Browse > Article

Enhancement of Paracellular Transport of Heparin Disaccharide Across Caco-2 Cell Monolayers  

Kim, Yeong-Shik (National Products Research Institute, Seoul National University)
Cho, So-Yean (National Products Research Institute, Seoul National University)
Kim, Jong-Sik (National Products Research Institute, Seoul National University)
Li, Hong (College of Pharmacy, Seoul National University)
Shim, Chang-Koo (College of Pharmacy, Seoul National University)
Linhardt, Robert-J. (Division of Medicinal and Natural Products Chemistry, Department of Chemistry and Department of Chemical and Biochemical Engineering, University of lowa.)
Publication Information
Archives of Pharmacal Research / v.25, no.1, 2002 , pp. 86-92 More about this Journal
Abstract
The enhancement of paracellular transport of heparin disaccharide using several absorption enhancers across Caco-2 cell monolayers was tested . The cytotoxicity of these enhancers was also examined. The enhancing effects by Quillaja saponin, diponin glycyrrhizinate, $18{\beta}-glycyrrhetinic$ acid, sodium caprate and taurine were determined by changes in transepithelial electrical resistance (TEER) and the amount of heparin disaccharide transported across Caco-2 cell monolayers. Among the absorption enhancers, $18{\beta}-glycyrrhetinic$ acid arid taurine decreased TEER and increased the permeability of heparin disaccharide in a dose-dependent and time-dependent manner with little or negligible cytotoxicity. Our results indicate that these absorption enhancers can widen the tight junction, which is a dominant paracellular absorption route of hydrophilic compounds . It is highly possible that these absorption enhancers can be applied as pharmaceutical excipients to improve the transport of macromolecules and hydrophilic drugs having difficulty in permeability across the intestinal epithelium.
Keywords
Heparin disaccharide; Caco-2 cell monolayers; Tight junction; Absorption enhancers, Paracellular transport;
Citations & Related Records

Times Cited By Web Of Science : 8  (Related Records In Web of Science)
Times Cited By SCOPUS : 10
연도 인용수 순위
1 Palmi, M., Youmbi, G. T., Fusi, F., Sgaragli, G. P., Dixon, H. B. F., Frosini, M., and Tipton, K. F., Potentiation of mitochondrial $Ca^{2+}$ sequestration by taurine. Biochem. Pharmacol., 58, 1123-1131 (1999)   DOI   PUBMED   ScienceOn
2 Walsh, S. V., Hopkins, A. M., and Nusrat, A., Modulation of tight junction structure and function by cytokines. Adv. Drug Deliv. Rev., 41 ,303-313 (2000)   DOI   ScienceOn
3 Brayden, D., Creed, E., O'Connell, A., Leipold, H., Agarwal, R., and Leone-Bay, A., Heparin absorption across the intestine: effects of sodium N-[8-(2-hydroxybenzoyl)amino]caprylate in rat in situ intestinal instillations and in Caco-2 monolayers. Pharm. Res., 14, 1772-1779 (1997)   DOI   ScienceOn
4 Fasano, A. and Uzzau, S., Modulation of intestinal tight junctions by Zonula occludens toxin permits enteral administration of insulin and other macromolecules in an animal model. J. Clin. lnvest., 99, 1158-1164 (1997)   DOI   ScienceOn
5 Harenberg, J. and Casu, B., Nonanticoagulant actions of glycosaminoglycans, Plenum Press, New York (1996)
6 Hopkins, A. M., Li, D., Mrsny, R. J., Walsh, S. V., and Nusrat, A., Modulation of tight junction function by G protein-coupled events. Adv. Drug Deliv. Rev., 41, 329-340 (2000)   DOI   ScienceOn
