Targeting of tetrathiomolybdate on the copper accumulating in the liver of LEC rats.
The uptake of tetrathiomolybdate (TTM) by the liver and the removal of copper (Cu) accumulating in the liver in a form bound to metallothionein (MT) by TTM were studied in Long-Evans cinnamon (LEC) rats, an animal model of Wilson disease, in order to develop better treatments for the disease and Cu toxicity. Although molybdenum (Mo) was incorporated in a dose-dependent manner into the livers of both LEC and Long-Evans agouti (LEA) rats, the original strain of LEC rats used as a reference animal, the uptake into the liver of LEC rats was 13 times higher than that in LEA rats. The concentration of Mo in the soluble fraction plateaued and it was distributed more in the insoluble fraction with a higher dose in LEC rats. The concentration of Cu in the whole livers of LEC rats was decreased by TTM in a dose-dependent manner only at lower doses. However, the concentration of Cu in the soluble fraction continued to decrease with the dose of TTM. The results can be explained in terms of complex formation. Namely, TTM forms a complex with Cu, tentatively referred to a Cu/TTM complex, that can be effluxed into the bloodstream, and then binds selectively to albumin when the dose of TTM is low. On the other hand, TTM forms an insoluble complex, named as a Cu/TTM polymer that is precipitated in the liver when the dose is high. The results further indicate that TTM taken up by a cell is immobilized in the cell through the dose-dependent formation of a complex containing Cu, Mo and sulfur (S), which causes further uptake of TTM. TTM injected into rats or incubated in vitro with serum does not remove Cu from ceruloplasmin. TTM is, thus, suggested to target a cell accumulating excess Cu as Cu-MT, and to remove Cu selectively without interacting with Cu in Cu-enzymes. The results indicate that TTM is taken up by the liver depending on the amount of Cu accumulating in the form of MT, and then Cu is effluxed together with Mo in the form of Cu/TTM complex into the bloodstream.
Ogra
Y
Y
Faculty of Pharmaceutical Sciences, Chiba University, Japan. ogra@athenaeum.p.chiba-u.ac.jp
Suzuki
K T
KT
D000818:Animals; D001693:Biological Transport, Active; D002570:Ceruloplasmin / Q000378:metabolism; D003300:Copper / Q000097:blood / Q000378:metabolism* / Q000633:toxicity; D004195:Disease Models, Animal; D005260:Female; D006527:Hepatolenticular Degeneration / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008668:Metallothionein / Q000378:metabolism; D008982:Molybdenum / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011485:Protein Binding; D051381:Rats; D011922:Rats, Mutant Strains
D003300:Copper; D008982:Molybdenum; D008668:Metallothionein; C020809:tetrathiomolybdate; D002570:Ceruloplasmin