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 H₂S

Abstract

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.

Cyanobacteria in Sulfidic Spring Microbial Mats Can Perform Oxygenic and Anoxygenic Photosynthesis Simultaneously during an Entire Diurnal Period

“…Production of oxygen in the presence of sulfide is tied to severe toxification risks by reactive oxygen species (ROS) generation (Latifi et al, 2009; Hoffman et al, 2012). A counterbalancing advantage of such adaptation strategy remains mysterious to us – especially in the modern world where potential competitors for space and resources [e.g., SOB and obligate anoxygenic phototrophs (Klatt et al, 2016)] as well as microorganisms that might affect this competition via feedback mechanisms on the S- and C-cycle (e.g., sulfate reducers) have developed sophisticated strategies to cope with fluctuating oxygen and sulfide concentrations (e.g., Blankenship and Matsuura, 2003; Baumgartner et al, 2006; Berghoff et al, 2011).…”

Chemical foundations of hydrogen sulfide biology

“…Chen et al concluded that the reaction is too slow overall to be biologically relevant [35]. However, metals [123,126,127,134–139] (also see 5.2.2 ) and other biological substances such as phenols and aldehydes [134] can accelerate the reaction. Indeed, it has been known since 1958 that certain metalloprotein complexes (including ferritin) can catalyze H 2 S oxidation [140].…”

“…This suggests that in cells H 2 S could function biologically to mask the chelatable or labile iron pool and prevent formation of highly reactive oxygen species and thus contribute to its salutatory function in a variety of pathologies involving disturbances in O 2 , a possibility for which there is indeed evidence [224]. However, as mentioned in 4.1 , metal catalyzes H 2 S autoxidation that causes reactive oxygen species formation and consequent oxidative damage to cellular components (including DNA) [139]. …”

Electrophilic sulfhydration of 8-nitro-cGMP involves sulfane sulfur

“…However, as most of the metal catalysts used in the previous study were redox active, they would nicely fit into our mechanisms involving sulfhydryl radical species formation as a starting point. 32 …”