Direct evidence for a role in protection against metal toxicity is derived from gene deletion experiments showing that targeted disruption of MT expression in yeast and mice compromises resistance to copper, cadmium, or zinc toxicity, yet does not otherwise alter the phenotype of the affected organisms under nonstressed conditions ( Hamer et al., 1985 Kelly et al., 1996 Masters et al., 1994 Michalska and Choo, 1993 Thiele et al., 1986). There is now a considerable body of evidence in support of such a function (reviewed recently in Klaassen et al., 1999), although the significance remains a topic of discussion ( Klaassen et al., 1999 Palmiter, 1998 Vallee, 1995). A specific role in protection against cadmium toxicity was later proposed ( Piscator, 1964). Metal detoxification was recognized as a possible function for metallothionein (MT) in early studies describing characteristics associated with its high metal content and metal affinity ( Kägi and Vallee, 1960, 1961). Metallothionein, cadmium, copper, zinc, antisense, phosphorothioate, oligodeoxynucleotide, lysosome, hemocyte, mollusc, oyster The findings represented evidence that expression of MT protects against cadmium toxicity in an estuarine mollusc. The resulting toxicity was greater than that caused by a comparable concentration of copper. Administration of 2.5 μM CdCl 2, which induced MT but had no effect on lysosomal membrane stability when administered alone, reduced neutral red retention time to 41% of control levels when administered in the presence of antisense. This was verified by disrupting MT expression with antisense phosphorothioate-substituted oligodeoxynucleotides. This reversal in the rank order of cadmium and copper suggested that the toxicity of cadmium was tempered by the protective effects of MT. In contrast, copper was highly cytotoxic at concentrations below that which resulted in peak MT induction. Cadmium, which was intermediate in toxicity, required concentrations in excess of that causing peak induction of MT to have substantial effects on lysosomal membrane integrity. Zinc was relatively nontoxic and a poor inducer of MT. Cytotoxicity of the metals, based on decreases in lysosomal neutral red retention times, was copper > cadmium > zinc. The effectiveness of these metals as inducers of MT was cadmium > copper > zinc, with cadmium the most effective inducer in magnitude of induction and sensitivity to dose. In all cases MT induction increased to peak levels with increased metal dose, then declined with continued increases in dose. The relationship between metallothionein (MT) induction and cytotoxicity was examined in isolated oyster hemocytes exposed in vitro to cadmium, copper, and zinc.
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