Cadmium (Cd) and
arsenic (As) are known toxic metals in humans. As trioxide (
As(2)0(3)) has been recently used as a mitochondria-targeting
drug in
acute promyelocytic leukemia. In the present study, we examined the intracellular action of these metals using rat kidney tubular cells and cells tolerant to the metals. The cells were cultured with CdCl(2) (1-10 micro M) or
As(2)O(3) (1-2.5 micro M). Cells tolerant to Cd and As (Cd-T and As-T, respectively) were defined as cells that survived at toxic concentrations of each
metal. Both Cd and As induced cell toxicity in a dose-dependent fashion, which was accompanied by fragmented
DNA and decreased mitochondrial membrane potential. Intracellular
glutathione (GSH) increased with the increase of Cd and As concentration. In Cd-T and As-T cells, GSH levels were twice those observed in normal cells. When each
metal-tolerant culture was exposed to the other different
metal, i.e., As or Cd, the protective property was maintained. However, when
buthionine sulfoximine (BSO) was added to the
metal-tolerant cultures, apoptosis was restored in both Cd-T and As-T. Our results indicate that (1) although GSH is increased in NRK52E by the addition of Cd and As, mitochondria-mediated apoptosis can be still induced, (2) the protective property against
metal-induced cytotoxicity is identical in Cd-T and As-T cultures, and (3) although GSH was higher in the
metal-tolerant cell lines, depression of GSH by BSO induced apoptosis. We conclude that Cd- and As-induced apoptosis is mediated by an identical mechanism involving intracellular GSH reactive oxidation.