Skip to main content
SpringerLink
Log in

Protective effect of MDL28170 against thioacetamide-induced acute liver failure in mice

  • Original Paper
  • Published:
Journal of Biomedical Science

Abstract

Liver injury is known to often progress even after the hepatotoxicant is dissipated. The hydrolytic enzyme calpain, which is released from dying hepatocytes, destroys the surrounding cells and results in progression of injury. Therefore, control of calpain activation may be a suitable therapeutic intervention in cases of fulminant hepatic failure. This study evaluated the effects of a potent cell-permeable calpain inhibitor, MDL28170, and its mechanisms of action on thioacetamide (TAA)-induced hepatotoxicity in mice. We found that MDL28170 significantly decreased mortality and change in serum transaminase after TAA administration. The necroinflammatory response in the liver was also suppressed. Furthermore, a significant suppression of hepatocyte apoptosis could be found by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assay. The upregulation of inducible nitric oxide synthase (iNOS) and tumor necrosis factor-α (TNF-α), both of which are known to mediate the propagation of inflammation, was abolished. MDL2810 also effectively blocked hepatic stellate cell activation, which is assumed to be the early step in liver fibrosis. These results demonstrated that MDL28170 attenuated TAA-induced acute liver failure by inhibiting hepatocyte apoptosis, abrogating iNOS and TNF-α mRNA upregulation and blocking hepatic stellate cell activation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Al-Khalidi JA, Czaja AJ. Current concepts in the diagnosis, pathogenesis, and treatment of autoimmune hepatitis. Mayo Clin Proc 76:1237–1252;2001.

    Google Scholar 

  2. Aragon B, Poussard S, Dulong S, Touyarot K, Dargelos E, Brustis JJ, Levieux D, Ducastaing A, Cottin P. Protein kinase C alpha is a calpain target in cultured embryonic muscle cells. Mol Cell Biochem 231:97–106;2002.

    Google Scholar 

  3. Azam M, Andrabi SS, Sahr KE, Kamath L, Kuliopulos A, Chishti AH. Disruption of the mouse mu-calpain gene reveals an essential role in platelet function. Mol Cell Biol 21:2213–2220;2001.

    Google Scholar 

  4. Bedda S, Laurent A, Conti F, Chereau C, Tran A, Tran-Van Nhieu J, Jaffray P, Soubrane O, Goulvestre C, Calmus Y, Weill B, Batteux F. Mangafodipir prevents liver injury induced by acetaminophen in the mouse. J Hepatol 39:765–772;2003.

    Google Scholar 

  5. Bruck R, Aeed H, Shirin H, Matas Z, Zaidel L, Avni Y, Halpern Z. The hydroxyl radical scavengers dimethylsulfoxide and dimethylthiourea protect rats against thioacetamide-induced fulminant hepatic failure. J Hepatol 31:27–38;1999.

    Google Scholar 

  6. Chen ZF, Schottler F, Lee KS. Neuronal recovery after moderate hypoxia is improved by the calpain inhibitor MDL28170. Brain Res 769:188–192;1997.

    Google Scholar 

  7. Cheng J, Imanishi H, Liu W, Iwasaki A, Ueki N, Nakamura H, Hada T. Inhibition of the expression of alpha-smooth muscle actin in human hepatic stellate cell line, L190, by a selective cyclooxygenase 2 inhibitor, NS-398. Biochem Biophys Res Commun 297:1128–1134;2002.

    Google Scholar 

  8. Cuzzocrea S, McDonald MC, Mazzon E, Mota-Filipe H, Centorrino T, Terranova ML, Ciccolo A, Britti D, Caputi AP, Thiemermann C. Calpain inhibitor I reduces colon injury caused by dinitrobenzene sulphonic acid in the rat. Gut 48:478–488;2001.

    Google Scholar 

  9. Cuzzocrea S, McDonald MC, Mazzon E, Siriwardena D, Serraino I, Dugo L, Britti D, Mazzullo G, Caputi AP, Thiemermann C. Calpain inhibitor I reduces the development of acute and chronic inflammation. Am J Pathol 157:2065–2079;2000.

