Cadmium-induced DNA strand damage in cultured liver cells: reduction in cadmium genotoxicity following zinc pretreatment.

It is well established that zinc can decrease the carcinogenicity and toxicity of cadmium. In some tissues this may be due to the induction of metallothionein (MT). Therefore, in the present investigation, the effect of zinc pretreatment on cadmium-induced DNA strand damage was determined. The alkaline elution technique was used to assess DNA single strand damage (SSD) in cultured cells derived from rat hepatocytes (TRL-1215), a cell line previously shown to have an active MT gene. The ability to detect SSD in TRL-1215 was established following exposure to gamma-irradiation. Exposure to increasing doses of gamma-irradiation (150-600 rad) resulted in a dose-dependent increase in SSD. Exposure of TRL-1215 cells to CdCl2 for 1 hr at 37 degrees C, using concentrations from 5 to 250 microM, failed to induce detectable SSD in these cells; however, exposure to 500 microM CdCl2 resulted in significant SSD. A time-dependent increase in SSD was demonstrated following a 2 hr continuous exposure to 500 microM CdCl2. Pretreatment of cells with 80 microM zinc acetate, 18 hr prior to exposure to 500 microM CdCl2, resulted in markedly reduced SSD when compared to non-pretreated cells. Zinc pretreatment increased the level of MT gene expression as well as MT protein production. The decrease in DNA strand damage associated with cadmium exposure was not due to a decrease in cadmium accumulation by zinc pretreated cells. In fact, cellular cadmium burden was increased over 2-fold following zinc pretreatment. In addition to protection against cadmium genotoxicity, zinc pretreatment also reduced the cytotoxicity associated with a 2-hr, 500 microM cadmium exposure. These data indicate that zinc pretreatment reduces cadmium genotoxicity, possibly through alterations in MT gene expression.