The therapeutic potential of hydrogen sulfide: Separating hype from hope

Hydrogen sulfide (H₂S) has become the hot new signaling molecule that seemingly affects all organ systems and biological processes in which it has been investigated. It has also been shown to have both proinflammatory and anti-inflammatory actions and proapoptotic and anti-apoptotic effects and has even been reported to induce a hypometabolic state (suspended animation) in a few vertebrates. The exuberance over potential clinical applications of natural and synthetic H₂S-"donating" compounds is understandable and a number of these function-targeted drugs have been developed and show clinical promise. However, the concentration of H₂S in tissues and blood, as well as the intrinsic factors that affect these levels, has not been resolved, and it is imperative to address these points to distinguish between the physiological, pharmacological, and toxicological effects of this molecule. This review will provide an overview of H₂S metabolism, a summary of many of its reported "physiological" actions, and it will discuss the recent development of a number of H₂S-donating drugs that show clinical potential. It will also examine some of the misconceptions of H₂S chemistry that have appeared in the literature and attempt to realign the definition of "physiological" H₂S concentrations upon which much of this exuberance has been established.