DOI QR코드

DOI QR Code

Oral Single Dose Toxicity Study of Low Molecular Fucoidan in Mice

  • Published : 2008.03.31

Abstract

This study was conducted to obtain information of the oral dose toxicity of low molecular fucoidan (LMF) in male and female mice. In order to calculate 50% lethal dose ($LD_{50}$) and approximate lethal dose (LD), test material was once orally administered to male and female ICR mice at dose levels of 2000, 1000, 500, 250, 125 and 0 (vehicle control) mg/kg (body wt.). The mortality and the changes on body weight, clinical signs, gross observation and organ weight and histopathology of principle organs were monitored 14 days after LMF treatment. We could not find any mortalities, clinical signs, body weight changes and gross findings. In addition, significant changes in the organ weight and histopathology of principal organs were not observed except for some sporadic findings. The results obtained in this study suggest that LMF may not be toxic in mice and may be therefore safe for clinical use. The $LD_{50}$ and approximate LD in mice after single oral dose of LMF were considered over 2000 mg/kg in both female and male mice.

Keywords

References

  1. Alkhatib, B., Freguin-Bouilland, C., Lallemand, F., Henry, J.P., Litzler, P.Y., Marie, J.P., Richard, V., Thuillez, C. and Plissonnier, D. (2006). Low molecular weight fucan prevents transplant coronaropathy in rat cardiac allograft model. Transpl. Immunol., 16, 14-19 https://doi.org/10.1016/j.trim.2006.03.003
  2. Banks, W.J. (1986). Female reproductive system in Applied veterinary histology (Banks, W.J. Ed.). Williams & Wilkins, Baltimore, pp. 506-526
  3. Béress, A., Wassermann, O., Tahhan, S., Bruhn, T., Beress, L. and Kraiselburd, E.N. (1993). A new procedure for the isolation of anti-HIV compounds (polysaccharide and polyphenols) from the marine algae Fucus vesiculosus. J. Nat. Prod., 56, 478-488 https://doi.org/10.1021/np50094a005
  4. Berteau, O. and Mulloy, B. (2003). Sulfated fucans, fresh perspectives: structures, functions, and biological properties of sulfated fucans and an overview of enzymes active toward this class of polysaccharide. Glycobiology, 13, 29R-40R https://doi.org/10.1093/glycob/cwg058
  5. Blondin, C., Chaubet, F., Nardella, A., Sinquin, C. and Jozefonvicz, J. (1996). Relationships between chemical characteristics and anticomplementary activity of fucans. Biomaterials Biomaterials, 17, 597-603 https://doi.org/10.1016/0142-9612(96)88710-2
  6. Bojakowski, K., Abramczyk, P., Bojakowska, M., Zwolinska, A., Przybylski, J. and Gaciong, Z. (2001). Fucoidan improves the renal blood flow in the early stage of renal ischemia/reperfusion injury in the rat. J. Physiol. Pharmacol., 52, 137-143
  7. Colliec, S., Fischer, A.M., Tapon-Bretaudiere, J., Boisson, C., Durand, P. and Jozefonvicz, J. (1991). Anticoagulant properties of a fucoidan fraction. Thromb. Res., 64, 143-154 https://doi.org/10.1016/0049-3848(91)90114-C
  8. Dourish, C.T. (1987). Effects of drugs on spontaneous motor activity in Experimental Psychopharmacology (Greenshaw, A.J. and Dourish, C.T. Eds.). Humana Press, Clifton, pp. 325-334
  9. Dubois, M., Gilles, K.A., Hamilton, J.K., Rebers, P.A. and Smith, F. (1956). Colorimetric method for determination of sugars and related substances. Anal. Chem., 28, 350-354 https://doi.org/10.1021/ac60111a017
  10. Farndale, R.W., Buttle, D.J. and Barret, A.J. (1986). Improved quantification and discrimination of sulphated glycosaminoglycans by use of dimethylmethylene blue. Biochim. Biophys. Acta, 883, 173-177 https://doi.org/10.1016/0304-4165(86)90306-5
  11. Fréguin-Bouilland, C., Alkhatib, B., David, N., Lallemand, F., Henry, J.P., Godin, M., Thuillez, C. and Plissonnier, D. (2007). Low molecular weight fucoidan prevents neointimal hyperplasia after aortic allografting. Transplantation, 83, 1234-1241 https://doi.org/10.1097/01.tp.0000261109.97928.9c
  12. Haroun-Bouhedja, F., Ellouali, M., Sinquin, C. and Boisson-Vidal, C. (2000). Relationship between sulfate groups and biological activities of fucans. Thromb. Res., 100, 453-459 https://doi.org/10.1016/S0049-3848(00)00338-8
  13. Hodge, H.C. and Sterner, J.H. (1949). Tabulation of toxicity classes, Am. Ind. Hyg. Q., 10, 93
