Gene Expression Profiling of 6-MP (6-mercaptopurine) in Liver

  • Kim Hyung-Lae (Department of Biochemistry, College of Medicine, Ewha Womans University) ;
  • Kim Han-Na (Department of Biochemistry, College of Medicine, Ewha Womans University) ;
  • Lee Eun-Ju (Department of Biochemistry, College of Medicine, Ewha Womans University)
  • Published : 2006.03.01

Abstract

The KFDA (Korea Food & Drug Administration) has performed a collaborative toxicogenomics project since 2003. Its aim is to construct a toxicology database of 12 compounds administered to mice at initial phase. We chose 6-MP (6-mercaptopurine) which has been used in the treatment of childhood leukemia. It was administered at low (0.224 mg/kg) and at high (2.24 mg/kg) dose (5 mice per group) intraperitonealy to the postnatal 6 weeks mice, then the serum and liver were collected at the indicated time (6, 24 and 72 h) after scarification. 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. By self-organization maps (SOM), we identified groups with unique gene expression patterns, some of them are supposed to be related to 6-MP induced toxicity, including lipid metabolism abnormality, inflammatory response, oxidative stress, ATP depletion and cell death. The potential toxic effects appearing as gene expression changes are dependent of the time of 6-MP but independent of the dosage of it. This study would contribute to establishment of international database as well as national one about hepatotoxicity.

Keywords

References

  1. Berkovitch, M., Matsui, D., Zipursky, A., Blanchette, V.S., Verjee, Z., Giesbrecht, E., Saunders, E.F., Evans, W.E., and Koren, G. (1996). Hepatotoxicity of 6-mercaptopurine in childhood acute lymphocytic leukemia: pharmacokinetic characteristics. Med. Pediatr. Oncol. 26, 85-89 https://doi.org/10.1002/(SICI)1096-911X(199602)26:2<85::AID-MPO3>3.0.CO;2-Q
  2. Burchenal, J.H., Murphy, M.L.,and Ellison, R.R. (1953).Clinical evaluation of a new antimetabolite, 6-mercaptopurine, in the treatment of leukaemia and allied diseases. Blood 8, 965-998
  3. 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.(2004). Comprehensive analysis of differential gene expression profiles on carbon tetrachlorideinduced rat liver injury and regeneration. Toxical. Appl. Pharmacal. 10,1016
  4. Farrell, G.C. (1994). Drug-Induced Liver Disease. Edinburgh: Churchill Livingstone
  5. Heijne, W.H., Slitt, A.L., van Bladeren, P.J., Groten, J.P., Klaassen, C.D., Stierum, R.H., and van Ommen, B. (2004). Bromobenzene-induced hepatotoxicity at the transcriptome level. Toxieol. Sci. 79, 411-422 https://doi.org/10.1093/toxsci/kfh128
  6. Kim, J.E., Chang, H.Y., Park, D.Y., Lee, H.Y., Yoon, J.H., and Kim, S.N. (2005). A unique gene expression signature of 5-fluorouracil. Molecular&CeIluar Toxicol. 1. 248-255
  7. Lennard, L., Davies, H.A., and Lilleyman, J.S. (1993). Is 6-thioguanine more appropriate than 6-mercaptopurine for children with acute lymphoblastic leukaemia. Br. J. Cancer. 68, 186-190 https://doi.org/10.1038/bjc.1993.311
  8. Makino, I.,Shinozaki,K., Nakagawa, S.,and Mashimo, K. (1974). Measurement of sulfated and nonsulfated bile acids in human serum and urine. J. Lipid Res. 15, 132-138
  9. Michael, J., Tapner, Brett, E. Jones, Wan M. Wu, Geoffrey, C. and Farrell. (1974). Toxicity of low dose azathioprine and 6-mercaptopurine in rat hepatocytes. Roles of xanthine oxidase and mitochondrial injury. J. Hepatol. 40, 454-463 https://doi.org/10.1016/j.jhep.2003.11.024
  10. Nygaard, U, Toft, N, and Schmiegelow, K. (2004). Methylated metabolites of 6-mercaptopurine are associated with hepatotoxicity. Clin. Pharmacol. Ther. 75, 274-281 https://doi.org/10.1016/j.clpt.2003.12.001
  11. Phillips, M.J., Poucell, S., and ada, M.(1986). Mechanisms of cholestasis. Lab Invest. 54, 593-608
  12. Ramadori, G., and Christ, B. (1999). Cytokinesand the hepatic acute-phase response. Semin. Liver Dis. 19, 141-155 https://doi.org/10.1055/s-2007-1007106
  13. Runnegar, M.T., Bemdt, N.,and Kaplowits, N. (1995). Microcystin uptake and inhibition of protein phosphatases: Effects of chemoprotectants and selfinhibition in relation to known hepatic transporter. Tox. Appl. Pharmacol. 134, 264-272 https://doi.org/10.1006/taap.1995.1192
  14. Scheig, R. (1996). Evaluation of test used to screen patients with liver disorders. Prim. Care, 23, 551-560 https://doi.org/10.1016/S0095-4543(05)70347-X
  15. Schmiegelow, K. (1991). Prognostic significanceof methotrexate and 6-mercaptopurine dosage during maintenance chemotherapy for childhood acute lymphoblastic leukemia. Pediatr. Hematol. Oncol. 8, 301-312 https://doi.org/10.3109/08880019109028803
  16. Schmiegelow, K. Prognostic significanceof methotrexate and 6-mercaptopurine dosage during maintenance chemotherapy for childhood acute lymphoblastic leukemia. Erratum in: Pediatr. Hematol. Oncol. (1992) 9, following 198
  17. Suffredini, .., Fantuzzi, G., Badolato, R., Oppenheim, J.J., and O'Grady, N.P. (1999). New insights into the biology of the acute phase response. J. Clin. Immunol. 19, 203-214 https://doi.org/10.1023/A:1020563913045
  18. Takikawa, H., Beppu, T., and Seyama, Y. (1984). Urinary concentrations of bile acid glucuronides and sulfates in hepatobiliary diseases. Gastroenterol. Jpn. 19, 104-109 https://doi.org/10.1007/BF02806931
  19. Tapner, M.J., Jones, B.E, Wu, W.M., and Farrell, G.C. (2004). Toxicity of low dose azathioprine and 6-mercaptopurine in rat hepatocytes. Roles of xanthine oxidase and mitochondrial injury. J Hepatol. 40, 454-463 https://doi.org/10.1016/j.jhep.2003.11.024