A 90-day repeated-dose oral toxicity study on Chelidonium majus extract in Fischer 344/N rats

백굴채(Chelidonium majus) 추출물의 Fischer 344/N 랫드를 이용한 90일간 반복 경구투여 독성시험

  • Accepted : 2009.03.24
  • Published : 2009.03.30

Abstract

This study was performed to evaluate repeated-dose oral toxicities of Chelidonium majus extract in Fischer 344/N rats. Chelidonium majus extract was administered orally to rats at dose levels of 0, 25, 74, 222, 666 and 2,000 mg/kg/day. Each group consisted of 10 rats of each gender. The Chelidonium majus extract was given once a day, 5 times a week, for 90 day repeatedly. This study was conducted in accordance with the Protocol of Korea National Toxicology Program (issued by National Institute of Toxicological Research) and The Standards of Toxicity Study for Medicinal Products (issued by Korea Food and Drug Administration). In the present study, There were no toxicologically significant changes in mortality, clinical signs, body weight gains, ophthalmoscopy, urine analysis, hematology, serum biochemistry, necropsy findings, organ weights, histopathology, estrus cycle and sperm examination of all animals treated with Chelidonium majus extract. These results suggest that the oral no observed adverse-effect level of the test item, Chelidonium majus extract, in rats is higher than 2,000 mg/kg/day in both genders. The target organs were not established.

