Apical acidity decreases inhibitory effect of omeprazole on Mg2+ absorption and claudin-7 and -12 expression in Caco-2 monolayers.
- Author:
Narongrit THONGON
1
;
Nateetip KRISHNAMRA
Author Information
1. Faculty of Allied Health Sciences, Burapha University, Chonburi 20131, Thailand. narongritt@buu.ac.th
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
claudins;
intestines;
magnesium;
omeprazole;
proton pump inhibitors;
tight junctions
- MeSH:
Absorption/drug effects;
Caco-2 Cells;
Calcium/metabolism;
Claudins/genetics/*metabolism;
Dose-Response Relationship, Drug;
Gene Expression/drug effects;
Humans;
Hydrogen-Ion Concentration;
Magnesium/*metabolism;
Omeprazole/*pharmacology;
Proton Pump Inhibitors/*pharmacology;
Receptors, Calcium-Sensing/metabolism
- From:Experimental & Molecular Medicine
2012;44(11):684-693
- CountryRepublic of Korea
- Language:English
-
Abstract:
Clinical studies reported hypomagnesaemia in long-term omeprazole usage that was probably due to intestinal Mg2+ wasting. Our previous report demonstrated the inhibitory effect of omeprazole on passive Mg2+ transport across Caco-2 monolayers. The present study aimed to identify the underlying mechanism of omeprazole suppression of passive Mg2+ absorption. By using Caco-2 monolayers, we demonstrated a potent inhibitory effect of omeprazole on passive Mg2+, but not Ca2+, transport across Caco-2 monolayers. Omeprazole shifted the %maximum passive Mg2+ transport-Mg2+ concentration curves to the right, and increased the half maximal effective concentration of those dose-response curves, indicating a lower Mg2+ affinity of the paracellular channel. By continually monitoring the apical pH, we showed that omeprazole suppressed apical acid accumulation. Neomycin and spermine had no effect on passive Mg2+ transport of either control or omeprazole treated monolayers, indicating that omeprazole suppressed passive Mg2+ transport in a calcium sensing receptor (CaSR)-independent manner. The results of western blot analysis showed that omeprazole significantly suppressed claudin (Cldn)-7 and -12, but not Cldn-2, expression in Caco-2 cells. By using apical solution of pH 5.5, 6.0, 6.5, and 7.0, we found that apical acidity markedly increased passive Mg2+ transport, Mg2+ affinity of the paracellular channel, and Cldn-7 and -12 expression in Caco-2 monolayers. Apical acidity abolished the inhibitory effect of omeprazole on passive Mg2+ transport and Cldn-7 and -12 expression. Our results provided the evidence for the regulation of intestinal passive Mg2+ absorption by luminal acidity-induced increase in Cldn-7 and -12 expression.
