Laboraroty Animal Research

Korean Association for Laboratory Animal Science (한국실험동물학회)
권호 표지

Effect of Red Ginseng Extract on Cyclophosphamide Teratogenicity in Rats

랫드에서 cyclophosphamide로 유발된 기형에 대한 홍삼추출물의 효과

Lee, Yea-Eun;Byun, Sang-Kuk;Shin, Sun-Hee;Jang, Ja-Young;Choi, Byong-Il;Park, Dong-Sun;Jeon, Jeong-Hee;Lim, Sook-Hee;Hwang, Seock-Yeon;Kim, Yun-Bae
이예은;변상국;신선희;장자영;최병일;박동선;전정희;임숙희;황석연;김윤배

  • Published : 20050900
⟨ Previous Next ⟩

Abstract

Effects of repeated treatment with red ginseng extract on the teratogenicity of cyclophosphamide were investigated in rats. Pregnant rats were orally treated with red ginseng extract (100 or 500 mg/kg) for 7 days, from days 6 to 12 of gestation, and intraperitoneally challenged with cyclophosphamide (12 mg/kg) 1 hr after the final treatment. On day 20 of gestation, the maternal and fetal abnormalities were examined. Cyclophosphamide, administered on day 12 of gestation, reduced fetal and placental weights to 70 - 80% and 50% of control, respectively, and induced 80% of malformations in live fetuses. The malformations include cranial defect and exencephaly (80.0%), micrognathia and tongue extrusion (20.9%), edema and hematoma (29.1%), ventricular dilatation (16.7%), vertebral defects (78.6%), costal defects (44.6%), and delayed skeletal ossification (80.4%). Interestingly, red ginseng extract further decreased the fetal weights and remarkably aggravated fetal defects in a dose-dependent manner, resulting in 96.7% of cranial defect and exencephaly, 64.8% of micrognathia and tongue extrusion, 49.5% of limb defects, 90.7% of vertebral defects, 88.4% of costal defects, and 83.7% of delayed skeletal ossification in rats administered with 500 mg/kg of red ginseng extract followed by cyclophosphamide. These results demonstrate that a long-term pretreatment with red ginseng extract substantially enhance body weight loss and malformations of fetuses induced by intrauterine exposure to cyclophosphamide.