Keywords

Acknowledgement

Supported by : 식품의약품안전청

References

  1. 국립독성연구원. KNTP 독성시험 프로토콜. 국립독성연구원, 서울, 2005
  2. 김수철, 안상덕, 이상래. 원색 백두산자원식물. 제 1판. p.303, 아카데미서적, 서울, 1994
  3. 식품의약품안전청. 의약품등의독성시험기준 (고시 제2005-60 호). 식품의약품안전청, 서울, 2005
  4. 식품의약품안전청. 비임상시험관리기준 (고시 제2005-79 호). 식품의약품안전청, 서울, 2005
  5. Attele AS, Wu JA, Yuan CS. Ginseng pharmacology:multiple constituents and multiple actions. BiochemPharmacol 1999, 58, 1685-1693 https://doi.org/10.1016/S0006-2952(99)00212-9
  6. Benninger J, Schneider HT, Schuppan D, KirchnerT, Hahn EG. Acute hepatitis induced by greatercelandine (Chelidonium majus). Gastroenterology 1999,117, 1234-1237 https://doi.org/10.1016/S0016-5085(99)70410-5
  7. Biswas SJ, Khuda-Bukhsh AR. Effect of ahomeopathic drug, Chelidonium, in amelioration of p-DAB induced hepatocarcinogenesis in mice. BMCComplement Altern Med 2002, 2, 4 https://doi.org/10.1186/1472-6882-2-4
  8. Boorman GA, Eustis SL, Elwell MR, MontgomeryCA, Mackenzie WF. Pathology of the Fischer Rat. pp.127-154. Academic Press, San Diego, 1990
  9. Chung HS, An HJ, Jeong HJ, Won JH, Hong SH,Kim HM. Water extract isolated from Chelidonium majus enhances nitric oxide and tumour necrosis factor alpha production via nuclear factor-kappaB activationin mouse peritoneal macrophages. J Pharm Pharmacol2004, 56, 129-134 https://doi.org/10.1211/0022357022467
  10. Colombo ML, Bosisio E. Pharmacological activities of Chelidonium majus L. (Papaveraceae). Pharmacol Res1996, 33, 127-134 https://doi.org/10.1006/phrs.1996.0019
  11. Crijns AP, de Smet PA, van den Heuvel M, Schot BW, Haagsma EB. Acute hepatitis after use of a herbalpreparation with greater celandine (Chelidonium majus).Ned Tijdschr Geneeskd 2002, 146, 124-128
  12. Duke JA. CRC Handbook of Medicinal Herbs. p.113, CRC Press, Boca Raton, 1985
  13. Etxenagusia MA, Anda M, Gonzalez-Mahave I,Fernandez E, Fernandez de Corres L. Contactdermatitis from Chelidonium majus (greater celandine).Contact Dermatitis 2000, 43, 47
  14. Flood MT, Kondo M. Toxicity evaluation of a betagalactosidasepreparation produced by Penicilliummulticolor. Regul Toxicol Pharmacol 2004, 40, 281-292 https://doi.org/10.1016/j.yrtph.2004.07.011
  15. Gadzikowska M, Grynkiewicz G. Commentary on thechromatographic retention of Chelidonium alkaloids.Acta Chrom 2001, 11, 62-74
  16. Greaves P. Histopathology of Preclinical Toxicity Studies: Interpretation and Relevance in Drug Safety Evaluation. 2nd ed. pp. 254-676, Elsevier, Amsterdam, 2000
  17. Greving I, Meister V, Monnerjahn C, Muller KM,May B. Chelidonium majus: a rare reason for severehepatotoxic reaction. Pharmacoepidemiol Drug Saf1998, 7 (Suppl 1), S66-69 https://doi.org/10.1002/(SICI)1099-1557(199808)7:1+3.3.CO;2-7
  18. Hruby R. Ukrain: acute toxicity after intravenous,intramuscular and oral administration in rats. DrugsExp Clin Res 2000, 26, 157-161
  19. Jakkula M, Boucher TA, Beyendorff U, Conn SM,Johnson JE, Nolan CJ, Peine CJ, Albrecht JH. Arandomized trial of Chinese herbal medicines for thetreatment of symptomatic hepatitis C. Arch Intern Med2004, 164, 1341-1346 https://doi.org/10.1001/archinte.164.12.1341
  20. Jang IS, Yang CS, Lee SD, Han CH. A review ofherbal medicinal products associated with toxic eventsin Korea. J Kor Oriental Med 2007, 28, 1-10
  21. Jang SI, Kim BH, Lee WY, An SJ, Choi HG, JeonBH, Chung HT, Rho JR, Kim YJ, Chai KY.Stylopine from Chelidonium majus inhibits LPSinducedinflammatory mediators in RAW 264.7 cells.Arch Pharm Res 2004, 27, 923-929 https://doi.org/10.1007/BF02975845
  22. Kery A, Horvath J, Nasz I, Verzar-Petri G, Kulcsar G, Dan P. Antiviral alkaloid in Chelidonium majus L. Acta Pharm Hung 1987, 57, 19-25
  23. Kim JH, Kim YO, Park CB, Chae BS, Kang TW,Ahn YK. Studies on the acute oral toxicity and antiinflammatoryactivity of extract of chelidoni herba from korea. Res Food Drug Saf 1995, 8, 7-18
  24. Kim YS, Roh JH, Moon SK, Cho KH, Bae HS, Lee KS. The relations between constant use of herbalmedicine and liver injury. J Kyung Hee Univ Med Cent1999, 15, 71-77
  25. Kong LD, Cheng CH, Tan RX. Inhibition of MAOA and B by some plant-derived alkaloids, phenols andanthraquinones. J Ethnopharmacol 2004, 91, 351-355 https://doi.org/10.1016/j.jep.2004.01.013
