Tetrathiomolybdate protects against bile duct ligation-induced cholestatic liver injury and fibrosis.
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.
Song
Ming
M
Division of Gastroenterology/Hepatology, Department of Internal Medicine, University of Louisville School of Medicine, 550 S. Jackson St., Louisville, KY 40202, USA.
Song
Zhenyuan
Z
Barve
Shirish
S
Zhang
Jingwen
J
Chen
Theresa
T
Liu
Marcia
M
Arteel
Gavin E
GE
Brewer
George J
GJ
McClain
Craig J
CJ
D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001652:Bile Ducts / Q000601:surgery; D001663:Bilirubin / Q000378:metabolism; D002570:Ceruloplasmin / Q000378:metabolism; D002779:Cholestasis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003300:Copper / Q000378:metabolism; D004195:Disease Models, Animal; D005355:Fibrosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D008026:Ligation; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D008982:Molybdenum / Q000627:therapeutic use*; D020011:Protective Agents / Q000627:therapeutic use*; D053773:Transforming Growth Factor beta1 / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D005723:gamma-Glutamyltransferase / Q000097:blood
D020011:Protective Agents; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D003300:Copper; D008982:Molybdenum; C020809:tetrathiomolybdate; D002570:Ceruloplasmin; D005723:gamma-Glutamyltransferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D001663:Bilirubin