Keywords

References

  1. Abbott, B.D. (1995) Review of the interaction between TCDD and glucocorticoids in embryonic palate. Toxicology 105, 365-373 https://doi.org/10.1016/0300-483X(95)03234-7
  2. Ashby, R., Davis, L., Dewhurst, B.B., Espinal, R., Penn, R.N. and Upshall, D.G (1976) Aspects of the teratology of cyclophosphamide (NSC-26271). Cancer Treatm. Rep. 60, 477-482
  3. Chahoud, I., Kuriyama, S.N. and Paumgartten, F.J.R. (2002) Maternal protein-and-energy restriction reduces the developmental toxicity of cyclophosphamide and hydroxyuria in rats. Toxicology 179, 137-149 https://doi.org/10.1016/S0300-483X(02)00373-6
  4. Chan, L.Y., Chiu, P.Y. and Lau, T.K. (2003) An in-vitro study of ginsenoside RbI-induced teratogenicity using a whole rat embryo culture model. Human Reprod. 18, 2166-2168 https://doi.org/10.1093/humrep/deg401
  5. Chan, L.Y., Chiu, P.Y. and Lau, T.K. (2004) Embryotoxicity study of ginsenoside Rc and Re in in vitro rat whole embryo culture. Reprod. Toxicol. 19, 131-134 https://doi.org/10.1016/j.reprotox.2004.06.001
  6. Chang, T.K.H., Chen, J. and Benetton, S.A. (2002) In vitro effect of standardized ginseng extracts and individual ginsenosides on the catalytic activity of human CYP1A1, CYP1A2, and CYPIB. Drug Metab. Disposit. 30, 384
  7. Chen, B., Cyr, D.G and Hales, B.F. (1994) Role of apoptosis in mediating phosphoramide mustard-induced rat embryo malformations in vitro. Teratology 50, 1-12 https://doi.org/10.1002/tera.1420500102
  8. Cox, P.J. (1979) Cyclophosphamide cystitis-identification of acrolein as the causative agent. Biochem. Pharmacol. 28, 2045-2049 https://doi.org/10.1016/0006-2952(79)90222-3
  9. Czeizel, A.E. (2004) The primary prevention of birth defects: multivitamins or folic acid? Int. J. Med. Sci. 1, 50-61
  10. Dawson, A.B. (1926) A note on the staining of the skeleton of cleared specimens with Alizarin red S. Stain Technol. 1, 123-124
  11. Eriksson, U.J. and Borg, L.A. (1991) Protection by free oxygen radical scavenging enzymes against glucose-induced embryonic malformations in vitro. Diabetologia 34, 325-331 https://doi.org/10.1007/BF00405004
  12. Eriksson, U.J. and Siman, C.M. (1996) Pregnant diabetic rats fed the antitoxidant butylated hydroxytoluene show decreased occurrence of malformations in offspring. Diabetes 45, 1497-1502 https://doi.org/10.2337/diabetes.45.11.1497
  13. Fantel, G.E., Greenaway. J.C., Juchau. M.R. and Shepard, T.H. (1979) Teratogenic bioactivation of cyclophosphamide in vitro. Life Sci. 25, 67-72 https://doi.org/10.1016/0024-3205(79)90491-0
  14. Gibson, J.E. and Becker, B.A. (1968) The teratogenicity of cyclophosphamide in mice. Cancer Res. 28, 475-480
  15. Gomes-Carneiro, M.R., De-Oliveira, A.C.A.X., De-Carvalho, R.R., Araujo, I.B., Souza, C.A.M., Kuriyama, S.N. and Paumgartten, F.J.R. (2003) Inhibition of cyclophophamide-induced teratogenesis by $\beta$-ionone. Toxicol. Lett. 138, 205-213 https://doi.org/10.1016/S0378-4274(02)00413-7
  16. Hales, B.F. (1981) Modification of the teratogenicity and mutagenicity of cyclophosphamide with thiol compounds. Teratology 23, 373-381 https://doi.org/10.1002/tera.1420230312
  17. Hales, B.F. (1989) Effects of phosphoramide mustard and acrolein, cytotoxic metabolites of cyclophosphamide, on mouse limb development in vitro. Teratology 40, 11-20 https://doi.org/10.1002/tera.1420400103
  18. Han, S.-Y., Shin, J-H., Kwon, S.C., Kang, M.O., Lee, Y.M., Kim, P.G., Yang, M., Park, K.L. and Jang, S.J. (1995) Effects of enzyme inducers and glutathione on the embryotoxicity of cyclophosphamide in cultured rat embryos. Korean J. Toxicol. 11, 31-36
