Mechanisms of cell death induced by cadmium and arsenic.
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.
Jimi
Shiro
S
First Department of Internal Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonanku, Fukuoka 814-0180, Japan. sjimi@fukuoka-u.ac.jp
Uchiyama
Masanobu
M
Takaki
Aya
A
Suzumiya
Jyunji
J
Hara
Syuji
S
D000818:Animals; D001151:Arsenic / Q000633:toxicity*; D002104:Cadmium / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects*; D002460:Cell Line; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007684:Kidney Tubules / Q000166:cytology; D015227:Lipid Peroxidation; D008564:Membrane Potentials / Q000502:physiology; D008668:Metallothionein / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats
D002104:Cadmium; D008668:Metallothionein; D005978:Glutathione; D001151:Arsenic