消化管粘膜における透過性こう進シグナルの伝達機構

Abstract

The epithelial cell sheet in the gastrointestinal mucosa is a permselective sophisticated membrane, which serves as a potent permeation barrier to water-soluble and large molecular weight xenobiotics. Fatty acids such as oleic acid and capric acid efficiently enhance the intestinal absorption of poorly absorbed drugs due to the transient reduction of the barrier resistance. However, the mechanisms have not been completely elucidated and their effective and safe use should be desired in drug delivery. It was proposed that these fatty acids could enhance the permeation of drugs by perturbing the lipid bilayer of brush-border membrane. However, it seems unlikely to explain that they increase the mucosal permeation of macromolecular compounds which cannot pass through cell membranes. We have found that the permeability enhancement by the fatty acids is temperature-dependent with being maximal at 37°C, and that it is inhibited by the membrane-permeable SH-modifiers, corresponding with the reduction in sulfhydryl content in the brush-border membrane, and high concentration of potassium ion in the lumen. The sulfhydryl modification of brush-border membrane inhibited the oleic acid-induced increase in membrane fluidity in the SH-protein fraction but not in the lipid bilayer. In addition, W-7, a specific calmodulin inhibitor, significantly inhibited the oleic acid-induced increase in membrane permeability, suggesting the possible roles of calmodulin-dependent protein kinases in the mechanism underlying the permeability enhancement of the intestinal mucosa.The results discussed in this study suggest that a signal from the action of oleic acid on the brushborder membrane is transmitted via some subcellular molecular systems to the cell skeleton to increase the mucosal drug permeability. However, further detail studies are needed to estabilish this mechanism.