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

Cheng Haung Wang, Yann Jang Chen, Tsung Hsing Lee, Yi Shen Chen, Bruno Jawan, Kuo Sheng Hung, Cheng Nan Lu, Jong Kang Liu

Research output: Contribution to journalArticle

21 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)571-578
Number of pages8
JournalJournal of Biomedical Science
Volume11
Issue number5
DOIs
Publication statusPublished - 2004
Externally publishedYes

Fingerprint

Thioacetamide
Acute Liver Failure
Liver
Hepatocytes
Hepatic Stellate Cells
Calpain
Nitric Oxide Synthase Type II
Chemical activation
Up-Regulation
Tumor Necrosis Factor-alpha
Apoptosis
DNA Nucleotidylexotransferase
Wounds and Injuries
Transaminases
Liver Cirrhosis
Labeling
Inflammation
Assays
Messenger RNA
Mortality

Keywords

  • Apoptosis
  • Calpain inhibitor
  • MDL28170
  • Thioacetamide

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Protective effect of MDL28170 against thioacetamide-induced acute liver failure in mice. / Wang, Cheng Haung; Chen, Yann Jang; Lee, Tsung Hsing; Chen, Yi Shen; Jawan, Bruno; Hung, Kuo Sheng; Lu, Cheng Nan; Liu, Jong Kang.

In: Journal of Biomedical Science, Vol. 11, No. 5, 2004, p. 571-578.

Research output: Contribution to journalArticle

Wang, CH, Chen, YJ, Lee, TH, Chen, YS, Jawan, B, Hung, KS, Lu, CN & Liu, JK 2004, 'Protective effect of MDL28170 against thioacetamide-induced acute liver failure in mice', Journal of Biomedical Science, vol. 11, no. 5, pp. 571-578. https://doi.org/10.1159/000079668
Wang, Cheng Haung ; Chen, Yann Jang ; Lee, Tsung Hsing ; Chen, Yi Shen ; Jawan, Bruno ; Hung, Kuo Sheng ; Lu, Cheng Nan ; Liu, Jong Kang. / Protective effect of MDL28170 against thioacetamide-induced acute liver failure in mice. In: Journal of Biomedical Science. 2004 ; Vol. 11, No. 5. pp. 571-578.
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