Generation of DNA-damaging reactive oxygen species via the autoxidation of hydrogen sulfide under physiologically relevant conditions: chemistry relevant to both the genotoxic and cell signaling properties of H(2)S.

Hydrogen sulfide (H(2)S) 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 H(2)S is a DNA-damaging mutagen. In the work reported here, the chemical mechanisms of DNA damage by H(2)S were examined. Using a plasmid-based DNA strand cleavage assay, we found that micromolar concentrations of H(2)S generated single-strand DNA cleavage. Mechanistic studies indicate that this process involved autoxidation of H(2)S 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 H(2)S proceeded in the presence of physiological thiol concentrations, and the known byproducts of H(2)S oxidation such as thiosulfate, sulfite, and sulfate do not contribute to the strand cleavage process. However, initially generated oxidation products such as persulfide (S(2)(2-)) 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 H(2)S is discussed.