Silver ions induce oxidative stress and intracellular zinc release in human skin fibroblasts.

Silver compounds used as topical antimicrobial agents are known to exert toxic effects on skin cells. The aim of this study was to investigate whether the toxicity of silver ions, in analogy to other transition metal ions, depends on pro-oxidant effects. We treated human skin fibroblasts with concentrations of AgNO(3) not affecting cell proliferation, mitochondrial activity, or cell viability and found that Ag(+) strongly increases the production of reactive oxygen species, including superoxide anion radicals. These effects correspond to a strong decrease in intracellular reduced glutathione and to an increased susceptibility to H(2)O(2)-induced cell death. In addition, AgNO(3) down-regulates the expression of antioxidant genes such as the transcription factor Nrf2 and its target gene glutamate-cysteine ligase catalytic subunit. Furthermore Ag(+) induces a transient intracellular zinc release and increases the mRNA and protein expression of the zinc-binding protein metallothionein by activating the metal-responsive transcription factor 1, as verified by RNA interference. In conclusion, we show for the first time that Ag(+) induces oxidative stress and affects intracellular zinc homeostasis in human skin fibroblasts. The understanding of the mechanism involved in silver toxicity might contribute to new strategies for managing the therapy of skin infections.