7 Rivera, T. M., Leone-Bay, A., Paton, D. R., Leipold, H. R., and Baughman, R. A., Oral delivery of heparin in combination with sodium N-[8-(2-hydroxybenzoyl) amino]caprylate: pharmacological considerations. Pharm. Res., 14, 1830-1834 (1997)   DOI   ScienceOn
8 Leone-Bay, A., Paton, D. R., Freeman, J., Lercara, C., O'Toole, D., Gschneidner, D., Wang, E, Harris, E., Rosado, C., Rivera, T., DeVincent, A., Tai, M., Mercogliano, F., Agarwal, R., Leipold, H., and Baughman, R.A, Synthesis and evaluation of compounds that facilitate the gastrointestinal absorption of heparin. J Med. Chem., 41, 1163-1171 (1998)   DOI   ScienceOn
9 Madara, J. L., Increases in guinea pig small intestinal transepithelial resistance induced by osmotic loads are accompanied by rapid alterations in absorptive-cell tight-junction structure. J. Cell. Biol., 97, 125-136 (1983)   DOI   PUBMED   ScienceOn
10 Madara, J. L., Barenberg, D., and Carlson, S., Effects of cytochalasin D on occluding junctions of intestinal absorptive cells: further evidence that the cytoskeleton may influence paracellular permeability and junctional charge selectivity. J. Cell. Biol., 102, 2125-2136 (1986)   DOI   ScienceOn
11 Fasano, A., Novel approaches for oral delivery of macromolecules. J. Pharm. Sci., 87, 1351-1356 (1998)   DOI   PUBMED
12 Sakai, M., Imai, T., Ohtake, H., Azuma, H., and Otagiri, M., Simultaneous use of sodium deoxycholate and dipotassium glycyrrhizinate enhances the cellular transport of poorly absorbed compounds across Caco-2 cell monolayers. J. Pharm. Pharmacol., 51, 27-33 (1999)   DOI   ScienceOn
13 Pillion, D. J., Amsden, J. A., Kensil, C. R., and Recchia, J., Structure-function relationship among Quillaja saponins serving as excipients for nasal and ocuar delivery of insulin. J. Pharm. Sci., 85, 518-524 (1996)   DOI   ScienceOn
14 Hershkoviz, R., Schor, H., Ariel, A., Hecht, I., Cohen, I.R, Lider O., and Cahalon, L., Disaccharides generated from heparan sulphate or heparin modulate chemokine-induced T-cell adhesion to extracellular matrix. Immunology, 99, 87-93 (2000)   DOI   ScienceOn
15 Xie, X., Rivier, A. S., Zakrzewicz, A., Bernimoulin, M., Zeng, X. L., Wessel, H. P., Schapira, M., and Spertini, O., Inhibition of selectin-mediated cell adhesion and prevention of acute inflammation by nonanticoagulant sulfated saccharides. J Biol. Chem., 275, 34818-34825 (2000)   DOI   ScienceOn
16 Stenson, W. F., Easom, R. A., Riehl, -. E., and Turk, J., Regulation of paracellular permeability in Caco-2 cell monolayers by protein kinase C. Am. J Physiol., 265, G955-G962 (1993)   PUBMED
17 Anderson, J. M. and van Itallie, C. M., Tight junctions and the molecular basis for regulation of paracellular permeability. Am. J. Physiol., 269, G467-G475 (1995)   PUBMED
18 Clarke, H., Marano, C. W., Peralta Soler, A., and Mullin, J. M., Modification of tight junction function by protein kinase C isoforms. Adv. Drug Deliv. Rev., 41, 283-301 (2000)   DOI   ScienceOn
19 Nelson. R. M., Cecconi. O .. Roberts. W. G., Aruffo. A., Linhardt. R. J., and Bevilacqua, M. P., Heparin oligosaccharides bind L-selectin and P-selectin and inhibit acute inflammation. Blood, 82, 3253-3258 (1993)   PUBMED
