Two -week Oral Toxicity Study of 1- (4-methylpiperazinyl) -3- phenylisoquinoline (CWJ-a-5) in sprague-Dawley (SD) Rats

1-(4-methylpiperazinyl)-3-phenylisoquinoline (CWJ- a-5)의 Sprague-Dawley(SD) 랫드를 이용한 2주간 반복 경구투여 독성시험

  • 강부현 (한국화학연구원 안전성평가연구소) ;
  • 조원제 (전남대학교 약학대학) ;
  • 김대덕 (부산대학교 약학대학) ;
  • 김용범 (한국화학연구원 안전성평가연구소) ;
  • 차신우 (한국화학연구원 안전성평가연구소) ;
  • 장순재 (양지화학)
  • Published : 2002.03.01

Abstract

The subacute oral toxicity of 1-(4-methylpiperazinyl)-3-phenylisoquinoline (CWJ- a-5) was investigated in Sprague-Dawley (SD) rats. Five groups of 5 males and 5 females were orally administered at doses of 0, 37.5, 75, 150 and 200 mg/kg with CWJ-a-5 for 2 weeks. In clinical signs, Salivation was observed in the 75, 150 and 500 mg/kg male and female groups. Loss of fur was observed in the 500 mg/kg male and female group. Body weight were significantly decreased in the 150 and 500 mg/kg male groups and in the 500 mg/kg female group. Food consumption was significantly decreased in the 300 mg/kg male group. In serum biochemistry, total cholesterol and phospholipid were significantly increased in 500 mg/kg male and female group. Aspartate aminotransferase was significantly increased in the 500 mg/kg female group. In histopathological examination, vacuolar degeneration of renal tubules in the kidney, vacuolar degeneration of hepatocytes in the liver vacuolar degeneration of myocytes in the heart, vacuolar degeneration of histiocytes in the spleen and thymus, atrophy of seminiferous tubule and degeneration of germinal epithelium in the testis, vacuolar degeneration of corpus luteum, granulosa cell and theca cell in the ovary were observed in the 150 and 500 mg/kg male and female groups. Based on these results, the no observed adverse effect level (NOAEL) with CWJ-a-5 was considered to be 75 mg/kg and the absolute toxic dose was considered to be 150 mg/kg in this study

Keywords

References

  1. J. Pathol. v.135 Fat accumulation in the rat heart during fasting Adams M.G.;Barer R.;Joseph S.;Ominiabohs F. https://doi.org/10.1002/path.1711350203
  2. Antineoplastic agent In Goodman and Gilman's The Pharmaceutical Basts of Therapeutics (8th ed.) Calabresi, P.;Chabner, B.A.
  3. Introduction to veterinary pathology Cheville N.F.
  4. Bioorg. Med. Chem. v.6 Synthesis and Comparative Molecular Field Analysis (CoMFA) of Antitumor 3-Arylisoquinoline Derivatives Cho, W.J.;Kim, E.K.;Park, M.J.;Choi, S.U.;Lee, C.O.;Cheon, S.H.;Choi, B.G.;Chung, B.H. https://doi.org/10.1016/S0968-0896(98)80019-9
  5. Arch. Pharm. Res. v.19 Synthesis of Benzo[c]phenathridine Derivatives and their In Vitro Antitumor Activities Cho W.J.;Yoo S.J.;Chung B.H.;Cheon S.H.;Whang S.H.;Kim S.K.;Kang B.H.;Lee C.O. https://doi.org/10.1007/BF02976249
  6. Arch. Pharm. Res. v.20 Synthesis and Antitumor Activity of 3-Ary-lisoquinoline Derivatives Cho, W.J.;Yoo, S.J.;Park M.J.;Chung, B.H.;Lee, C.O. https://doi.org/10.1007/BF02976155
  7. J. Org. Chem. v.58 Inhibitors of DNA Topoisomerase I Isolated from the Roots of Zantholylum nitidum Fang S.D.;Wang L.K.;Hecht S.M. https://doi.org/10.1021/jo00071a001
  8. Ketoconazole;Summary Basis of Approval;NDA 18-533 Food and Drug Administration
  9. Histopathology of preclinical toxicity studies: Interpretation and relevance in drug evaluation(Second Edition) Greaves P.
  10. Rat histopathology: A glossary for use in toxicity and carcinogenicity studies(2nd revised edition) Greaves, P.;Faccini, J.M.
  11. Arch. Toxicol. Suppl. v.7 Cardiac hypertrophy in the dog and rat induced by oxfenicine, an agent which modifies muscle metabolism Greaves P.;Martin J.;Michel M.C.;Mompon P.
  12. Quart. J. Med. v.40 Chloroquine myopathy Hughes J.T.;Esiri M.;Oxbury J.M.;Whitty C.W.M.
  13. Res. Exp. Med. (Berl) v.181 Effect of isoproterenol on lipid accumulation in myocardial cells Jodalen, H.;Lie, R.;Rotevatn, S. https://doi.org/10.1007/BF01851196
  14. Int. J. Pharm. v.217 Pharmacokinetics of a new antitumor 3-arylisoquinoline derivative Kim K.E.;Cho W.J.;Chang S.J.;Yong C.S.;Lee C.H.;Kim D.D. https://doi.org/10.1016/S0378-5173(01)00593-2
  15. Drug Devel. Ind. Pharm. Physicochemical properties of CWJ-a-5, a new antibutor 3-arylisoquinoline derivative Kim, K.E.;Cho, W.J.;Kim, T.S.;Kang, B.H.;Chang, S.J.;Lee, C.H.;Kim, D.D.
  16. Chem. Abstr. v.118 Kobayashi, F.;Yokumoto, H.;Suzuki, M.;Tsubaki, M.
  17. Lysosomes in Applied Biology and therapeutics Drug related lysosomal storage disorders Lullmann-Rauch R.;J.T. Dingle(eds.);P.J. Jacques(eds.);I.H. Shaw(eds.)
  18. Virchows Arch. B v.19 Effects of repeated injections of sucrose in the kidney: Histologic, cytochemical and functional studies in an animal model Monserrat A.J.;Chandler A.E.
  19. Pharmazie v.44 Pharmacological activities of benzophenan-thridine and phenanthrene alkaloids Simeon, S.;Rios, J.L.;Villar, A.
  20. The urinary system In Target organ pathology, A basic text Turton, J.;Hooson, J.
  21. Immunology v.39 Phagocytosis and lymphocyte migration: evidence that lymphocyte trapping in the spleen following carbon injection is not due to direct lymphocyte-macrophage adherence van Rooijen, J.;Roeterink, C.H.
  22. Am. J. Pathol. v.124 Myocardial diseases of animals van Vleet J.F.;Ferrans V.J.
  23. J.N.C.I. v.75 Splenotoxicity associated with splenic sarcomas in rats fed high doses of D&C Red No.9 or aniline hydrochloride Weinberger, M.A.;Albert, R.H.;Montgomery, S.B.
  24. J. Toxicol. Environ. Health v.18 Reference range data base for serum chemistry and hematology values in laboratory animals Wolford, S.T.;Schroer, R.A.;Gohs, F.X.;Gallo, P.P.;Brodec, M.;Falk, H.B.;Ruhren, F.R. https://doi.org/10.1080/15287398609530859
  25. 식품의약품안전청고시 제 1999-61호 의약품등의 독성시험기준 식품의약품안전청