Hydrogen sulfide (H2S) has long been known for its toxic properties; however, in recent years, evidence has emerged that this small, gaseous molecule may serve as an endogenous cell-signaling agent. Though perhaps surprising in light of its potential role as an endogenous signaling agent, a number of studies have provided evidence that H2S is a DNA-damaging mutagen. In the work reported here, the chemical mechanisms of DNA damage by H2S were examined. Using a plasmid-based DNA strand cleavage assay, it was found that micromolar concentrations of H2S generated single-strand DNA cleavage. Mechanistic studies indicate that this process involved autoxidation of H2S to generate superoxide, hydrogen peroxide and, ultimately, the well-known DNA-damaging agent hydroxyl radical via a trace metal-mediated Fenton-type reaction. Strand cleavage by H2S proceeded in the presence of physiological thiol concentrations and the known byproducts of H2S oxidation such as thiosulfate, sulfite, and sulfate do not contribute to the strand cleavage process. On the other hand, initially-generated oxidation products such as persulfide (S22−) likely undergo rapid autoxidation reactions that contribute to the generation of superoxide. The potential relevance of autoxidation processes to the genotoxic and cell signaling properties of H2S is discussed.
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