Effects of Bupleuri Radix on the Rat Hypothyroidism Induced by PTU (6-n-propyl-2-thiouracil)

시호가 PTU (6-n-propyl-2-thiouracil)로 유발된 Rat 갑상샘 기능저하증에 미치는 영향

  • Kim, Seong Mo (College of Oriental Medicine, Daegu Haany University) ;
  • Ku, Sae Kwang (College of Oriental Medicine, Daegu Haany University) ;
  • Cho, Su Yeon (College of Oriental Medicine, Daegu Haany University) ;
  • Park, Soo Jin (College of Oriental Medicine, Daegu Haany University)
  • 김승모 (대구한의대학교 한의과대학) ;
  • 구세광 (대구한의대학교 한의과대학) ;
  • 조수연 (대구한의대학교 한의과대학) ;
  • 박수진 (대구한의대학교 한의과대학)
  • Received : 2012.05.24
  • Accepted : 2012.09.17
  • Published : 2012.10.25

Abstract

The object of this study was to evaluate the effect of Bupleuri Radix, aqueous extracts of the root part of Bupleurum falcatum on the 6-n-propyl-2-thiouracil (PTU)-induced rat hypothyroidism. Aqueous extracts of Bupleuri Radix (BR; yield = 11.73%) were administered, once day for 42 days from 2 weeks before start of PTU treatment as an oral dose of 300 and 150 mg/kg (body weight), and hypothyroidism was induced by daily subcutaneous treatment of PTU 10 mg/kg for 28 days. The changes on the body weight, thyroid gland weights, serum thyroid hormone - thyroid stimulating hormone (TSH), triiodothyronine ($T_3$) and thyroxine ($T_4$), serum lipid profiles - total cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL) and triglyceride, liver antioxidant defense system - lipid peroxidation, $H_2O_2$, superoxide dismutase (SOD) and catalase (CAT), serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were observed with histopathology of thyroid glands. Results were compared with $LevoT_4$ 0.5 mg/kg treated rats. As results of PTU treatment, marked decreases of body weights, triglyceride contents, liver CAT activities and changes of serum thyroid hormone levels were observed with increases of serum AST, HDL contents, liver $H_2O_2$ and SOD activities and thyroid gland weight. In addition, marked hyperplasia of follicular cells with decreases of follicular colloid contents and sizes were demonstrated at histopathological inspections. However, these PTU induced hypothyroidism were dose-dependently inhibited by treatment of BR extracts, and BR extracts effectively regulated the hypothyroidism related changes on the antioxidant defense system. The results obtained in this study suggest that BR extracts have favorable effects on the thyroid hormone productions with beneficial effects on the hypothyroidism mediated by the modulatory effects on the antioxidant defense system.

