Emerging role of hydrogen sulfide in health and disease: critical appraisal of biomarkers and pharmacological tools

H₂S (hydrogen sulfide) is a well known and pungent gas recently discovered to be synthesized enzymatically in mammalian and human tissues. In a relatively short period of time, H₂S has attracted substantial interest as an endogenous gaseous mediator and potential target for pharmacological manipulation. Studies in animals and humans have shown H₂S to be involved in diverse physiological and pathophysiological processes, such as learning and memory, neurodegeneration, regulation of inflammation and blood pressure, and metabolism. However, research is limited by the lack of specific analytical and pharmacological tools which has led to considerable controversy in the literature. Commonly used inhibitors of endogenous H₂S synthesis have been well known for decades to interact with other metabolic pathways or even generate NO (nitric oxide). Similarly, commonly used H₂S donors release H₂S far too quickly to be physiologically relevant, but may have therapeutic applications. In the present review, we discuss the enzymatic synthesis of H₂S and its emerging importance as a mediator in physiology and pathology. We also critically discuss the suitability of proposed ‘biomarkers’ of H₂S synthesis and metabolism, and highlight the complexities of the currently used pharmacological H₂S ‘donor’ molecules and ‘specific’ H₂S synthesis inhibitors in their application to studying the role of H₂S in human disease.