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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Tetrathiomolybdate Protects against Bile Duct Ligation-Induced Cholestatic Liver Injury and Fibrosis

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.)

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)- 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 -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- 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.

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