Tetrathiomolybdate protects against bile duct ligation-induced cholestatic liver injury and fibrosis.

Abstract

Tetrathiomolybdate (TM), a potent copper-chelating drug, was initially developed for the treatment of Wilson's disease. Our working hypothesis is that the fibrotic pathway is copper-dependent. Because biliary excretion is the major pathway for copper elimination, a bile duct ligation (BDL) mouse model was used to test the potential protective effects of TM. TM was given in a daily dose of 0.9 mg/mouse by means of intragastric gavage 5 days before BDL. All the animals were killed 5 days after surgery. Plasma liver enzymes and total bilirubin were markedly decreased in TM-treated BDL mice. TM also inhibited the increase in plasma levels of tumor necrosis factor (TNF)-alpha and transforming growth factor (TGF)-beta1 seen in BDL mice. Cholestatic liver injury was markedly attenuated by TM treatment as shown by histology. Hepatic collagen deposition was significantly decreased, and it was paralleled by a significant suppression of hepatic smooth muscle alpha-actin and fibrogenic gene expression in TM-treated BDL mice. Although the endogenous antioxidant ability was enhanced, oxidative stress as shown by malondialdehyde and 4-hydroxyalkenals, hepatic glutathione/oxidized glutathione ratio, was not attenuated by TM treatment, suggesting the protective mechanism of TM may be independent of oxidative stress. In summary, TM attenuated BDL-induced cholestatic liver injury and fibrosis in mice, in part by inhibiting TNF-alpha and TGF-beta1 secretion. The protective mechanism seems to be independent of oxidative stress. Our data provide further evidence that TM might be a potential therapy for hepatic fibrosis.

• Authors: Ming Song, Zhenyuan Song, Shirish Barve, Jingwen Zhang, Theresa Chen, Marcia Liu, Gavin E Arteel, George J Brewer, Craig J McClain
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 325 Issue 2 Pg. 409-16 (May 2008) ISSN: 1521-0103 [Electronic] United States
• PMID: 18299419 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Protective Agents
• Transforming Growth Factor beta1
• Tumor Necrosis Factor-alpha
• Copper
• Molybdenum
• tetrathiomolybdate
• Ceruloplasmin
• gamma-Glutamyltransferase
• Aspartate Aminotransferases
• Alanine Transaminase
• Alkaline Phosphatase
• Bilirubin

Topics

• Alanine Transaminase (blood)
• Alkaline Phosphatase (blood)
• Animals
• Aspartate Aminotransferases (blood)
• Bile Ducts (surgery)
• Bilirubin (metabolism)
• Ceruloplasmin (metabolism)
• Cholestasis (drug therapy, metabolism, pathology)
• Copper (metabolism)
• Disease Models, Animal
• Fibrosis (drug therapy, metabolism, pathology)
• Gene Expression (drug effects)
• Ligation
• Liver (drug effects, metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Molecular Sequence Data
• Molybdenum (therapeutic use)
• Protective Agents (therapeutic use)
• Transforming Growth Factor beta1 (blood)
• Tumor Necrosis Factor-alpha (blood)
• gamma-Glutamyltransferase (blood)