PuSH - Publication Server of Helmholtz Zentrum München

Klein, D. ; Arora, U. ; Lichtmannegger, J. ; Finckh, M. ; Heinzmann, U. ; Summer, K.H.

Tetrathiomolybdate in the treatment of acute hepatitis in an animal model for Wilson disease.

J. Hepatol. 40, 409-416 (2004)
DOI
Open Access Green as soon as Postprint is submitted to ZB.
Tetrathiomolybdate (TTM) is a potent copper-chelating agent that has been shown to be effective in Wilson disease patients with neurological symptoms. Here, we investigate the potential use of TTM in treating the acute hepatic copper toxicosis in Long-Evans Cinnamon (LEC) rats, an authentic model for Wilson disease. METHODS: After the onset of acute hepatitis, LEC rats were treated once with 10 mg TTM/kg. After 1 and 4 days, parameters of liver toxicity and the subcellular distribution and binding of copper and iron were studied. RESULTS: In 11 out of 12 rats TTM rapidly improved acute hepatitis. Hepatic copper decreased through removal from cytosolic metallothionein and lysosomal metallothionein polymers. The remaining lysosomal copper forms a metallothionein-copper-TTM complex. In an almost moribund rat, however, TTM caused severe hepatotoxicity with fatal outcome. CONCLUSIONS: TTM is effective in treating acute hepatitis in LEC rats when applied before the animals become moribund. TTM appears to act by removing the presumable reactive copper associated to lysosomal metallothionein polymers. The remaining lysosomal copper seems to be inactivated by forming a complex with TTM. Moreover, TTM removes copper from cytosolic copper-containing metallothionein. As a consequence, metallothionein is degraded and the uptake of copper-metallothionein into the lysosomes and the formation of the metallothionein polymer associated copper is reduced.
Altmetric
Additional Metrics?
[➜Log in]
Edit extra informations Login
Publication type Article: Journal article
Document type Scientific Article
Keywords Wilson disease; Long-Evans Cinnamon rat; Therapy; Ammonium tetrathiomolybdate; Copper toxicity; Iron overload; Hepatitis
ISSN (print) / ISBN 0168-8278
e-ISSN 1600-0641
Journal Journal of Hepatology
Quellenangaben Volume: 40, Issue: 3, Pages: 409-416 Article Number: , Supplement: ,
Publisher Elsevier
Reviewing status Peer reviewed
Institute(s) Institute of Molecular Toxicology and Pharmacology (TOX)
Institute of Pathology (PATH)