    Google Scholar 

  10. Daniel KG, Anderson JS, Zhong Q, Kazi A, Gupta P, Dou QP. Association of mitochondrial calpain activation with increased expression and autolysis of calpain small subunit in an early stage of apoptosis. Int J Mol Med 12:247–252;2003.

    Google Scholar 

  11. Diez-Fernandez C, Sanz N, Bosca L, Hortelano S, Cascales M. Involvement of nitric oxide synthesis in hepatic perturbations induced in rats by a necrogenic dose of thioacetamide. Br J Pharmacol 121:820–826;1997.

    Google Scholar 

  12. Dogru-Abbasoglu S, Balkan J, Kanbagli O, Cevikbas U, Aykac-Toker G, Uysal M. Amino-guanidine, an inducible nitric oxide synthase inhibitor, plus N-acetylcysteine treatment reduce the lipopolysaccharide-augmented hepatotoxicity in rats with cirrhosis. Hum Exp Toxicol 21:359–364;2002.

    Google Scholar 

  13. Dooley S, Hamzavi J, Breitkopf K, Wiercinska E, Said HM, Lorenzen J, Ten Dijke P, Gressner AM. Smad7 prevents activation of hepatic stellate cells and liver fibrosis in rats. Gastroenterology 125:178–192;2003.

    Google Scholar 

  14. Gilligan DM, Sarid R, Weese J. Adducin in platelets: Activation-induced phosphorylation by PKC and proteolysis by calpain. Blood 99:2418–2426;2002.

    Google Scholar 

  15. Hayami S, Ikeda K, Sun F, Tanaka K, Kojo S. Increase of caspase-3 activity in rat liver and plasma by thioacetamide. Biochem Pharmacol 58:1941–1943;1999.

    Google Scholar 

  16. Hon WM, Lee KH, Khoo HE. Nitric oxide in liver diseases: Friend, foe, or just passerby? Ann NY Acad Sci 962:275–295;2002.

    Google Scholar 

  17. Kim KH, Bae JH, Cha SW, Han SS, Park KH, Jeong TC. Role of metabolic activation by cytochrome P450 in thioacetamide-induced suppression of antibody response in male BALB/c mice. Toxicol Lett 114:225–235;2000.

    Google Scholar 

  18. Kohli V, Madden JF, Bentley RC, Clavien PA. Calpain mediates ischemic injury of the liver through modulation of apoptosis and necrosis. Gastroenterology 116:168–178;1999.

    Google Scholar 

  19. Laroux FS, Pavlick KP, Hines IN, Kawachi S, Harada H, Bharwani S, Hoffman JM, Grisham MB. Role of nitric oxide in inflammation. Acta Physiol Scand 173:113–118;2001.

    Google Scholar 

  20. Lee WR. Acute liver failure. N Engl J Med 329:1862–1872;1993.

    Google Scholar 

  21. Leifeld L, Fielenbach M, Dumoulin FL, Speidel N, Sauerbruch T, Spengler U. Inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) expression in fulminant hepatic failure. J Hepatol 37:613–619;2002.

    Google Scholar 

  22. Limaye PB, Apte UM, Shankar K, Bucci TJ, Warbritton A, Mehendale HM. Calpain released from dying hepatocytes mediates progression of acute liver injury induced by model hepatotoxicants. Toxicol Appl Pharmacol 191:211–226;2003.

    Google Scholar 

  23. Liu X, Schnellmann RG. Calpain mediates progressive plasma membrane permeability and proteolysis of cytoskeleton-associated paxillin, talin, and vinculin during renal cell death. J Pharmacol Exp Ther 304:63–70;2003.

    Google Scholar 

  24. Lokuta MA, Nuzzi PA, Huttenlocher A. Calpain regulates neutrophil chemotaxis. Proc Natl Acad Sci USA 100:4006–4011;2003.

