Abstract
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.
Footnotes
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Send reprint requests to: Prof. Per Artursson, Department of Pharmacy, Division of Pharmaceutics, Uppsala University, Box 580, S-75123 Uppsala, Sweden. E-mail:per.artursson{at}galenik.uu.se
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↵1 This work was supported by grants from The Swedish Medical Research Council (9478), Centrala Försöksdjursnämnden (97–46), the Wallenberg Foundation and Astra AB.
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↵2 Present address: Department of Food Science and Technology, Kyoto University, Japan.
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↵3 Johan Gråsjö, unpublished observations.
- Abbreviations:
- C10
- sodium caprate
- C12
- sodium laurate
- BAPTA-AM
- the membrane-permeant acetoxymethyl ester of 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid
- DAG
- diacylglycerol
- Flu
- sodium fluorescein
- IP3, inositol triphosphate
- MCFA, medium chain fatty acid
- MLCK
- myosin light chain kinase
- PIP2, phosphatidylinositol bisphosphate
- PKC, protein kinase C
- PLC
- phospholipase C
- TER
- transepithelial electrical resistance
- HBSS
- Hanks’ balanced salt solution
- HEPES
- 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
- MTT
- 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
- PBS
- phosphate-buffered saline
- Received May 23, 1997.
- Accepted September 12, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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