Metal binding drugs induce synthesis of four proteins in normal cells

Abstract

The synthesis of four proteins in chick embryo cells in culture is induced by exposure to several metal binding drugs and several cations. We reported previously that two chelating agents, kethoxal bis(thiosemicarbazone) and disulfiram induce these proteins. We now extend these findings to include 8-hydroxyquinoline, ortho-phenanthroline, and thiosemicarbazide. The non-chelating analogues of these latter three compounds; 4-hydroxyquinoline, metaphenanthroline, and semicarbazide, do not induce. Other chelating agents, such as thenoyl trifluoroacetone, mercaptopyridine N-oxide, mercaptobenzothiazole, and methimazole induce. However, not all chelators induce since EDTA, penicillamine, α,α-dipyridyl, and several others are ineffective. Several cations, such as copper, zinc, cadmium, and mercuric ions induce, but cobalt, nickel, manganese, iron, lead, and platinum do not. The anions arsenite and arsenate induce, but bromide, dichromate, fluoride, metabisulfite, molybdate, nitrite, permanganate, phosphate, sulfite, and sulfate ions do not. The chelating agents that induce the proteins are ionophores for⁶⁴Cu. The chelating agents that do not induce, such as EDTA, penicillamine, and the nonchelating analogs of the inducers, are not ionophores for copper. Since arsenite induces but is not a copper ionophore, we hypothesize that the common mechanism for both these compounds and the inducing cations is an interaction with a sulfhydryl group site.