Toxicological Sciences 64, 208-215 (2001)
Copyright © 2001 by the Society of Toxicology
MOLECULAR AND GENETIC TOXICOLOGY |
Induction of Apoptosis in Cells by Cadmium: Quantitative Negative Correlation between Basal or Induced Metallothionein Concentration and Apoptotic Rate
,1
* First Department of Internal Medicine, Gunma University School of Medicine, Maebashi 371-8511, Japan;
National Cancer Institute at the National Institute of Environmental Health Science, Research Triangle Park, North Carolina 27709; and
Department of Health Science, Gunma University School of Medicine, Maebashi 371-8511, Japan
Metallothionein (MT) often reduces the adverse effects of cadmium (Cd), but how it may alter Cd-induced apoptosis is unclear. The goal of this study was to define the role of MT in Cd-induced apoptosis using cell lines with widely varying sensitivity to Cd. Effects of Cd on growth of human hepatocellular carcinoma cell lines (HepG2 and PLC/PRF/5) were investigated and compared with Chang cells. These cells were cultured with 0, 5, 10, 20, 40, 80, and 120 µM of Cd for 3, 6, 12, and 24 h. Significant cytolethality was observed in HepG2 and PLC/PRF/5 cells in a time- and concentration-dependent manner, with LC50 values of 24 µM and 13 µM, respectively. However, Chang cells were much less sensitive to Cd-induced cytotoxicity (LC50, 64 µM). Apoptotic cell death occurring at cytolethal concentrations was demonstrated in all cell lines by DNA fragmentation on agarose gel electrophoresis or by ELISA. When MT was measured, there was a highly significant negative linear correlation between the basal cellular MT concentration or Cd-induced MT and the rate of apoptosis induced by Cd in these cell lines. Treating HepG2 cells with zinc (Zn) made the relatively sensitive HepG2 cell line resistant to Cd-induced apoptosis, likely due to Zn-induced MT. In fact, there was also a significant negative linear correlation between the amount of Zn-induced MT in HepG2 cells and the rate of Cd-induced apoptosis. These findings revealed that basal or induced MT perturbs Cd-induced apoptotic cell death in various cell lines, and a strong negative correlation exists between cellular MT content and the rate of apoptosis induced by Cd.
Key Words: cadmium; human; hepatoma; apoptosis; metallothionein; zinc; in vitro.
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