Tetrathiomolybdate Protects against Bile Duct Ligation-Induced Cholestatic Liver Injury and Fibrosis
- Ming Song,
- Zhenyuan Song,
- Shirish Barve,
- Jingwen Zhang,
- Theresa Chen,
- Marcia Liu,
- Gavin E. Arteel,
- George J. Brewer and
- Craig J. McClain
- Division of Gastroenterology/Hepatology, Departments of Internal Medicine (M.S., Z.S., S.B., J.Z., C.J.M.) and Pharmacology and Toxicology (S.B., T.C., M.L., G.E.A., C.J.M.), University of Louisville School of Medicine, Louisville, Kentucky; Veterans Administration Medical Center, Louisville, Kentucky (C.J.M.); and Departments of Human Genetics and Internal Medicine, University of Michigan, Ann Arbor, Michigan (G.J.B.)
- Address correspondence to:
Dr. Craig J. McClain, Division of Gastroenterology/Hepatology, Department of Internal Medicine, University of Louisville School of Medicine, 550 S. Jackson St., Louisville, KY 40202. E-mail: cjmccl01{at}gwise.louisville.edu
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)-α and transforming growth factor (TGF)-β1 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 α-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-α and TGF-β1 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.
Footnotes
-
This study was supported in part by National Institute on Alcohol Abuse and Alcoholism Grant AA015970 (to C.J.M.). G.J.B. is the recipient of research support from Pipex Therapeutics, Inc. The University of Michigan has recently licensed the antifibrotic and anti-inflammatory uses of TM to Pipex Therapeutics, Inc. (Ann Arbor, MI). G.J.B. has equity in and is a paid consultant to Pipex Therapeutics, Inc.
-
This manuscript was presented as a poster presentation as follows: Song M, Deaciuc IV, Song Z, Barve S, Zhang J, Lin M, Chen T, Arteel GE, Brewer G, and McClain CJ (2007) Tetrathiomolybdate protects against hepatic fibrosis induced by bile duct ligation in mice. Digestive Disease Week; 2007 May 19–24; Washington, DC. American Association for the Study of Liver Diseases (AASLD), Alexandria, VA.
-
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
-
doi:10.1124/jpet.107.131227.
-
ABBREVIATIONS: TM, tetrathiomolybdate; VEGF, vascular endothelial growth factor; IL, interleukin; TGF, transforming growth factor; Con A, concanavalin A; SOD, superoxide dismutase; BDL, bile duct ligation; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; γ-GTP, γ-glutamyl transpeptidase; TNF, tumor necrosis factor; RT, reverse transcriptase; PCR, polymerase chain reaction; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; MDA, malondialdehyde; 4-HAE, hydroxyalkenal; GSH, glutathione; GSSG, oxidized glutathione; α-SMA, smooth muscle α-actin; TIMP, tissue inhibitor of metalloprotease; MMP, matrix metalloprotease; PAI, plasminogen activator inhibitor; HIF, hypoxia-inducible factor.
-
- Received September 4, 2007.
- Accepted February 21, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
