This study evaluated the kinetic signature of toxicity of four heavy metals known to cause severe health and environmental issues—cadmium (Cd), mercury (Hg) lead (Pb) arsenic (As)—and the mixture of all four metals (Mix) on MCF7 cancer cells, in the presence and absence of the antioxidant glutathione (GSH). The study was carried out using real time cell electronic sensing (RT-CES). RT-CES monitors in real time the electrical impedance changes at the electrode/culture medium interface due to the number of adhered cells, which is used as an index of cell viability. Cells were seeded for 24 h before exposure to the metals and their mixtures. The results showed that in the presence and absence of cellular glutathione, arsenic was the most cytotoxic of all five treatments, inducing cell death after 5 h of exposure. Lead was the least cytotoxic in both scenarios. In the presence of cellular GSH, the cytotoxic trend was As > Cd > MIX > Hg > Pb, while in the absence of GSH, the cytotoxic trend was As > Hg > MIX > Cd > Pb. The findings from this study indicate the significance of glutathione-mediated toxicity of the metals examined—particularly for mercury—and may be clinically relevant for disorders such as autism spectrum disorder where decreased glutathione-based detoxification capacity is associated with increased mercury intoxication.
The effect of intracellular level of GSH on the cytotoxicity and interaction of four environmentally relevant metals arsenic, cadmium, mercury and lead (As, Cd, Hg, and Pb) was investigated. L-Buthionine Sulfoximine (LBSO) was used to inhibit the intracellular level of GSH in MCF 7 cells. Both individual and combined cytotoxicities of the four metals on the cells were assayed by spectrofluorometric counting of the surviving cells after 24-hour exposure. Exposure of the cells to three of the studied metals: As, Cd, and Hg resulted in the production of significantly (p<0.5) higher level of cellular GSH relative to the control. However, cells exposed to Pb with or without pretreatment with LBSO exhibited about 50% decrease in cellular GSH. Individual metal toxicity was higher in GSH-depleted cells relative to GSH-rich cells; However, the effect of GSH depletion was slightly metal selective as As and Hg exhibited toxicities. Cells exposed to the composite mixture of all four metals indicated additive and antagonistic interactions in GSH depleted cells and GSH rich respectively.
Breast cancer is the second major cause of death in women. Reports show that breast cancer cells have high level of glutathione. This research was done to characterize the kinetic signature and mechanism of cell death using the oxidative stress pathway when mercury (Hg) and L‐buthionine sulphoximine (LBSO, inhibits glutathione production) are presented to MCF‐7 cells. The hypothesis tested is that the potentiating effects of LBSO will be higher with Hg than with As. Production was inhibited by treating the MCF7 cell line with 2.5 mM (LBSO) and then exposed to mercury 5.4ppm Hg. The cytotoxic effect was studied in real time using Real Time Cell Electronic Sensing (RTCES). To determine the oxidative stress pathway used, mitochondrial transmembrane potential (∆øm), Reactive Oxygen Species (ROS), superoxide anion and Glutathione (GSH) levels were studied using Rhodamine123 fluorescent (Rho123), 2′,7′‐Dichlorodihydrofluorescein (H2DCFDA), Dihydroethidium (DHE), 5‐Chloromethylfluorescein diacetate (CMFDA) dyes respectively. Each sample, 10,000 events were collected using FACSCalibur flow cytometer. ROS and O2 • levels were expressed as mean fluorescence intensities (MFI), calculated with CellQuest. The results did not show a vast difference between Hg and LBSO and Hg alone. Results reveal that Hg might be a better candidate for cancer therapy compared to As due to As high toxicity.
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