  26. Lee YC, Kim SH, Roh SS, Choi HY, Seo YB. Suppressive effects of Chelidonium majus methanolextract in knee joint, regional lymph nodes, and spleenon collagen-induced arthritis in mice. J Ethnopharmacol 2007, 112, 40-48 https://doi.org/10.1016/j.jep.2007.01.033
  27. Lenfeld J, Kroutil M, Marsalek E, Slavik J,Preininger V, Simanek V. Antiinflammatory activityof quaternary benzophenanthridine alkaloids fromChelidonium majus. Planta Med 1981, 43, 161-165 https://doi.org/10.1055/s-2007-971493
  28. Mei N, Arlt VM, Phillips DH, Heflich RH, Chen T. DNA adduct formation and mutation induction byaristolochic acid in rat kidney and liver. Mutat Res 2006, 602, 83-91 https://doi.org/10.1016/j.mrfmmm.2006.08.004
  29. Ministry of Public Health of the People's Republicof China. Pharmacopoeia of the People's Republic of China. p. 177, Chemical Industry Press, Beijing, 2000
  30. Mitra S, Gole M, Samajdar K, Sur RK,Chakraborty BN. Antihepatotoxic activity of Chelidonium majus. Int J Pharmacognosy 1992, 30,125-128 https://doi.org/10.3109/13880209209053974
  31. Mitra S, Sur RK, Roy A, Mukherjee AS. Effect ofChelidonium majus L. on experimental hepatic tissueinjury. Phytother Res 1996, 10, 354-356 https://doi.org/10.1002/(SICI)1099-1573(199606)10:4<354::AID-PTR838>3.0.CO;2-7
  32. Mohr U, Dungworth DL, Capen CC. Pathobiology of the Aging Rat. pp. 161-172, International Life Sciences Institute, Washington DC, 1992
  33. Park HM, Choi KH, Jung JY, Lee SD. Metalexposure through consumption of herbal medicine, andestimation of health risk among Korean population.Korean J Environ Health Soc 2006, 32, 186-191
  34. Pittler MH, Ernst E. Systematic review: hepatotoxicevents associated with herbal medicinal products.Aliment Pharmacol Ther 2003, 18, 451-471 https://doi.org/10.1046/j.1365-2036.2003.01689.x
  35. Ritter R, Schatton WFH. Clinical trial on standardizedcelandine extract in patients with functional epigastriccomplaints: results of placebo-controlled double-blindtrial. Comp Ther Med 1993, 1, 189-193 https://doi.org/10.1016/0965-2299(93)90029-D
  36. Schulz V, Hansel R, Tyler VE. Rational Phytotherapy:A Physician's Guide to Herbal Medicine. p. 176, Springer, New York, 1998
  37. Song JY, Yang HO, Pyo SN, Jung IS, Yi SY, YunYS. Immunomodulatory activity of protein-boundpolysaccharide extracted from Chelidonium majus.Arch Pharm Res 2002, 25, 158-164 https://doi.org/10.1007/BF02976557
  38. Song JY, Yang HO, Shim JY, Ahn JY, Han YS, JungS, Yun YS. Radiation protective effect of an extractfrom Chelidonium majus. Int J Hematol 2003, 78, 226-232 https://doi.org/10.1007/BF02983799
  39. Stein U, Greyer H, Hentschel H. Nutmeg (myristicin)poisoning--report on a fatal case and a series of casesrecorded by a poison information centre. Forensic SciInt 2001, 118, 87-90 https://doi.org/10.1016/S0379-0738(00)00369-8
  40. Stickel F, Poschl G, Seitz HK, Waldherr R, HahnEG, Schuppan D. Acute hepatitis induced by greatercelandine (Chelidonium majus). Scand J Gastroenterol 2003, 38, 565-568 https://doi.org/10.1080/00365520310000942
  41. Strahl S, Ehret V, Dahm HH, Maier KP. Necrotizinghepatitis after taking herbal remedies. Dtsch MedWochenschr 1998, 123, 1410-1414 https://doi.org/10.1055/s-2007-1024196
  42. Then M, Szentmihalyi K, Sarkozi A, Illes V, Forgacs E. Effect of sample handling on alkaloid and mineralcontent of aqueous extracts of greater celandine(Chelidonium majus L.). J Chromatography A 2000,889, 69-74 https://doi.org/10.1016/S0021-9673(00)00236-3
  43. Then M, Szentmihalyi K, Sarkozi A, Szollosi-Varga I. Examination on antioxidant activity in the greatercelandine (Chelidonium majus L.) extracts by FRAPmethod. Acta Biol Szeged 2003, 47, 115-117
  44. Vanherweghem JL, Depierreux M, Tielemans C,Abramowicz D, Dratwa M, Jadoul M, Richard C,Vandervelde D, Verbeelen D, Vanhaelen-Fastre R,Vanhaelen M. Rapidly progressive interstitial renalfibrosis in young women: association with slimmingregimen including Chinese herbs. Lancet 1993, 341,387-391 https://doi.org/10.1016/0140-6736(93)92984-2
  45. Weiss RF. Herbal Medicine. pp. 84-88, Arcanum and Beaconsfield, Gothenburg, 1985
  46. Wirth JH, Hudgins JC, Paice JA. Use of herbaltherapies to relieve pain: a review of efficacy andadverse effects. Pain Manag Nurs 2005, 6, 145-167 https://doi.org/10.1016/j.pmn.2005.08.003
  47. Wolf BW, Weisbrode SE. Safety evaluation of anextract from Salacia oblonga. Food Chem Toxicol 2003, 41, 867-874 https://doi.org/10.1016/S0278-6915(03)00038-3