Modulation of the tight junctions of the Caco-2 cell monolayers by H2-antagonists.
OBJECTIVE
The tight junctions in the intestinal epithelium represent highly specialized intercellular junctions. Ranitidine, an H2-antagonist, causes a tightening of the tight junctions. Hence, we have investigated the effect of ranitidine and other H2-antagonists on the function of the intestinal tight junctions.


METHODS
Effect of the H2-antagonists on the tight junctions has been investigated using the transepithelial electrical resistance (TEER) and the transport of mannitol across the Caco-2 cell monolayers.


RESULTS
Four different H2-antagonists caused an increase in the TEER across the Caco-2 cell monolayers, accompanied by a decrease in the permeability for mannitol. The effect was concentration-dependent and saturable. Ranitidine and famotidine, caused a decrease in their own transport rate across the Caco-2 cells. Ranitidine competitively inhibited the increase in TEER caused by famotidine, whereas compounds which represent molecular fragments of ranitidine had no effect. The relative potency of the four H2-antagonists in causing an increase in the TEER correlated inversely with the oral bioavailability of these compounds in humans.


CONCLUSIONS
We hypothesize that the H2-antagonists exert their effect on the tight junctions of Caco-2 cells by modulation of interactions among proteins associated with the tight junctional complex.
Gan
L S
LS
Department of Drug Metabolism, Glaxo Inc., Research Triangle Park, North Carolina 27709, USA.
Yanni
S
S
Thakker
D R
DR
D001682:Biological Availability; D018938:Caco-2 Cells / Q000187:drug effects* / Q000502:physiology; D017097:Electric Impedance; D006635:Histamine H2 Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D011899:Ranitidine / Q000493:pharmacokinetics / Q000494:pharmacology*; D019108:Tight Junctions / Q000187:drug effects*
D006635:Histamine H2 Antagonists; D011899:Ranitidine