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

Tetrathiomolybdate (TTM) can be used as a specific chelator to remove coppe r (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 c olor (LEC rats). However, an adverse effect, hepatotoxicity, was observed o ccasionally on its clinical application. The mechanism underlying the adver se 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 me chanism. The activity of glutamic-pyruvic transaminase (GPT) in serum was s hown to increase significantly on the treatment of Wistar rats with sulfide produced through hydrolytic degradation of TTM and DTM, the latter being m ore easily degraded. The hydrolytic degradation of TTM was enhanced under a cidic conditions. Cu in Cu-containing enzymes such as Cu,Zn-superoxide dism utase (SOD) in liver and ceruloplasmin (Cp) in plasma was decreased by exce ssive 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 we re explained by the sequestration of Cu from their chaperones by thiomolybd ates rather than the direct removal of Cu from the enzymes. Although both T TM 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. ( C) 1999 Elsevier Science Inc. All rights reserved.