title: Depletion of ATP and oxidative stress underlie zinc-induced cell injury.
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.
authors.affiliation: Charles University in Prague, Faculty of Medicine in Hradec Králové, Department of Medical Biology and Genetics, Czech Republic. rudolf@lfhk.cuni.cz
authors.forename: Emil
authors.initials: E
authors.lastname: Rudolf
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology; D016923:Cell Death / Q000502:physiology*; D045744:Cell Line, Tumor; D006801:Humans; D008668:Metallothionein / Q000378:metabolism; D018384:Oxidative Stress; D013481:Superoxides / Q000378:metabolism; D015032:Zinc / Q000378:metabolism / Q000633:toxicity*
chemical_list: D013481:Superoxides; D000255:Adenosine Triphosphate; D008668:Metallothionein; D015032:Zinc