ENHANCED SENSITIVITY TO OXIDATIVE STRESS IN CULTURED EMBRYONIC-CELLS FROM TRANSGENIC MICE DEFICIENT IN METALLOTHIONEIN-I AND METALLOTHIONEIN-II GENES

Embryonic cells from transgenic mice with targeted disruption of metal lothionein I and II genes expressed no detectable metallothionein eith er constitutively or after treatment with cadmium, in contrast to cult ured cells that were wild type or heterozygous for the loss of the met allothionein genes. Metallothionein null cells were most sensitive to the cytotoxic effects of cadmium, the membrane permeant oxidant tert-b utylhydroperoxide, and the redox cycling toxin paraquat. No marked dif ferences were seen among the wild type, heterozygous, or metallothione in null cells in glutathione levels or in the activity of CuZn-superox ide dismutase, glutathione peroxidase, or catalase. Nevertheless, meta llothionein null cells were more sensitive to tert-butylhydroperoxide- induced oxidation as ascertained by confocal microscopic imaging of di chlorofluoroscein fluorescence. These results indicate basal metalloth ionein levels can function to regulate intracellular redox status in m ammalian cells.