Lindmark T, Kimura Y, Artursson P
Department of Pharmacy, Uppsala University, Sweden.
J Pharmacol Exp Ther. 1998 Jan;284(1):362-9.
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.
中链脂肪酸（MCFAs）被用于增强黏膜组织对亲水性药物的通透性，但其作用机制在很大程度上尚不清楚。在本研究中，研究了两种中链脂肪酸癸酸（C10）和月桂酸（C12）的钠盐对人肠上皮Caco-2细胞单层的吸收增强作用。两种中链脂肪酸均能使上皮细胞对亲水性标记分子荧光素钠的通透性迅速增加。抑制磷脂酶C、抑制或激活各种激酶以及缓冲细胞内钙表明，对上皮通透性的影响是通过磷脂酶C依赖的肌醇三磷酸/二酰基甘油途径介导的。令人惊讶的是，发现肌醇三磷酸和二酰基甘油途径对细胞旁通透性有相反的影响。暴露于中链脂肪酸还导致细胞脱氢酶活性和ATP水平呈浓度依赖性降低。C10而非C12诱导紧密连接蛋白ZO-1和闭合蛋白的重新分布。这些结果表明，这两种中链脂肪酸具有比以前认识到的部分不同且更复杂的机制，这对它们在体内的应用具有重要意义。
