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 of the sodium salts of two MCFAs, capric acid (C10) and lauric acid (C12), were studied in monolayers of human intestinal epithelial Caco-2 cells. Both MCFAs induced a rapid increase in epithelial permeability to the hydrophilic marker molecule sodium fluorescein. Inhibition of phospholipase C and inhibition or activation of various kinases and buffering of intracellular calcium indicated that the effects on epithelial permeability were mediated through phospholipase C-dependent inositol triphosphate/diacylglycerol pathways. Surprisingly, the inositol triphosphate and diacylglycerol pathways were found to have opposing effects on paracellular permeability. Exposure to the MCFAs also resulted in a concentration dependent reduction of cellular dehydrogenase activity and ATP levels. C10, but not C12, induced redistribution of the tight junction proteins ZO-1 and occludin. These results indicate that the two MCFAs have partially different and more complex mechanisms than previously recognized, which has important implications for their use in vivo.
Lindmark
T
T
Department of Pharmacy, Uppsala University, Sweden.
Kimura
Y
Y
Artursson
P
P
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000032:analysis; D018938:Caco-2 Cells; D002118:Calcium / Q000378:metabolism; D003652:Decanoic Acids / Q000494:pharmacology*; D004075:Diglycerides / Q000502:physiology; D006801:Humans; D007408:Intestinal Absorption; D007850:Lauric Acids / Q000494:pharmacology*; D010539:Permeability; D019108:Tight Junctions / Q000378:metabolism*
D003652:Decanoic Acids; D004075:Diglycerides; D007850:Lauric Acids; C030358:lauric acid; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000255:Adenosine Triphosphate; D002118:Calcium