Keywords

Acknowledgement

Supported by : 보건복지부

References

  1. 조보연. 임상갑상선학. 2판. 서울, 고려의학, pp 409-441, 2001.
  2. 杜鎬京. 東醫腎系學. 서울, 東洋醫學硏究院, pp 729, 867-874, 1042, 1059-1065, 1993.
  3. 송영기, 오연상. 갑상선학. 서울, 고려의학, pp 131-188, 223-247, 1995.
  4. Devdhar, M., Ousman, Y.H., Burman, K.D. Hypothyroidism. Endocrinol Metab Clin North Am 36(3):595-615, 2007. https://doi.org/10.1016/j.ecl.2007.04.008
  5. Surks, M.I., Ortiz, E., Daniels, G.H., Sawin, C.T., Col, N.F., Cobin, R.H., Franklyn, J.A., Hershman, J.M., Burman, K.D., Denke, M.A., Gorman, C., Cooper, R.S., Weissman, N.J. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA 291(2):228-238, 2004. https://doi.org/10.1001/jama.291.2.228
  6. Canaris, G.J., Manowitz, N.R., Mayor, G., Ridgway, E.C. The Colorado thyroid disease prevalence study. Arch Intern Med 160(4):526-534, 2000. https://doi.org/10.1001/archinte.160.4.526
  7. Andreoli, T.E., Carpenter, C.J., Plum, F., Smith, L. Cecil Essentials of Medicine. Philadilphia, WB Saunder's Company, pp 436-437, 1986.
  8. Guyton, A.C. Textbook of Medical Physiology. Philadelphia, WB Saunder's Company, pp 906-908, 1986.
  9. Schmidt, R.F., Thews, G. Human Physiology, Berlin Heidelberg: Springer-Verlag, pp 385-386, 1989.
  10. 金祐謙. 內分泌.生殖. 서울, 생명의 이치, pp 60-69, 1994.
  11. 안세영. 갑상선클리닉. 서울, 성보사, pp 132-154, 248, 2004.
  12. Wiersinga, W.M. Thyroid hormone replacement therapy. Horm Res 56(Suppl 1):74-81, 2001.
  13. Das, K., Chainy, G.B. Modulation of rat liver mitochondrial antioxidant defence system by thyroid hormone. Biochim Biophys Acta 1537(1):1-13, 2001. https://doi.org/10.1016/S0925-4439(01)00048-5
  14. Subudhi, U., Das, K., Paital, B., Bhanja, S., Chainy, G.B. Supplementation of curcumin and vitamin E enhances oxidative stress, but restores hepatic histoarchitecture in hypothyroid rats. Life Sci 84(11-12):372-379, 2009. https://doi.org/10.1016/j.lfs.2008.12.024
  15. Sarandol, E., Tas, S., Dirican, M., Serdar, Z. Oxidative stress and serum paraoxonase activity in experimental hypothyroidism: effect of vitamin E supplementation. Cell Biochem Funct 23(1):1-8, 2005. https://doi.org/10.1002/cbf.1119
  16. Cooper, D.S. Antithyroid drugs. New Engl J Med 311: 1353-1362, 1984. https://doi.org/10.1056/NEJM198411223112106
  17. Yang, Y., Gordon, C.J. Regulated hypothermia in the hypothyroid rat induced by administration of propylthiouracil. Am J Physiol 272(5 Pt 2):R1390-R1395, 1997.
  18. O'Connor, J.C., Frame, S.R., Ladics, G.S. Evaluation of a 15-day screening assay using intact male rats for identifying steroid biosynthesis inhibitors and thyroid modulators. Toxicol Sci 69(1):79-91, 2002. https://doi.org/10.1093/toxsci/69.1.79
  19. Carmeli, E., Bachar, A., Barchad, S., Morad, M., Merrick, J. Antioxidant status in the serum of persons with intellectual disability and hypothyroidism: a pilot study. Res Dev Disabil 29(5):431-438, 2008. https://doi.org/10.1016/j.ridd.2007.08.001
  20. Erdamar, H., Demirci, H., Yaman, H., Erbil, M.K., Yakar, T., Sancak, B., Elbeg, S., Biberoglu, G., Yetkin, I. The effect of hypothyroidism, hyperthyroidism, and their treatment on parameters of oxidative stress and antioxidant status. Clin Chem Lab Med 46(7):1004-1010, 2008.
  21. Rayman, M.P., Thompson, A.J., Bekaert, B., Catterick, J., Galassini, R., Hall, E., Warren-Perry, M., Becket,t G.J. Randomized controlled trial of the effect of selenium supplementation on thyroid function in the elderly in the United Kingdom. Am J Clin Nutr 87(2):370-278, 2008. https://doi.org/10.1093/ajcn/87.2.370
  22. Bhanja, S., Chainy, G.B. PTU-induced hypothyroidism modulates antioxidant defence status in the developing cerebellum. Int J Dev Neurosci 28(3):251-262, 2010. https://doi.org/10.1016/j.ijdevneu.2010.01.005
  23. 김동현, 김형민, 류종훈, 엄재영, 김상찬, 양재하, 조민경, 임종필, 홍승헌. 한방약리학. 서울, 신일상사, pp 186-192, 2006.
  24. Yamamoto, M., Kumagai, A., Yamamura, Y. Structure and actions of saikosaponins isolated from Bupleurum falcatum L. I. Anti-inflammatory action of saikosaponins. Arzneimittelforschung 25(7):1021-1023, 1975.
