A comparison of the effects of penicillamine, trientine, and trithiomolybdate on [35S]-labeled metallothionein in vitro; implications for Wilson's disease therapy.
The synthesis of radiolabeled metallothionein was induced in rats in vivo by the injection of CuSO4 and [35S]-cysteine. Treatment of "cold" rat liver cytosol "spiked" with purified [35S] metallothionein with Penicillamine and Trientine showed that even at relatively high concentrations (up to 50 mg/g liver, wet weight), these compounds had no effect on the copper peak or the position of the [35S] label in the cytosol eluate after Sephadex G-75 gel filtration. By contrast, incubation of the "spiked" liver cytosol with Trithiomolybdate, even at relatively low concentrations (0.5 mg/g liver, wet weight), resulted in a transfer of metallothionein copper to high molecular weight protein fractions; the position of the [35S] apoprotein was unaffected. This copper "stripping" effect on metallothionein supports clinical and other evidence that thiomolybdates have a genuine decoppering effect in vivo whereas Penicillamine and Trientine have another mode of action and indicates that thiomolybdates might provide a more rational alternate therapy for Wilson's disease patients.
McQuaid
A
A
Biochemistry Department, University of Dublin, Trinity College, Ireland.
Mason
J
J
D000818:Animals; D003300:Copper / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D006527:Hepatolenticular Degeneration / Q000188:drug therapy*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008668:Metallothionein / Q000378:metabolism*; D008982:Molybdenum / Q000494:pharmacology*; D010396:Penicillamine / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013462:Sulfur Radioisotopes; D014266:Trientine / Q000494:pharmacology*
D013462:Sulfur Radioisotopes; C034540:trithiomolybdic acid; D003300:Copper; D008982:Molybdenum; D008668:Metallothionein; D010396:Penicillamine; D014266:Trientine