    Google Scholar 

  25. Margeli AP, Skaltsas SD, Spiliopoulou CA, Mykoniatis MG, Theocharis SE. Hepatic stimulator substance activity in the liver of thioacetamide-intoxicated rats. Liver 19:519–525;1999.

    Google Scholar 

  26. Mookerjee RP, Sen S, Davies NA, Hodges SJ, Williams R, Jalan R. Tumour necrosis factor alpha is an important mediator of portal and systemic haemodynamic derangements in alcoholic hepatitis. Gut 52:1182–1187;2003.

    Google Scholar 

  27. Okuyama H, Nakamura H, Shimahara Y, Araya S, Kawada N, Yamaoka Y, Yodoi J. Overexpression of thioredoxin prevents acute hepatitis caused by thioacetamide or lipopolysaccharide in mice. Hepatology 37:1015–1025;2003.

    Google Scholar 

  28. Rahman TM, Hodgson HJ. The effects of early and late administration of inhibitors of inducible nitric oxide synthase in a thioacetamide-induced model of acute hepatic failure in the rat. J Hepatol 38:583–590;2003.

    Google Scholar 

  29. Rami A, Ferger D, Krieglstein J. Blockade of calpain proteolytic activity rescues neurons from glutamate excitotoxicity. Neurosci Res 27:93–97;1997.

    Google Scholar 

  30. Sindram D, Kohli V, Madden JF, Clavien PA. Calpain inhibition prevents sinusoidal endothelial cell apoptosis in the cold ischemic rat liver. Transplantation 68:136–140;1999.

    Google Scholar 

  31. So EC, Wong KL, Huang TC, Tasi SC, Liu CF. Tetramethylpyrazine protects mice against thioacetamide-induced acute hepatotoxicity. J Biomed Sci 9:410–414;2002.

    Google Scholar 

  32. Taniguchi K, Umeshita K, Sakon M, Miyoshi H, Tokunaga M, Ariyoshi H, Yamano T, Kaneda Y, Monden M. Suppression of oxidative stress-induced hepatocyte injury by calpain antisense. J Surg Res 111:23–27;2003.

    Google Scholar 

  33. Waris G, Livolsi A, Imbert V, Peyron JF, Siddiqui A. Hepatitis C virus NS5A and subgenomic replicon activate NF-κB via tyrosine phosphorylation of IκBα and its degradation by calpain protease. J Biol Chem 278:40778–40787;2003.

    Google Scholar 

  34. Yang R, Gallo DJ, Baust JJ, Uchiyama T, Watkins SK, Delude RL, Fink MP. Ethyl pyruvate modulates inflammatory gene expression in mice subjected to hemorrhagic shock. Am J Physiol Gastrointest Liver Physiol 283:G212-G221;2002.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Anesthesiology, Kaohsiung Chang-Gung Memorial Hospital, Kaohsiung

    Cheng-Haung Wang, Tsung-Hsing Lee, Yi-Shen Chen & Bruno Jawan

  2. Department of Neurosurgery, Kaohsiung Chang-Gung Memorial Hospital, Kaohsiung

    Kuo-Sheng Hung

  3. Department of Chinese Medicine, Kaohsiung Chang-Gung Memorial Hospital, Kaohsiung

    Cheng-Nan Lu

  4. Department of Life Sciences, National Yang-Ming University, Taipei, Taiwan, ROC

    Yann-Jang Chen

  5. Department of Biological Sciences, National Sun Yat-sen University, No. 70 Lien-Hai Road, 804, Kaohsiung, Taiwan (ROC)

    Cheng-Haung Wang & Jong-Kang Liu PhD

Authors
  1. Cheng-Haung Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yann-Jang Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tsung-Hsing Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yi-Shen Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bruno Jawan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kuo-Sheng Hung
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Cheng-Nan Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jong-Kang Liu PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, CH., Chen, YJ., Lee, TH. et al. Protective effect of MDL28170 against thioacetamide-induced acute liver failure in mice. J Biomed Sci 11, 571–578 (2004). https://doi.org/10.1007/BF02256121

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02256121

Key Words

Search

Navigation