  25. Abe, H., Sakaguchi, M., Yamada, M., Arichi, S., Odashima, S. Pharmacological actions of saikosaponins isolated from Bupleurum falcatum. 1. Effects of saikosaponins on liver function. Planta Med 40(4):366-372, 1980. https://doi.org/10.1055/s-2008-1074987
  26. Yamamoto, M., Kumagai, A., Yamamura, Y. Structure and action of saikosaponins isolated from Bupleurum falcatum L. II. Metabolic actions of saikosaponins, especially a plasma cholesterol-lowering action. Arzneimittelforschung 25(8):1240-1243, 1975.
  27. Abe, H., Sakaguchi, M., Odashima, S., Arichi, S. Protective effect of saikosaponin-d isolated from Bupleurum falcatum L. on $CCl_4$-induced liver injury in the rat. Naunyn Schmiedebergs Arch Pharmacol 320(3):266-271, 1982. https://doi.org/10.1007/BF00510139
  28. Lin, C.C., Chiu, H.F., Yen, M.H., Wu, C.C., Chen, M.F. The pharmacological and pathological studies on Taiwan folk medicine (III): The effects of Bupleurum kaoi and cultivated Bupleurum falcatum var. komarowi. Am J Chin Med 18(3-4):105-112, 1990. https://doi.org/10.1142/S0192415X90000149
  29. Hattori, T., Ito, M., Suzuki, Y. Studies on antinephritic effects of plant components in rats (1). Effects of saikosaponins original-type anti-GBM nephritis in rats and its mechanisms. Nippon Yakurigaku Zasshi 97(1):13-21, 1991. https://doi.org/10.1254/fpj.97.1_13
  30. Sakurai, M.H., Matsumoto, T., Kiyohara, H., Yamada, H. B-cell proliferation activity of pectic polysaccharide from a medicinal herb, the roots of Bupleurum falcatum L. and its structural requirement. Immunology 97(3):540-547, 1999. https://doi.org/10.1046/j.1365-2567.1999.00774.x
  31. Guo, Y., Matsumoto, T., Kikuchi, Y., Ikejima, T., Wang, B., Yamada, H. Effects of a pectic polysaccharide from a medicinal herb, the roots of Bupleurum falcatum L. on interleukin 6 production of murine B cells and B cell lines. Immunopharmacology 49(3):307-316, 2000. https://doi.org/10.1016/S0162-3109(00)00245-9
  32. Matsumoto, T., Sun, X.B., Hanawa, T., Kodaira, H., Ishii, K., Yamada, H. Effect of the antiulcer polysaccharide fraction from Bupleurum falcatum L. on the healing of gastric ulcer induced by acetic acid in rats. Phytother Res 16(1):91-93, 2002. https://doi.org/10.1002/ptr.986
  33. Chang, W.C., Hsu, F.L. Inhibition of platelet activation and endothelial cell injury by flavan-3-ol and saikosaponin compounds. Prostaglandins Leukot Essent Fatty Acids 44(1):51-56, 1991. https://doi.org/10.1016/0952-3278(91)90144-T
  34. Nose, M., Amagaya, S., Ogihara, Y. Corticosterone secretion-inducing activity of saikosaponin metabolites formed in the alimentary tract. Chem Pharm Bull (Tokyo) 37(10):2736-2740, 1989. https://doi.org/10.1248/cpb.37.2736
  35. Niikawa, M., Sakai, Y., Ose, Y., Sato, T., Nagase, H., Kito, H., Sato, M., Mizuno, M. Enhancement of the mutagenicity of Trp-P-1, Trp-P-2 and benzo[a]pyrene by bupleuri radix extract. Chem Pharm Bull (Tokyo) 38(7):2035-2039, 1990. https://doi.org/10.1248/cpb.38.2035
  36. 문진영, 최미정, 남경수, 임종국. 柴胡가 free radical에 의한 脂質過酸化物 生成에 미치는 效果. 東國論集 15: 361-375, 1996.
  37. Matsumoto, T., Moriguchi, R., Yamada, H. Role of polymorphonuclear leucocytes and oxygen-derived free radicals in the formation of gastric lesions induced by HCl/ethanol, and a possible mechanism of protection by anti-ulcer polysaccharide. J Pharm Pharmacol 45(6):535-539, 1993. https://doi.org/10.1111/j.2042-7158.1993.tb05594.x
  38. Kavutcu, M., Canbolat, O., Ozturk, S., Olcay, E., Ulutepe, S., Ekinci, C., Gokhun, I.H., Durak, I. Reduced enzymatic antioxidant defense mechanism in kidney tissues from gentamicin-treated guinea pigs: effects of vitamins E and C. Nephron 72(2):269-274, 1996. https://doi.org/10.1159/000188853
  39. Lowry, O.H., Rosenbrough, N.J., Far,r A.L., Randall, R.J. Protein measurement with the Folin phenol reagent. J Biol Chem 193(1):265-275, 1951.
  40. Jamall, I.S., Smith, J.C. Effects of cadmium on glutathione peroxidase, superoxidase dismutase and lipid peroxidation in the rat heart: a possible mechanism of cadmium cardiotoxicity. Toxicol Appl Pharmacol 80(1):33-42, 1985. https://doi.org/10.1016/0041-008X(85)90098-5
