
  • Organometallic Compounds / pharmacokinetics
  • Protein Synthesis Inhibitors / pharmacology
  • Rhodamines
  • Tight Junctions / drug effects*
  • Tight Junctions / metabolism*
  • Tight Junctions / ultrastructure


  • Actins
  • Fluorescent Dyes
  • Organometallic Compounds
  • Protein Synthesis Inhibitors
  • Rhodamines
  • copper bis(histidinate)
  • tetramethylrhodamine isothiocyanate
  • Histidine
  • Copper
  • Cycloheximide
  • cupric chloride