  14. Irwin, S. (1968). Comprehensive observational assessment: Ia. A systemic, quantitative procedure for assessing the behavioral and physiological state of the mouse. Psychopharmacology, 13, 222-257 https://doi.org/10.1007/BF00401402
  15. Jung, Y.M., Kim, T.K., Park, D.C. and Lee, Y.H. (2007). Bioavailable Fucoidan and Methods for Preparing the Same, Korean Patent 0705975
  16. Korea Food and Drug Administration. (2005). Testing Guidelines for Safety Evaluation of Drugs (Notification No. 2005-60, issued by the Korea Food and Drug Administration on October 21, 2005)
  17. Lake, A.C., Vassy, R., Di Benedetto, M., Lavigne, D., Le Visage, C., Perret, G.Y. and Letourneur, D. (2006). Low molecular weight fucoidan increases VEGF165-induced endothelial cell migration by enhancing VEGF165 binding to VEGFR-2 and NRP1. J. Biol. Chem., 281, 37844-37852 https://doi.org/10.1074/jbc.M600686200
  18. Lee, H.S., Lee, I.G. and Ku, S.K. (2006). Single oral dose toxicity study of water extracts of Picrorrhiza Rhizoma in mice. J. Toxicol. Pub. Health, 22, 117-126
  19. Lee, H.S., Yang, K.J., Shin, H.D., Park, B.R., Son, C.W., Jang, H.J., Park, D.C., Jung, Y.M. and Ku, S.K. (2005). Single oral dose toxicity study of polycan, $\beta$-glucan originated from Aureobasidium in mice. J. Toxicol. Pub. Health, 21, 361-365
  20. Lee, Y.H., Son, M.K., Jung, Y.M., Kim, T.K., Park, D.C., Lee, H.S., Kim, P.S. and Ku, S.K. (2007). Mouse single oral dose toxicity studies of PGB-1, a novel polyglucosamine polymer produce from Enterobacter sp. BL-2. J. Toxicol. Pub. Health, 23, 373-382 https://doi.org/10.5487/TR.2007.23.4.373
  21. Li, N., Zhang, Q. and Song, J. (2005): Toxicological evaluation of fucoidan extracted from Laminaria japonica in Wistar rats. Food Chem. Toxicol., 43, 421-426 https://doi.org/10.1016/j.fct.2004.12.001
  22. Marais, M.F. and Joseleau, J.P. (2001). A fucoidan fraction from Ascophyllum nodosum. Carbohydr. Res., 336, 155-159 https://doi.org/10.1016/S0008-6215(01)00257-9
  23. Matsubara, K., Xue, C., Zhao, X., Mori, M., Sugawara, T. and Hirata, T. (2005). Effects of middle molecular weight fucoidans on in vitro and ex vivo angiogenesis of endothelial cells. Int. J. Mol. Med., 15, 695-699
  24. Nardella, A., Chaubet, F., Sinquin, C., Colliec Jouault, S., Boisson-Vidal, C., Durand, P. and Jozefonvicz, J. (2000). Method for Obtaining Sulfated Polysaccharides, United States Patent 6,028,191
  25. Organization for Economic Co-Operation and Development (Ed.). (2001): OECD guideline (423) for testing of chemicals-acute oral toxicity-acute toxic class method
  26. Patankar, M.S., Oehninger, S., Barnett, T., Williams, R.L. and Clark, G.F. (1993). A revised structure for fucoidan may explain some of its biological activities. J. Biol. Chem., 268, 21770-21776
  27. Plata, E.J. and Murphy, W.H. (1972). Growth and haematologic properties of the BALB/wm strain of inbred mice. ., 22, 712-720
  28. Senni, K., Gueniche, F., Foucault-Bertaud, A., Igondjo-Tchen, S., Fioretti, F., Colliec-Jouault, S., Durand, P., Guezennec, J., Godeau, G. and Letourneur, D. (2006). Fucoidan a sulfated polysaccharide from brown algae is a potent modulator of connective tissue proteolysis. Arch. Biochem. Biophys. 445, 56-64 https://doi.org/10.1016/j.abb.2005.11.001
  29. Shimizu, J., Wada-Funada, U., Mano, H. Matahira, Y. Kawaguchi, M. and Wada, M. (2005). Proportion of murine cytotoxic T cells is increased by high molecular-weight fucoidan extracted from Okinawa mozuku (Cladosiphon okamuranus). J. Health Sci., 51, 394-397 https://doi.org/10.1248/jhs.51.394
  30. US Environmental Protection Agency. (1998). Health Effects Test Guidelines OPPTS 870.100, Acute Toxicity Testing Background, US EPA August, Washington, USA
  31. Yamaguchi, C., Fujita, S., Obara, T. and Ueda, T. (1983). Effects of room temperature on reproduction, body weight and organ weights, food and water intakes, and hematology in mice. Exp. Anim., 32, 1-11 https://doi.org/10.1538/expanim1978.32.1_1
  32. Zemani, F., Benisvy, D., Galy-Fauroux, I., Lokajczyk, A., Colliec-Jouault, S., Uzan, G., Fischer, A.M. and Boisson-Vidal, C. (2005). Low-molecular-weight fucoidan enhances the proangiogenic phenotype of endothelial progenitor cells. Biochem. Pharmacol., 70, 1167-1175 https://doi.org/10.1016/j.bcp.2005.07.014

Cited by

  1. Green technologies for cascade extraction of Sargassum muticum bioactives pp.1573-5176, 2019, https://doi.org/10.1007/s10811-018-1725-6