  41. Pick, E., Keisari, Y. Superoxide anion and hydrogen peroxide production by chemically elicited peritoneal macrophages--induction by multiple nonphagocytic stimuli. Cell Immunol. 59(2):301-318, 1981. https://doi.org/10.1016/0008-8749(81)90411-1
  42. Aebi, H. Catalase. In: Bergmeyer HU (Ed.), Methods in Enzymatic Analysis. New York, Academic Press Inc., pp 673-686, 1974.
  43. Nishikimi, M., Rao, N.A, Yagi, K. The occurrence of superoxide anion in the reaction of reduced PMS and molecular oxygen. Biochem Biophys Res Comm 46(2):849-854, 1972. https://doi.org/10.1016/S0006-291X(72)80218-3
  44. Kakkar, P., Das, B., Viswanathan, P.N. Modified spectrophotometric assay of SOD. Indian J Biochem Biophys 21(2):130-132, 1984.
  45. 김민성. 갑상선질환에 대한 形象醫學的연구. 大韓形象醫學會誌 9: 351-392, 2008.
  46. Roti, E., Minelli, R., Gardini, E., Braverman, L.E. The use and misuse of thyroid hormone. Endocr Rev 14(4):401-424, 1993.
  47. Axelstad, M., Hansen, P.R., Boberg, J., Bonnichsen, M., Nellemann, C., Lund, S.P., Hougaard, K.S., Hass, U. Developmental neurotoxicity of propylthiouracil (PTU) in rats: relationship between transient hypothyroxinemia during development and long-lasting behavioural and functional changes. Toxicol Appl Pharmacol 232(1):1-13, 2008. https://doi.org/10.1016/j.taap.2008.05.020
  48. Oner, J., Kukne,r A., Oner, H., Ozan, E., Yekeler, H. Effect of vitamin E on follicular cell proliferation and expression of apoptosis-associated factors in rats with 6-N-propyl-2-thiouracil-induced goitrogenesis. Folia Histochem Cytobiol 41(4):213-217, 2003.
  49. Dory, L., Roheim, P.S. Rat plasma lipoproteins and apolipoproteins in experimental hypothyroidism. J Lipid Res 22(2):287-296, 1981.
  50. Frost, P.H., Havel, R.J. Rationale for use of non-high-density lipoprotein cholesterol rather than low-density lipoprotein cholesterol as a tool for lipoprotein cholesterol screening and assessment of risk and therapy. Am J Cardiol 81(4A):26B-31B, 1998. https://doi.org/10.1016/S0002-9149(98)00034-4
  51. Ito, M., Arishima, T., Kudo, T., Nishihara, E., Ohye, H., Kubota, S., Fukata, S., Amino, N., Kuma, K., Sasaki, I., Hiraiwa, T., Hanafusa, T., Takamatsu, J., Miyauchi, A. Effect of levo-thyroxine replacement on non-high-density lipoprotein cholesterol in hypothyroid patients. J Clin Endocrinol Metab 92(2):608-611, 2007. https://doi.org/10.1210/jc.2006-1605
  52. Teixeira, P.D.F., Reuters, V.S., Ferreira, M.M., Almeida, C.P., Reis, F.A., Buescu, A., Costa, A.J., Vaisman, M. Lipid profile in different degrees of hypothyroidism and effects of levothyroxine replacement in mild thyroid failure. Transl Res 151(4):224-231, 2008. https://doi.org/10.1016/j.trsl.2007.12.006
  53. Andreoli, T.E., Carpenter, C.J., Plum, F., Smith, L. Cecil Essentials of Medicine, Philadilphia: WB Saunder's Company, pp 436-437, 1986.
  54. Feng, X., Jiang, Y., Melzer, P., Yen, P.M. Thyroid hormone regulation of hepatic genes in vivo detected by complementary DNA microarray. Mol Endocrinol 14(7):947-955, 2000. https://doi.org/10.1210/me.14.7.947
  55. Simon-Giavarotti, K.A., Giavarotti, L., Gomes, L.F., Lima, A.F., Veridiano, A.M., Garcia, E.A., Mora, O.A., Fernandez, V., Videla, L.A., Junqueira, V.B. Enhancement of lindane-induced liver oxidative stress and hepatotoxicity by thyroid hormone is reduced by gadolinium chloride. Free Radic Res 36(10):1033-1039, 2002. https://doi.org/10.1080/1071576021000028280
  56. Amin, A., Hamza, A.A. Oxidative stress mediates drug-induced hepatotoxicity in rats: a possible role of DNA fragmentation. Toxicology 208(3):367-375, 2005. https://doi.org/10.1016/j.tox.2004.11.039
  57. Chattopadhyay, S., Sahoo, D.K., Subudhi, U., Chainy, G.B. Differential expression profiles of antioxidant enzymes and glutathione redox status in hyperthyroid rats: a temporal analysis. Comp Biochem Physiol C Toxicol Pharmacol 146(3):383-391, 2007. https://doi.org/10.1016/j.cbpc.2007.04.010
  58. Williams, K.V., Nayak, S., Becker, D., Reyes, J., Burmeister, L.A. Fifty years of experience with propylthiouracil-associated hepatotoxicity: what have we learned? J Clin Endocrinol Metab 82(6):1727-1733, 1997. https://doi.org/10.1210/jc.82.6.1727