The Intestinal Permeability of Neolignans from the Seeds of Myristica fragrans in the Caco-2 Cell Monolayer Model

Abstract

The intestinal permeability and transport of 10 neolignans isolated from Myristica fragrans were studied by using the Caco-2 cell monolayer model. The 10 neolignans were measured by HPLC. Transport parameters and permeability coefficients were then calculated and compared with those of the model compounds, propranolol and atenolol. Among the 10 neolignans, the 8-O-4′-type neolignans demonstrated high permeability while the benzofuran-type neolignans were of poor to moderate permeability. Among them, eight neolignans were transported mainly via passive diffusion. These findings indicate that the 8-O-4′-type neolignans are well-absorbed compounds and can be used as oral leading compounds in drug discovery.

Key words

Myristicaceae - Myristica fragrans - neolignans - intestinal permeability - Caco‐2 cell monolayer

References

• 1 Hall R L. Toxicants occurring naturally in spices and flavours. Food Protection Committee, National Research Council Toxicants occurring naturally in foods, 2nd edition. Washington DC; National Academy of Sciences 1973: 448-463
• 2 Jin D Q, Lim C S, Hwang J K, Ha I, Han J S. Anti-oxidant and anti-inflammatory activities of macelignan in murine hippocampal cell line and primary culture of rat microglial cells.  Biochem Biophys Res Commun. 2005;  331 1264-1269
• 3 Yang S, Kyun N M, Jang J P, Kim K A, Kim B Y, Sung N J, Oh W K, Ahn J S. Inhibition of protein tyrosine phosphatase 1B by lignans from Myristica fragrans.  Phytother Res. 2006;  20 680-682
• 4 Morita T, Jinno K, Kawagishi H, Arimoto Y, Suganuma H, Inakuma T, Sugiyama K. Hepatoprotective effect of myristicin from nutmeg (Myristica fragrans) on lipopolysaccharide/β-galactosamine-induced liver injury.  J Agric Food Chem. 2003;  51 1560-1565
• 5 Mukherjee P K, Kumar V, Houghton P J. Screening of Indian medicinal plants for acetylcholinesterase inhibitory activity.  Phytother Res. 2007;  21 1142-1145
• 6 Hussain S P, Rao A R. Chemopreventive action of mace (Myristica fragrans Houtt.) onmethylcholanthrene-induced carcinogenesis in the uterine cervix in mice.  Cancer Lett. 1991;  56 231-234
• 7 Hattori M, Yang X W, Miyashiro H, Namba T. Inhibitory effects of monomeric and dimeric phenylpropanoids from mace on lipid peroxidation in vivo and in vitro.  Phytother Res. 1993;  7 395-401
• 8 Ozaki Y, Soedigdo S, Wattimena Y R, Suganda A G. Anti-inflammatory effects of mace, aril of Myristica fragrans Houtt., and its active principles.  Jpn J Pharmacol. 1989;  49 155-163
• 9 Checker R, Chatterjee S, Sharma D, Gupta S, Variyar P, Sharma A, Poduval T B. Immunomodulatory and radioprotective effects of lignans derived from fresh nutmeg mace (Myristica fragrans) in mammalian splenocytes.  Int Immunopharmacol. 2008;  8 661-669
• 10 Wang Y, Yang X W. Quantitative determination of neolignanoids in the seeds of Myristica fragrans.  Modern Chin Med. 2008;  10 10-13
• 11 Yang X W, Huang X, Ahmat M. New neolignan from seed of Myristica fragrans.  China J Chin Mater Med. 2008;  33 397-402
• 12 Hada S, Hattori M, Tezuka Y, Kikuchi T, Namba T. New neolignans and lignans from the aril of Myristica fragrans.  Phytochemistry. 1988;  27 563-568
• 13 Hattori M, Hada S, Kawata Y, Tezuka Y, Kikuchi T, Namba T. New 2,5-bis-aryl-3,4-dimethyltetrahydrofuran lignans from the aril of Myristica fragrans.  Chem Pharm Bull. 1987;  35 3315-3322
• 14 Hattori M, Hada S, Shu Y Z, Kikuchi T, Namba T. New acyclic bis-phenylpropanoids from the aril of Myristica fragrans.  Chem Pharm Bull. 1987;  35 668-674
• 15 Hattori M, Yang X W, Shu Y Z, Kakiuchi N, Tezuka Y, Kikuchi T, Namba T. New constituents of the aril of Myristica fragrans Houtt.  Chem Pharm Bull. 1988;  36 648-654
• 16 Isogai A, Murakoshi S, Suzuki A, Tamura S. Isolation from nutmeg of growth inhibitory substances to Silkworm larvae.  Agric Biol Chem. 1973;  37 889-895
