ABSORPTION ENHANCEMENT THROUGH INTRACELLULAR REGULATION OF TIGHT JUNCTION PERMEABILITY BY MEDIUM-CHAIN FATTY-ACIDS IN CACO-2 CELLS

Medium chain fatty acids (MCFAs) are used to enhance the permeability of mucosal tissues to hydrophilic drugs, but their mechanism of action is largely unknown, In this study, the absorption-enhancing effects o f the sodium salts of two MCFAs, capric acid (C10) and lauric acid (C1 2), were studied in monolayers of human intestinal epithelial Caco-2 c ells, Both MCFAs induced a rapid increase in epithelial permeability t o the hydrophilic marker molecule sodium fluorescein. Inhibition of ph ospholipase C and inhibition or activation of various kinases and buff ering of intracellular calcium indicated that the effects on epithelia l permeability were mediated through phospholipase C-dependent inosito l triphosphate/diacylglycerol pathways. Surprisingly, the inositol tri phosphate and diacylglycerol pathways were found to have opposing effe cts on paracellular permeability. Exposure to the MCFAs also resulted in a concentration dependent reduction of cellular dehydrogenase activ ity and ATP levels. C10, but not C12, induced redistribution of the ti ght junction proteins ZO-1 and occludin. These results indicate that t he two MCFAs have partially different and more complex mechanisms than previously recognized, which has important implications for their use in vivo.