title: Tetrathiomolybdate in the treatment of acute hepatitis in an animal model for Wilson disease.
abstract: OBJECTIVE
  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.
authors.affiliation: Institute of Toxicology and Environmental Hygiene, Technical University Munich, Germany. dominik.klein@gsf.de
authors.forename: Dominik
authors.initials: D
authors.lastname: Klein
authors.forename: Uma
authors.initials: U
authors.lastname: Arora
authors.forename: Josef
authors.initials: J
authors.lastname: Lichtmannegger
authors.forename: Matthias
authors.initials: M
authors.lastname: Finckh
authors.forename: Ulrich
authors.initials: U
authors.lastname: Heinzmann
authors.forename: Karl H
authors.initials: KH
authors.lastname: Summer
mesh_terms: D000208:Acute Disease; D000818:Animals; D002614:Chelating Agents / Q000494:pharmacology*; D003300:Copper / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006520:Hepatitis, Animal / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D006527:Hepatolenticular Degeneration / Q000150:complications*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008854:Microscopy, Electron; D008982:Molybdenum / Q000494:pharmacology*; D051381:Rats; D020332:Rats, Inbred LEC; D020318:Rats, Long-Evans; D013347:Subcellular Fractions / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D002614:Chelating Agents; D003300:Copper; D008982:Molybdenum; C020809:tetrathiomolybdate