• 17 Isogai A, Suzuki A, Tamura S. Structures of dimeric from Myristica fragrans Houtt.  Agric Biol Chem. 1973;  37 193-194
• 18 Li F, Yang X W. Three new neolignans from the Aril of Myristica fragrans.  Helv Chim Acta. 2007;  90 1491-1496
• 19 Murakami Y, Shoji M, Hirata A, Tanaka S, Yokoe I, Fujisawa S. Dehydrodiisoeugenol, an isoeugenol dimer, inhibits lipopolysaccharide-stimulated nuclear factor kappa B activation and cyclooxygenase-2 expression in macrophages.  Arch Biochem Biophys. 2005;  434 326-332
• 20 Tsai I L, Hsieh C F, Duh C Y, Chen I S. Further study on the chemical constituents and their cytotoxicity from the leaves of Persea obovatifolia.  Chin Pharm J. 1999;  51 335-345
• 21 Lee S U, Shim K S, Ryu S Y, Min Y K, Kim S H. Machilin A isolated from Myristica fragrans stimulates osteoblast differentiation.  Planta Med. 2009;  75 152-157
• 22 Li F, Yang X W. Quantification of myrislignan in rat plasma by solid-phase extraction and reversed-phase high-performance liquid chromatography.  Biomed Chromatogr. 2008;  22 601-605
• 23 Li F, Yang X W. Determination of dehydrodiisoeugenol in rat tissues using HPLC method.  Biomed Chromatogr. 2008;  22 1202-1212
• 24 Li F, Yang X W. Simultaneous determination of diastereomers (+)-licarin A and isolicarin A from Myristica fragrans in rat plasma by HPLC and its application to their pharmacokinetics.  Planta Med. 2008;  74 880-884
• 25 Kasahara H, Miyazawa M, Kameoka H. Biotransformation of an acyclic neolignan in rats.  Phytochemistry. 1995;  38 343-346
• 26 Li F, Yang X W. Biotransformation of myrislignan by rat liver microsomes in vitro.  Phytochemistry. 2008;  69 765-771
• 27 Yang X W, Yang X D, Wang Y, Ma L, Zhang Y, Yang X G, Wang K. Establishment of Caco-2 cell monolayer model and the standard operation procedure for assessing intestinal absorption of chemical components of traditional Chinese medicine.  J Chin Integr Med. 2007;  5 634-641
• 28 Lennernas H, Palm K, Fagerholm U, Artursson P. Comparison between active and passive drug transport in human intestinal epithelial (Caco-2) cells in vitro and human jejunum in vivo.  Int J Pharm. 1996;  127 103-107
• 29 Artursson P A, Karlsson J. Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells.  Biochem Biophys Res Commun. 1991;  175 880-885
• 30 Chong S, Dando S A, Morrison R A. Evaluation of biocoat intestinal epithelium differentiation environment (3-day cultured Caco-2 cells) as an absorption screening model with improved productivity.  Pharm Res. 1997;  14 1835-1837
• 31 Takahashi Y, Kondo H, Yasuda T, Watanabe T, Kobayashi S I, Yokohama S. Common solubilizers to estimate the Caco-2 transport of poorly water-soluble drugs.  Int J Pharm. 2002;  246 85-94
• 32 Yee S Y. In vitro permeability across Caco-2 cells (colonic) can predict in vivo (small intestinal) absorption in man – fact or myth.  Pharm Res. 1997;  14 763-766
• 33 Sharom F J. The P-glycoprotein efflux pump: how does it transport drugs?.  J Membr Biol. 1997;  160 161-175
• 34 Tsuruo T, Iida H, Tsukagoshi S, Sakurai Y. Overcoming of vincristine resistance in P388 leukemia in vivo and in vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil.  Cancer Res. 1981;  41 1967-1972
• 35 Jedlitschky G, Leier I, Buchholz U. ATP-dependent transport of glutathine S-conjugates by the multidrug resistance-associated protein.  Cancer Res. 1994;  54 4833-4836
• 36 Leier I, Jedlitschky G, Buchholz U, Cole S P C, Deeley R G, Keppler D. The MRP gene encodes an ATP-dependent export pump for leukotriene C₄ and structurally related conjugates.  J Biol Chem. 1994;  269 27807-27810
• 37 Madgula V L M, Avula B, Choi Y W, Pullela S V, Khan I A, Walker L A, Khan S I. Transport of Schisandra chinensis extract and its biologically active constituents across Caco-2 cell monolayers – an in vitro model of intestinal transport.  J Pharm Pharmacol. 2008;  60 363-370
• 38 Wils P, Warnery A, Phung-Ba V, Legrain S, Scherman D. High lipophilicity decreases drug transport across intestinal epithelial cells.  J Pharm Exp Ther. 1994;  269 654-658