  19. Hwang, S.-Y., Kang, EX., Wee, J.J., Kyung, J.-S., Cho, J.-H. and Kim, Y.-B. (2004a) Protective effect of red ginseng saponin on potassium bromate-induced oxidative damage of kidneys and liver in rats. Korean J. Lab. Anim. Sci. 20, 260-266
  20. Hwang, S.-Y., Kim, W.-J., Wee, J.-J., Choi, J.-S. and Kim, S.-K. (2004b) Panax ginseng improves survival and sperm quality in guinea pigs exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. BJU Int. 93, 663-668
  21. Kang, J.-K., Lee, Y.-J, No, K.-O., Jung, E.-Y., Sung, J-H., Kim, Y.B. and Nam, S.-Y. (2002) Ginseng intestinal metabolite-1 (GIM-I) reduces doxorubicin toxicity in the mouse testis. Reprod. Toxicol. 16, 291-298 https://doi.org/10.1016/S0890-6238(02)00021-7
  22. Kang, H.-G, Lee, C.-H., Lee, K.-C., Lee, J.-E., Kim, H.-J., Choi, E.K., Yun, Y.W. and Kim, Y.-B. (2003) Effects of butylated hydroxyanisole on glutathione S-transferases activity and cyclophosphamide-induced teratogenicity in rats. J. Toxicol. Pub. Health 19, 181-187
  23. Kim, H.-J., Lee, J-E., Choi, E.-K. and Kim, Y.-B. (2003) Effects of butylated hydroxyanisole on glutathione S-transferases activity and teratogenicity of cyclophosphamide in mice. Korean J. Lab. Anim. Sci. 19, 120-125
  24. Kim, J.-C., Lim, K.-H., Suh, J.-E., Wee, J.-J., Nam, K.-Y. and Chung, M.-K. (2001) Effects of Korean red ginseng water extract on bisphenol A-induced developmental toxicity in rats. J. Toxicol. Pub. Health 17, 225-234
  25. Kim, W., Hwang, S., Lee, H., Song, H. and Kim, S. (1999) Panax ginseng protects the testis against 2,3,7,8-tetrachlorodibenzo-p-dioxin induced testicular damage in guinea pigs. BJU Int. 83, 842-849 https://doi.org/10.1046/j.1464-410x.1999.00046.x
  26. Lee, H.-C., Hwang, S.-G., Leem Y.-G., Sohn, H.-O., Lee, D.-W, Hwang, S.-Y., Kwak, Y.-S., Wee, J.-J., Joo, W.-H., Cho, Y.-K. and Moon, J.-Y. (2002) In vivo effects of Panax ginseng extracts on the cytochrome P450-dependent monooxygenase system in the liver of 2,3,7,8-tetrachlorodibenzo-p-dioxin-exposed guinea pigs. Life Sci. 71, 759-769 https://doi.org/10.1016/S0024-3205(02)01742-3
  27. Liu, Y., Li, W., Li, P., Deng, M.-C., Yang, S.-L. and Yang, L. (2004) The inibitory effect of intestinal bacterial metabolite of ginsenisides on CYP3A activity. Biol. Pharm. Bull. 27, 1555-1560 https://doi.org/10.1248/bpb.27.1555
  28. Manson, J.M. and Kang, Y.J. (1989) The methods for assessing female reproductive and developmental toxicology. In Principles and Methods of Toxicology (Hayes, A.W. ed.), pp. 311-359, Raven Press, New York
  29. Marinello, A.J., Bansal, S.K., Paul, B., Koser, P.L., Love, J., Struck, R.F. and Gurtoo, H.L. (1984) Metabolism and binding of cyclophosphamide and its metabolite acrolein to rat hepatic microsomal cytochrome P-450. Cancer Res. 44, 4615-4621
  30. Meirow, D., Epstein, M., Lewis, H., Nugent, D. and Gosden, R.G. (2001) Administration of cyclophosphamide at different stages of follicular maturation in mice: effects on reproductive performance and fetal malformations. Human Reprod. 16, 632-637 https://doi.org/10.1093/humrep/16.4.632
  31. Mirkes, P.E. (1985) Cyclophosphamide teratogenesis: a review. Teratogen. Carcinogen. Mutagen. 5, 75-88 https://doi.org/10.1002/tcm.1770050202
  32. Mirkes, P.E., Fantel, A.G., Greenaway, J.C. and Shepard, T.H. (1981) Teratogenicity of cyclophosphamide metabolites: phosphoramide mustard, acrolein and 4-ketocyclophosphamide in rat embryos cultured in vitro. Toxicol. Appl. Pharmacol. 58, 322-330 https://doi.org/10.1016/0041-008X(81)90436-1
  33. Neubert, D. and Barrach, H.-J. (1977) Organotropic effects and doseresponse relationship in teratology. In Methods in Prenatal Toxicology (Neubert, D. ed.), pp. 405-412, Georg Thieme Publishers, Stuttgart
