The role of intracellular zinc in chromium(VI)-induced oxidative stress, DNA damage and apoptosis.
Several studies have demonstrated that zinc is required for the optimal functioning of the skin. Changes in intracellular zinc concentrations have been associated with both improved protection of skin cells against various noxious factors as well as with increased susceptibility to external stress. Still, little is known about the role of intracellular zinc in hexavalent chromium (Cr(VI))-induced skin injury. To address this question, the effects of zinc deficiency or supplementation on Cr(VI)-induced cytotoxicity, oxidative stress, DNA injury and cell death were investigated in human diploid dermal fibroblasts during 48 h. Zinc levels in fibroblasts were manipulated by pretreatment of cells with 100 microM ZnSO4 and 4 or 25 microM zinc chelator TPEN. Cr(VI) (50, 10 and 1 microM) was found to produce time- and dose-dependent cytotoxicity resulting in oxidative stress, suppression of antioxidant systems and activation of p53-dependent apoptosis which is reported for the first time in this model in relation to environmental Cr(VI). Increased intracellular zinc partially attenuated Cr(VI)-induced cytotoxicity, oxidative stress and apoptosis by enhancing cellular antioxidant systems while inhibiting Cr(VI)-dependent apoptosis by preventing the activation of caspase-3. Decreased intracellular zinc enhanced cytotoxic effects of all the tested Cr(VI) concentrations, leading to rapid loss of cell membrane integrity and nuclear dispersion--hallmarks of necrosis. These new findings suggest that Cr(VI) as a model environmental toxin may damage in deeper regions residing skin fibroblasts whose susceptibility to such toxin depends among others on their intracellular Zn levels. Further investigation of the impact of Zn status on skin cells as well as any other cell populations exposed to Cr(VI) or other heavy metals is warranted.
Rudolf
Emil
E
Department of Medical Biology and Genetics, Charles University in Prague, Faculty of Medicine in Hradec Králové, Simkova 870, 500 38 Hradec Králové, Czech Republic. rudolf@lfhk.cuni.cz
Cervinka
Miroslav
M
D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002857:Chromium / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis; D004249:DNA Damage / Q000187:drug effects* / Q000235:genetics; D020405:Dermis / Q000166:cytology / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D005979:Glutathione Peroxidase / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D006801:Humans; D008668:Metallothionein / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015032:Zinc / Q000378:metabolism*
D000975:Antioxidants; D016159:Tumor Suppressor Protein p53; D002857:Chromium; C074702:chromium hexavalent ion; D004247:DNA; D008668:Metallothionein; D005979:Glutathione Peroxidase; D005980:Glutathione Reductase; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D015032:Zinc