Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
권호 표지

Gene Expression Analysis of Phenylbutazone-induced Liver Damage in Mice

페닐부타존에 의해 간손상이 유발된 생쥐의 유전자 발현 분석

  • Lee Eun-Ju (Department of Biochemistry, College of Medicine, Ewha Womans University) ;
  • Jeong In-Hye (Department of Biochemistry, College of Medicine, Ewha Womans University) ;
  • Kim Han-Na (Department of Biochemistry, College of Medicine, Ewha Womans University) ;
  • Chung Hee-Kyoung (Department of Pathology, College of Medicine, Hanyang University) ;
  • Kong Gu (Department of Pathology, College of Medicine, Hanyang University) ;
  • Kang Kyung-Sun (Department of Veterinary Public Health, College of Veterinary Medicine, Seoul National University) ;
  • Yoon Byung-Il (Department of Veterinary Medicine, Kangwon National University) ;
  • Lee Byeong-Hoon (College of Pharmacy and Bio-MAX Institute) ;
  • Lee Mi-Ock (College of Pharmacy and Bio-MAX Institute) ;
  • Kim Ju-Han (Seoul National University Biomedical Informatics (SNUBI), Seoul National University College of Medicine) ;
  • Kim Hyung-Lae (Department of Biochemistry, College of Medicine, Ewha Womans University)
  • 이은주 (이화여자대학교 의과대학 생화학교실) ;
  • 정인해 (이화여자대학교 의과대학 생화학교실) ;
  • 김한나 (이화여자대학교 의과대학 생화학교실) ;
  • 정희경 (한양대학교 의과대학 병리학교실) ;
  • 공구 (한양대학교 의과대학 병리학교실) ;
  • 강경선 (서울대학교 수의과대학 수의공중보건학과) ;
  • 윤병일 (강원대학교 수의학과) ;
  • 이병훈 (서울대학교 약학대학, Bio-MAX 연구소) ;
  • 이미옥 (서울대학교 약학대학, Bio-MAX 연구소) ;
  • 김주한 (서울대학교 의과대학 biomedical informatics(SNUBI)) ;
  • 김형래 (이화여자대학교 의과대학 생화학교실)
  • Published : 2006.06.01
Download PDF
⟨ Previous Next ⟩

Abstract

The KFDA (Korea Food & Drug Administration) has performed a collaborative toxico-genomics project since 2003. Its aim is to construct a toxicologenomic database of 12 hepatotoxic compounds from mice livers. Phenylbutazone which is non-steroidal anti-inflammatory drug was assigned. It was administered at low (0.0238 mg/kg) and at high (0.238 mg/kg) dose (5 mice per group) orally to the postnatal 6 weeks ICR mice, then the serum and liver were collected at the indicated time (6, 24 and 72 h) after administration. Serum biochemical markers for liver toxicity were measured and histopathologic studies also were carried out. The gene expression profiling was carried out by using Applied Biosystems 1700 Full Genome Expression Mouse. The 2-way ANOVA was used to find genes that reflected phenylbutazone-induced acute toxicity or dose-dependant changes. By self-organization maps (SOM), we identified groups with unique gene expression patterns, some of them are supposed to be related to phenylbutazone induced toxicity, including lipid metabolism abnormality, oxidative stress, cell death and cytoskeleton destruction.

