Hydrogen Sulfide in Biochemistry and Medicine

Significance: An abundance of experimental evidence suggests that hydrogen sulfide (H2S) plays a prominent role in physiology and pathophysiology. Many targets exist for H2S therapy. The molecular targets of H2S include proteins, enzymes, transcription factors, and membrane ion channels. Recent Advances: Novel H2S precursors are being synthesized and discovered that are capable of releasing H2S in a slow and sustained manner. This presents a novel and advantageous approach to H2S therapy for treatment of chronic conditions associated with a decline in endogenous H2S, such as diabetes and cardiovascular disease. Critical Issues: While H2S is cytoprotective at physiological concentrations, it is not universally cytoprotective, as it appears to have pro-apoptotic actions in cancer cells and is well known to be toxic at supraphysiological concentrations. Many of the pleiotropic effects of H2S on health are associated with the inhibition of inflammation and upregulation of prosurvival pathways. The powerful anti-inflammatory, cytoprotective, immunomodulating, and trophic effects of H2S on the vast majority of normal cells seem to be mediated mainly by its actions as an extremely versatile direct and indirect antioxidant and free radical scavenger. While the overall effects of H2S on transformed (i.e., malignant) cells can be characterized as pro-oxidant and pro-apoptotic, they contrast sharply with the cytoprotective effects on most normal cells. Future Directions: H2S has become a molecule of great interest, and several slow-releasing H2S prodrugs are currently under development. We believe that additional agents regulating H2S bioavailability will be developed during the next 10 years. Antioxid. Redox Signal. 17, 119-140.