20 Chowers, Y., Lider, O., Schor, H., Barshack, I., Tal, R., Ariel, A., Bar-Meir, S., Cohen I.R., and Cahalon, L., Disaccharides derived from heparin or heparan sulfate regulate IL-8 and IL-1 beta secretion by intestinal epithelial cells. Gastroenterology, 120, 449-459 (2001)   DOI   PUBMED   ScienceOn
21 Merchant, Z. M., Kim, Y. S., Rice, K. G., and Linhardt, R. J., Structure of heparin-derived tetrasaccharides. Biochem. J, 229, 369-377 (1985)   DOI   PUBMED
22 Bjork I, Olson, S. T.,and Shore J. D., Molecular mechanisms of the accelerating efffect of heparin on the reactions between antithrombin and clotting proteinases. In: Lane D., Lindahl U. (Eds.). Heparin: Chemical and biological properties, clinical applications. CRC Press, Boca Raton, pp. 229-255 (1989)
23 Ward, P. D., Tippin, T. K., and Thakker, D. R., Enhancing paracellular permeability by modulating epithelial tight junctions. Pharm. Sci. Tech. Today, 3, 346-358 (2000)   DOI   ScienceOn
24 Baughman, R. A., Kapoor, S. C., Agarwal, R. K., Kisicki, J., Catella-Lawson, F., and FitzGerald, G. A., Oral delivery of anticoagulant doses of heparin. A randomized, double-blind, controlled study in humans. Circulation, 98, 1610-1615 (1998)   DOI   PUBMED   ScienceOn
25 Kim, B. T., Kim, W. S., Kim, Y. S., Linhardt, R. J., and Kim, D. H., Purification and characterization of a novel heparinase from Bacteroides stercoris HJ-15. J. Biochem. (Tokyo), 128, 323-328 (2000)   DOI   ScienceOn
26 Choksakulnimitr S., Masuda, S., Tokuda H., Takakura Y., and Hashida M., In vitro cytotoxicity of macromolecules in different cell culture system. J. Control. Release, 34, 233-241 (1995)   DOI   ScienceOn
27 Liu, D. Z., LeCluyse, E. L., and Thakker, D. R., Dodecylphosphocholine- mediated enhancement of paracellular permeability and cytotoxicity in Caco-2 cell monolayers. J. Pharm. Sci., 88, 1161-1168 (1999)   DOI   PUBMED
28 Sakai, M., Imai, T., Ohtake, H., Azuma, H., and Otagiri, M., Effects of absorption enhancers on cytoskeletal actin filaments in Caco- 2 cell monolayers. Life Sci., 63, 45-54 (1998)   DOI   ScienceOn
29 Duffey, M. E., Hainau, B., Ho, S., and Bentzel, C. J., Regulation of epithelial tight junction permeability by cyclic AMP. Nature, 294, 451-453 (1981)   DOI   ScienceOn
30 Cahalon, L., Lider,O., Schor, H., Avron,A, Gilat, D., Hershkoviz, R., Margalit, R., Eshel, A., Shoseyev O., and Cohen, I.R., Heparin disaccharides inhibit tumor necrosis factor-alpha production by macrophages and arrest immune inflammation in rodents. lnt. lmmunol., 9, 1517-1522 (1997)
31 Palant, C. E., Duffey, M. E., Mookerjee B. K., Ho, S., and Bentzel, C.J., $Ca^{2+}$ regulation of tight-junction permeability and structure in Necturus gall bladder. Am. J. Physiol., 245, C203-C212 (1983)   DOI   PUBMED
32 Hiebert, L. M., Wice, S. M., Ping, T., Hileman, R. E., Capila, I., and Linhardt, R. J., Tissue distribution and antithrombotic activity of unlabeled or $ ^{14}C$-labeled porcine intestinal mucosal heparin following administration to rats by the oral route. Can. J. Physiol. Pharmacol., 78, 307-320 (2000)   DOI   ScienceOn
33 Lindmark, T., Kimura, Y., Artursson, P., Absorption enhancement through intracellular regulation of tight junction permeability by medium chain fatty acids in Caco-2 cells. J. Pharmacol. Exp. Ther., 284, 362-369 (1998)   PUBMED
34 Ma, T. Y., Nguyen, D., Bui, V., Nguyen, H., and Hoa, N., Ethanol modulation of intestinal epithelial tight junction barrier. Am. J. Physiol. 276, G965-G974 (1999)   PUBMED