Gene Expression Analysis of Acetaminophen-induced Liver Toxicity in Rat

아세트아미노펜에 의해 간손상이 유발된 랫드의 유전자 발현 분석

  • Chung, Hee-Kyoung (Department of Pathology, College of Medicine, Hanyang University)
  • 정희경 (한양대학교 의과대학 병리학교실)
  • Published : 2006.12.30

Abstract

Global gene expression profile was analyzed by microarray analysis of rat liver RNA after acute acetaminophen (APAP) administration. A single dose of 1g/kg body weight of APAP was given orally, and the liver samples were obtained after 24, 48 h, and 2 weeks. Histopathologic and biochemical studies enabled the classification of the APAP effect into injury (24 and 48 h) and regeneration (2 weeks) stages. The expression levels of 4900 clones on a custom rat gene microarray were analyzed and 484 clones were differentially expressed with more than a 1.625-fold difference(which equals 0.7 in log2 scale) at one or more time points. Two hundred ninety seven clones were classified as injury-specific clones, while 149 clones as regeneration-specific ones. Characteristic gene expression profiles could be associated with APAP-induced gene expression changes in lipid metabolism, stress response, and protein metabolism. We established a global gene expression profile utilizing microarray analysis in rat liver upon acute APAP administration with a full chronological profile that not only covers injury stage but also later point of regeneration stage.

Keywords

References

  1. Chanda, S., Mangipudy, R.S., Warbritton, A., Bucci, T.J. and Mehendale, H.M. (1995): Stimulated hepatic tissue repair underlies heteroprotection by thioacetamide against acetaminophen- induced lethality. Hepatology, 21, 477-486
  2. Chung, H., Hong, D.-P., Jung, J.-Y., Kim, H.-J., Jang, K.-S., Sheen, Y.-Y., Ahn, J.-I., Lee, Y.-S. and Kong, G. (2005a): Comprehensive analysis of differential gene expression profiles on carbon tetrachloride-induced rat liver injury and regeneration. Toxicol. Appl. Pharmacol., 206, 27-42 https://doi.org/10.1016/j.taap.2004.11.004
  3. Chung, H., Hong, D.P., Kim, H.J., Jang, K.S., Shin, D.M., Ahn, J.I., Lee, Y.S. and Kong, G. (2005b): Differential gene expression profiles in the steatosis/fibrosis model of rat liver by chronic administration of carbon tetrachloride. Toxicol. Appl. Pharmacol., 208, 242-254 https://doi.org/10.1016/j.taap.2005.03.002
  4. Farber, E. (1973): ATP and cell integrity. Fed. Proc., 32, 1534-1539
  5. Heinloth, A.N., Irwin, R.D., Boorman, G.A., Nettesheim, P., Fannin, R.D., Sieber, S.O., Snell, M.L., Tucker, C.J., Li, L., Travlos, G.S., Vansant, G., Blackshear, P.E., Tennant, R.W., Cunningham, M.L. and Paules, R.S. (2004): Gene expression profiling of rat livers reveals indicators of potential adverse effects. Toxicol. Sci., 80, 193-202 https://doi.org/10.1093/toxsci/kfh145
  6. Huang, Q., Jin, X., Gaillard, E.T., Knight, B.L., Pack, F.D., Stoltz, J.H., Jayadev, S. and Blanchard, K.T. (2004). Gene expression profiling reveals multiple toxicity endpoints induced by hepatotoxicants. Mutat. Res., 549, 147-167 https://doi.org/10.1016/j.mrfmmm.2003.12.020
  7. Inaguma, Y., Hasegawa, K., Goto, S., Ito, H. and Kato, K. (1995): Induction of the synthesis of hsp27 and alpha B crystallin in tissues of heat-stressed rats and its suppression by ethanol or an alpha 1-adrenergic antagonist. J. Biochem. (Tokyo), 117, 1238-1243 https://doi.org/10.1093/oxfordjournals.jbchem.a124850
  8. Knight, T.R., Ho, Y.S., Farhood, A. and Jaeschke, H. (2002): Peroxynitrite is a critical mediator of acetaminophen hepatotoxicity in murine livers: protection by glutathione. J. Pharmacol. Exp. Ther., 303, 468-475 https://doi.org/10.1124/jpet.102.038968
  9. Lettieri, T. (2006): Recent applications of DNA microarray technology to toxicology and ecotoxicology. Environ. Health Perspect., 114, 4-9
  10. Liang, H.C., Li, H., McKinnon, R.A., Duffy, J.J., Potter, S.S., Puga, A. and Nebert, D.W. (1996): Cyp1a2(-/-) null mutant mice develop normally but show deficient drug metabolism. Proc. Natl. Acad. Sci. USA, 93, 1671-1676
  11. Minami, K., Saito, T., Narahara, M., Tomita, H., Kato, H., Sugiyama, H., Katoh, M., Nakajima, M. and Yokoi, T. (2005): Relationship between hepatic gene expression profiles and hepatotoxicity in five typical hepatotoxicant-administered rats. Toxicol. Sci., 87, 296-305 https://doi.org/10.1093/toxsci/kfi235
  12. Mitchell, J.R., Jollow, D.J., Potter, W.Z., Gillette, J.R. and Brodie, B.B. (1973): Acetaminophen-induced hepatic necrosis. IV. Protective role of glutathione. J. Pharmacol. Exp. Ther., 187, 211-217
  13. Nuwaysir, E.F., Bittner, M., Trent, J., Barrett, J.C. and Afshari, C.A. (1999): Microarrays and toxicology: the advent of toxicogenomics. Mol. Carcinog., 24, 153-159 https://doi.org/10.1002/(SICI)1098-2744(199903)24:3<153::AID-MC1>3.0.CO;2-P
  14. Potter, W.Z., Davis, D.C., Mitchell, J.R., Jollow, D.J., Gillette, J.R. and Brodie, B.B. (1973): Acetaminophen-induced hepatic necrosis. 3. Cytochrome P-450-mediated covalent binding in vitro. J. Pharmacol. Exp. Ther., 187, 203-210
  15. Pumford, N.R., Halmes, N.C. and Hinson, J.A. (1997): Covalent binding of xenobiotics to specific proteins in the liver. Drug. Metab. Rev., 29, 39-57 https://doi.org/10.3109/03602539709037572
  16. Rockett, J.C. and Hellmann, G.M. (2004): Confirming microarray data--is it really necessary? Genomics., 83, 541-549 https://doi.org/10.1016/j.ygeno.2003.09.017
  17. Sinclair, J., Jeffery, E., Wrighton, S., Kostrubsky, V., Szakacs, J., Wood, S. and Sinclair, P. (1998): Alcohol-mediated increases in acetaminophen hepatotoxicity: role of CYP2E and CYP3A. Biochem. Pharmacol., 55, 1557-1565 https://doi.org/10.1016/S0006-2952(97)00656-4
  18. Sobczak, J., Lotti, A.M., Taroux, P. and Duguet, M. (1987): Molecular cloning of mRNA sequences transiently induced during rat liver regeneration. Exp. Cell. Res., 169, 47-56 https://doi.org/10.1016/0014-4827(87)90223-0
  19. Yamamoto, T., Kikkawa, R., Yamada, H. and Horii, I. (2005): Identification of oxidative stress-related proteins for predictive screening of hepatotoxicity using a proteomic approach. J. Toxicol. Sci., 30, 213-227 https://doi.org/10.2131/jts.30.213