Abstract
The mechanisms of cell injury resulting in a special type of cell death combining the features of apoptosis and necrosis were examined in Hep-2 cells exposed to 300 microM zinc sulfate during 24 h. Acute exposure to zinc induced a rapid rise in metallothionein levels and increased oxidative stress occurring in the absence of a significant early ATP depletion. Accentuated ATP loss and elevated levels of superoxide at later treatment intervals (12 h and longer) were present along with increased DNA damage. Manipulation with ATP production and inhibition of NADPH oxidase had a positive effect on zinc-related increase in oxidative stress and influenced the observed type of cell death. These results suggest that Hep-2 cells acutely exposed to zinc increase intracellular labile zinc stores and over express metalothioneins. Elevated production of peroxides in zinc-treated cells is at later treatment intervals accompanied by an increase in superoxide levels, possibly by activation of NADPH oxidase, DNA damage and severe ATP loss. Prevention of critical ATP depletion and, in particular, inhibition of oxidative stress attenuates zinc-mediated cell injury and stimulates apoptosis-like phenotype in exposed cells.
Highlights
Besides its recognized contribution to many biological processes, zinc (Zn) may negatively influence cell homeostasis and bring about cell injury resulting in cell death
In our previous work we have shown that high external Zn concentrations stimulate morphologically distinct features in exposed Hep-2 cells and these features resemble some accepted characteristics of an apoptotic process [20]
Cell injury and cell death associated with exposures to external Zn are nowadays studied to [A] understand the toxicity of Zn in some known human pathologies such as neurodegenerative diseases, diabetes or renal damage [8] or to [B] investigate potential effects of Zn supplementation in several types of malignant diseases, including prostate cancer, gastrointestinal tumors or hemoproliferative diseases [5, 6, 14]
Summary
Besides its recognized contribution to many biological processes, zinc (Zn) may negatively influence cell homeostasis and bring about cell injury resulting in cell death. Cellular Zn trafficking and its intracellular compartmentalization are under strict control, with numerous recognized metallic sensors, transporters and inducible influx as well as efflux mechanisms controlling the optimal intracellular Zn levels [7]. Upon entry into the cell, Zn ions are rapidly sequestered by ligand-specific binding mechanisms and only a minor fraction of Zn remains in a free state. Still, certain events such as shifts in intracellular redox status or exposure to high external Zn concentrations may precipitate a rapid rise in intracellular free Zn leading to cytotoxicity and cell death, as demonstrated in several experimental models [22, 23, 26]. Elevated Zn can potently suppress cellular ATP synthesis at all levels; i.e., by inhibiting glycolysis, Krebs cycle or oxidative phosphorylation [3]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
