Induction of apoptosis in mammalian cells by cadmium and zinc.

In various mammalian cells, two group IIb metals, cadmium and zinc, induce several morphological and biochemical effects that are salient features of programmed cell death. In C6 rat glioma cells, cadmium caused externalization of phosphatidylserine, breakdown of the mitochondrial membrane potential, activation of caspase-9, internucleosomal DNA fragmentation, chromatin condensation, and nuclear fragmentation. In NIH3T3 murine fibroblasts, cadmium-induced apoptosis was inhibited by overexpression of the antiapoptotic protein Bcl-2. Cadmium-induced DNA fragmentation in C6 cells was independent of inhibition of protein kinase A (PKA), protein kinase C (PKC), mitogen-activated protein kinase (MAPK), phosphatidylinositol-3-kinase, Ca-calmodulin-dependent protein kinase, and protein kinase G. Zinc at moderate concentrations (10-50 microM) protected against programmed cell death induced by cadmium, whereas deprivation of zinc by the membrane-permeable chelator N,N,N',N-terakis-(2-pyridylmethyl)ethylenediamine (TPEN) caused cell death with features characteristic of apoptosis. On the other hand, at elevated extracellular levels (150-200 microM), zinc alone caused programmed cell death in C6 cells. Zinc-induced apoptosis was independent of inhibition of PKA, PKC, guanylate cyclase and MAPK, but it was suppressed in the presence of 100 microM lanthanum chloride.