Comparative mechanism and toxicity of tetra- and dithiomolybdates in the removal of copper

Tetrathiomolybdate (TTM) can be used as a specific chelator to remove copper (Cu) accumulating in the form bound to metallothionein (MT) in the livers of Wilson disease patients and Long–Evans rats with a cinnamon-like coat color (LEC rats). However, an adverse effect, hepatotoxicity, was observed o...

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Bibliographic Details
Published in:Journal of inorganic biochemistry 1999-06, Vol.75 (3), p.199-204
Main Authors: Ogra, Yasumitsu, Komada, Yoshiko, Suzuki, Kazuo T.
Format: Article
Language:English
Subjects:
Animals
Ceruloplasmin - metabolism
Chelating Agents - chemistry
Chelating Agents - therapeutic use
Chelating Agents - toxicity
Copper
Copper - blood
Copper - chemistry
Drug Stability
Hepatolenticular Degeneration - drug therapy
Humans
LEC rats
Liver - metabolism
Molybdenum - blood
Molybdenum - chemistry
Molybdenum - metabolism
Molybdenum - therapeutic use
Molybdenum - toxicity
Rats
Rats, Long-Evans
Sulfide
Tetrathiomolybdate
Wilson disease
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Summary:Tetrathiomolybdate (TTM) can be used as a specific chelator to remove copper (Cu) accumulating in the form bound to metallothionein (MT) in the livers of Wilson disease patients and Long–Evans rats with a cinnamon-like coat color (LEC rats). However, an adverse effect, hepatotoxicity, was observed occasionally on its clinical application. The mechanism underlying the adverse effect of TTM has been studied in comparison with dithiomolybdate (DTM), and a safer and more effective therapy by TTM was proposed based on the mechanism. The activity of glutamic-pyruvic transaminase (GPT) in serum was shown to increase significantly on the treatment of Wistar rats with sulfide produced through hydrolytic degradation of TTM and DTM, the latter being more easily degraded. The hydrolytic degradation of TTM was enhanced under acidic conditions. Cu in Cu-containing enzymes such as Cu,Zn-superoxide dismutase (SOD) in liver and ceruloplasmin (Cp) in plasma was decreased by excessive thiomolybdates, the Cu being found in the plasma in the form of a Cu/thiomolybdate/albumin complex. The decreased amounts of Cu in SOD and Cp were explained by the sequestration of Cu from their chaperones by thiomolybdates rather than the direct removal of Cu from the enzymes. Although both TTM and DTM remove Cu from MT, DTM is not appropriate as a therapeutic agent for Wilson disease due to its easy hydrolysis and production of sulfide.
ISSN:0162-0134
1873-3344
DOI:10.1016/S0162-0134(99)00057-4