tetrathiomolybdate and Fibrosis

Anticopper drugs that have been developed to treat Wilson's disease, a disease of copper toxicity, include tetrathiomolybdate, zinc, penicillamine, and trientine. Lowering copper levels by a modest amount in non-Wilson's patients with tetrathiomolybdate inhibits angiogenesis, fibrosis and inflammation while avoiding clinical copper deficiency. Through this mechanism tetrathiomolybdate has proven effective in numerous animal models of cancer, retinopathy, fibrosis, and inflammation. Penicillamine has efficacy in rheumatoid arthritis and trientine has efficacy in diabetic neuropathy and diabetic heart disease. If clinical studies support the animal work, anticopper therapy holds promise for therapy of cancer, fibrotic disease and inflammatory and autoimmune diseases.

Topics: Animals; Copper; Fibrosis; Humans; Inflammation; Molybdenum; Neoplasms; Neovascularization, Pathologic; Penicillamine; Trientine

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.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Aspartate Aminotransferases; Bile Ducts; Bilirubin; Ceruloplasmin; Cholestasis; Copper; Disease Models, Animal; Fibrosis; gamma-Glutamyltransferase; Gene Expression; Ligation; Liver; Male; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Molybdenum; Protective Agents; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

Tetrathiomolybdate was originally developed for use in Wilson's disease. However, lowering copper levels to below normal levels with tetrathiomolybdate has been found to have efficacy in cancer, probably by turning down signaling by angiogenic cytokines. More recently, we have shown in animals models that tetrathiomolybdate dramatically inhibits pulmonary and liver fibrosis. In other animal models, we have shown that the drug also inhibits liver damage from concanavalin A and acetaminophen, and heart damage from doxorubicin. These studies are briefly reviewed, and we then present data on tetrathiomolybdate's partially protective effect against diabetes in non-obese diabetic mice, an autoimmune model of type I diabetes. Possible mechanisms of tetrathiomolybdate's protective effect are briefly considered.

Topics: Animals; Autoimmune Diseases; Diabetes Mellitus, Type 1; Disease Models, Animal; Fibrosis; Inflammation; Mice; Mice, Inbred NOD; Molybdenum; Obesity