  34. Nishimura, K.A. (1974) Microdissection method for detecting theracic visceral malformations in mouse and rat fetuses. Congenit. Anom. 14, 23-40
  35. Park, K.L., Han, S.-Y., Kim, P.G., Lee, Y.-M., Shin, J.-H. and Jang, S.J. (2001) Effects of gamma-irradiated Korean ginseng on fertility and general reproductive toxicity in rats. J. Toxicol. Pub. Health 17, 97-106
  36. Pitt, J.A., Buckalew, A.R., House, D.E. and Abbott, B.D. (2000) Adrenocorticotropin (ACTH) and corticosterone secretion by perifused pituitary and adrenal glands from rodents exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Toxicology 151, 25-35 https://doi.org/10.1016/S0300-483X(00)00257-2
  37. Rogers, J.M. and Kavlock, R.J. (2001) Developmental toxicology. In Casarett & Doull's Toxicology (Klaassen, C.D. ed.), 6th ed., pp. 351-386, McGraw-Hill, New York
  38. Roh, Y.W., Ji, H..J., Chai, H.-Y., Hwang, S.-Y., Nam, S.-Y., Hong, J.T., Sung, J.H., Kim, H.-K., Kang, H.-G., Kim, Y.-B. and Kang, J.-K. (2004) Antitumor and cardioprotective effects of a ginseng intestinal metabolite in combination with doxorubicin in sarcoma-180 tumor-bearing mice. Korean J. Lab. Anim. Sci. 20, 348-356
  39. Shah, R.M., Izadnegahdar, M.F., Henh, B.M. and Young, A.V. (1996) In vivolin vitro studies on the effects of cyclophosphamide on growth an differentiation of hamster palate. Anticancer Drugs 7, 204-212 https://doi.org/10.1097/00001813-199602000-00010
  40. Sieber, S.M. and Adamson, R.H. (1975) Toxicity of antineoplastic agents in man: chromosome aberrations, antifertility effects, congenital malformations, and carcinogenic potential. Adv. Cancer Res. 22, 57-155
  41. Slott, V.L. and Hales, B.F. (1987) Enhancement of embryotoxicity of acrolein, but not phosphoramide mustard, by glutathione depletion in rat embryos in vitro. Biochem. Pharmacol. 36, 2019-2025 https://doi.org/10.1016/0006-2952(87)90503-X
  42. Slott, V.L. and Hales, B.F. (1988) Role of the 4-hydroxy intermediate in the in vitro embryotoxicity of cyclophosphamide and dechlorocyclophosphamide. Toxicol. Appl. Pharmacol. 92, 170-178 https://doi.org/10.1016/0041-008X(88)90377-8
  43. Ujhazy, E., Balonova, T., Durisova, M., Gajdosik, A., Jansak, J. and Molnarova, A. (1993) Teratogenicity of cyclophosphamide in New Zealand white rabbits. Neoplasma 40, 45-49
  44. Wexler, P. (1998) Encyclopedia of Toxicology, vol. 1. pp. 392-393, Academic Press, New York
  45. Wilson, J.G. (1965) Methods for administering agents and detecting malformations in experimental animals. In Teratology. Principles and Techniques (Wilson, J.G. ed.), pp. 262-277, University of Chicago Press, Chicago
  46. Yang, X., Borg, L.A.K., Siman, C.M. and Eriksson, U.J. (1998) Maternal antioxidant treatments prevent diabetes-induced alterations of mitochondrial morphology in rat embryos. Anatom. Rep. 251, 303-315 https://doi.org/10.1002/(SICI)1097-0185(199807)251:3<303::AID-AR5>3.0.CO;2-W
  47. Yu, L.J., Drewers, P., Gustafsson, K., Brain, E.G.C., Hecht, J.E.D. and Waxman, D.J. (1999) In vivo modulation of alternative pathways of P-450-catalyzed cyclophosphamide metabolism: Impact on pharmacokinetics and antitumor activity. J. Pharmacol. Exp. Ther. 288, 928-937
  48. Zemlickis, D., Lishner, M., Erlich, R. and Koren, G. (1993) Teratogenicity and carcinogenicity in a twin exposed in utero to cyclophosphamide. Teratogen. Carcinogen. Mutagen. 13, 139-143 https://doi.org/10.1002/tcm.1770130304
  49. Zinke, H. and Woods, J.E. (1977) Donor pretreatment in cadaver renal transplantation. Surgery Gynec. Obstet. 145, 183-188