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

 

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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.

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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 5 Mukherjee P K, Kumar V, Houghton P J. Screening of Indian medicinal plants for acetylcholinesterase inhibitory activity.  Phytother Res. 2007;  21 1142-1145
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 10 Wang Y, Yang X W. Quantitative determination of neolignanoids in the seeds of Myristica fragrans.  Modern Chin Med. 2008;  10 10-13
  PubMedGoogle Scholar
• 11 Yang X W, Huang X, Ahmat M. New neolignan from seed of Myristica fragrans.  China J Chin Mater Med. 2008;  33 397-402
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 17 Isogai A, Suzuki A, Tamura S. Structures of dimeric from Myristica fragrans Houtt.  Agric Biol Chem. 1973;  37 193-194
  PubMedGoogle Scholar
• 18 Li F, Yang X W. Three new neolignans from the Aril of Myristica fragrans.  Helv Chim Acta. 2007;  90 1491-1496
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  Article in Thieme ConnectPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 23 Li F, Yang X W. Determination of dehydrodiisoeugenol in rat tissues using HPLC method.  Biomed Chromatogr. 2008;  22 1202-1212
  PubMedGoogle Scholar
• 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
  Article in Thieme ConnectPubMedGoogle Scholar
• 25 Kasahara H, Miyazawa M, Kameoka H. Biotransformation of an acyclic neolignan in rats.  Phytochemistry. 1995;  38 343-346
  CrossrefPubMedGoogle Scholar
• 26 Li F, Yang X W. Biotransformation of myrislignan by rat liver microsomes in vitro.  Phytochemistry. 2008;  69 765-771
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 33 Sharom F J. The P-glycoprotein efflux pump: how does it transport drugs?.  J Membr Biol. 1997;  160 161-175
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar

Prof. Dr. Xiu-Wei Yang

State Key Laboratory of Natural and Biomimetic Drugs
School of Pharmaceutical Sciences
Peking University

38 Xueyuan Road

Haidian District

100191 Beijing

China

Phone: + 86 10 82 80 51 06

Fax: + 86 10 82 80 27 24

Email: xwyang@bjmu.edu.cn