Keywords

References

  1. Albano, E., Clot, P., Morimoto, M., Tomasi, A., Ingelman-Sundberg, M. and French, S.W. (1996): Role of cytochrome P4502E1-dependent formation of hydroxlethyl free radical in the development of liver damage in rats intragastrically fed with ethanol. Hepatology, 23, 155-163 https://doi.org/10.1002/hep.510230121
  2. Arai, I., Hirose, H., Muramatsu, M., Okuyama, S. and Aihara, H. (1985): Possible involvement of non-steroidal antiinflammatory drugs in vagal-mediated gastric acid secretion in rats. Jpn. J. Pharmacol., 37, 91-99 https://doi.org/10.1254/jjp.37.91
  3. Capdevila, J., Chocos, N., Werringloer, J., Prough, R.A. and Estabrook, R.W. (1981): Liver microsomal cytochrome P- 450 and the oxidative metabolism of arachidonic acid. Proc. Natl. Acad. Sci. USA, 78, 5362–5366
  4. Cutis, D. Klassen (2001): Casarett and Doull's Toxicology: The Basic science of poisons (6th edition), The McGraw- Hill Companies, Inc
  5. Faigle and Dieterle (1977): The biotransformation of phenylbutazone (Butazolidin). J. Int. Med. Res. 5 Suppl 2, 2-14
  6. Farrell, G.C. (1994): Drug-Induced Lever Diseas. Edinburgh: Churchill Living-stone
  7. Fowler, P. (1967): Marrow toxicity of the pyrazoles. Ann. Rheum. Dis., 26, 344-345
  8. Gilman, A.G., Goodman, L., Rall, T.W., Murad, F., Eds. (1985): Goodman and Gilman's: The harmacologic Basis of Therapeutics (7th edition). New York, Macmillan Publishing Co., Inc
  9. Hugo Caldas and Gail E. (2003): Herman NSDHL, an enzyme involved in cholesterol biosynthesis, traffics through the Golgi and accumulates on ER membranes and on the surface of lipid droplets. Hum. Mol. Genet., 12, 2981-2991 https://doi.org/10.1093/hmg/ddg321
  10. James W. Long and James J. Rybacki (1994): The Essential Guide to Prescription Drugs
  11. Kaplowitz, N., Aw, T.Y., Simon, F.R. and Stolz, A. (1986): Drug-induced hepatotoxicity. Ann. Intern. Med., 104, 826- 839 https://doi.org/10.7326/0003-4819-104-6-826
  12. Lieber, C.S. (1997): Cytochrome P-4502E1: its physiological and pathological role. Physiol. Rev., 77, 517-544 https://doi.org/10.1152/physrev.1997.77.2.517
  13. Lees, P. and Higgins, A.J. (1987): Physiological, biochemical and haematological effects on horses of a phenylbutazone paste. Vet. Rec., 121, 56-60 https://doi.org/10.1136/vr.121.3.56
  14. Ma, J., Qu, W., Scarborough, P.E., Tomer, K.B., Moomaw, C.R., Maronpot, R., Davis, L.S., Breyer, M.D. and Weldin, D.C. (1999) : Molecular cloning, enzymatic characterization, developmental expression, and cellular localization of a mouse cytochrome P450 highly expressed in kidney. J. Biol. Chem., 274, 17777-17788 https://doi.org/10.1074/jbc.274.25.17777
  15. MacAllister, C.G., Morgan, S.J., Borne, A.T. and Pollet, R.A. (1993): Comparison of adverse effects of phenylbutazone, flunixin meglumine, and ketoprofen in horses. J. Am. Vet. Med. Assoc., 202, 71-77
  16. Masato, O., Noboru, M., Yukiko, K. and Tamotsu, Y. (2003): Localization of mammalian NAD(P)H Steroid Dehydrogenase like protein on lipid droplets. J. Biol. Chem., 278, 36819-36829 https://doi.org/10.1074/jbc.M301408200
  17. Morrison, A.R. and Pascoe, N. (1981): Metabolism of arachidonate through NADPH-dependent oxygenase of renal cortex. Proc Natl Acad Sci USA, 78, 7375–7378
  18. Murphy, D.J. and Vance, J. (1999): Mechanisms of lipid-body formation. Trends Biochem. Sci., 24, 109-115 https://doi.org/10.1016/S0968-0004(98)01349-8
  19. Oliw, E.H., Lawson, J.A., Brash, A.R. and Oates, J.A. (1981): Arachidonic acid metabolism in rabbit renal cortex. Formation of two novel dihydroxyeicosatrienoic acids. J. Biol. Chem., 256, 9924–9931
  20. Qu, W., Bradbury, J.A., Tsao, C.C., Maronpot, R., Harry, G.J., Parker, C.E., Davis, L.S., Breyer, M.D., Waalkes, M.P., Falck, J.R., Chen, J., Rosenberg, R.L. and Zeldin, D.C. (2001): Cytochrome P-450 CYP2J9, a new mouse omega-1 hydroxylase predominately expressed in brain. J. Biol. Chem., 27, 25467-25479
  21. Reed, G.A., Griffin, L.O. and Eling, T.E. (1985): Inactivation of prostaglandin H synthase and prostacyclin synthase by phenylbutazone. Mol. Pharmacol., 27, 109-114
  22. Schena, M., Shalon, D., Davis, R.W. and Brown, P.O. (1995): Quantitative monitoring of gene expression patterns with a complementary DNA microarray. Science, 270, 467-470 https://doi.org/10.1126/science.270.5235.467
  23. Wang, X., Wang, W., Bengmark, S. and Andersson, R. (1995): Alterations of lipid contents in blood, hepatocytes, and enterocytes in the early stage of acute liver failure induced by 90% hepatectomy in the rat. J. Surg. Res., 59, 326-336 https://doi.org/10.1006/jsre.1995.1172
  24. Wu, S., Chen, W., Murphy, E., Gabel, S., Tomer, K.B., Foley, J., Steenbergen, C., Falck, J.R., Moomaw, C.R. and Zeldin, D.C. (1997): Molecular cloning, expression, and functional significance of a cytochrome P450 highly expressed in rat heart myocytes. J. Biol. Chem., 272, 12551-12559 https://doi.org/10.1074/jbc.272.19.12551
  25. Wu, S., Moomaw, C.R., Tomer, K.B., Falck, J.R. and Zeldin, D.C. (1996): Molecular cloning and expression of CYP2J2, a human cytochrome P450 arachidonic acid epoxygenase highly expressed in heart. J. Bio. Chem., 271, 3460-3468 https://doi.org/10.1074/jbc.271.7.3460
  26. Zimmerman, H.J. (1978) : Hepatotoxicity. The Adverse Effects of Drugs and Other Chemicals in the liver, Lippincott Williams & Wilkins, New York
  27. Zeldin, D.C., Moomaw, C.R., Jesse, N., Tomer, K.B., Beetham, J., Hammock, B.D. and Wu, S. (1996): Biochemical characterization of the human liver cytochrome P-450 arachidonic acid epoxygenase pathway. Arch Biochem Biophys, 330, 87-96 https://doi.org/10.1006/abbi.1996.0229