Tolerance to cadmium cytotoxicity is induced by zinc through non-metallothionein mechanisms as well as metallothionein induction in cultured cells

To investigate the relationship between metallothionein induction and zinc-induced tolerance to cadmium cytotoxicity at the cell level, Chang liver cells were pretreated with a wide range of concentrations of zinc sulfate and challenged with toxic levels of cadmium after removal of zinc. It was found that zinc-pretreated cells were significantly resistant even when the extracellular level of zinc was low and metallothionein was not induced by the metal. Pretreatment with zinc resulted in a lesser accumulation of cadmium and metallothionein after challenge with cadmium. In porcine kidney LLC-PK 1 cells and bovine aortic smooth muscle cells pretreated with low levels of zinc, the intracellular accumulation of cadmium was significantly less and cadmium-induced decrease in intracellular zinc was significantly prevented without a change of metallothionein content; as the result, the toxic effect of cadmium was significantly diminished. It was therefore concluded that a tolerance to cadmium cytotoxicity is induced by zinc via non-metallothionein mechanisms such as decreasing intracellular cadmium as well as metallothionein induction at the cell level. The non-metallothionein mechanism was postulated to be particularly importatnt when the extracellular concentration of zinc is under the threshold for metallothionein induction.