Hydrogen sulphide and its therapeutic potential

Key Points Hydrogen sulphide (H 2 S), together with nitric oxide and carbon monoxide, belongs to a family of labile biological mediators called gasotransmitters. H 2 S has long been known as a toxic gas emanating from sewers and as a by-product of industrial processes; however, the biological processes of sulphide and its metabolism and fate in biological systems is now beginning to be understood. H 2 S is synthesized endogenously in numerous mammalian tissues by two enzymes responsible for metabolizing L -cysteine — cystathionine β-synthase (CBS) and cystathionine γ-lyase (CGS). CBS is the predominant H 2 S-generating enzyme in the brain and nervous system. CSE is mainly expressed in the liver and in the vascular and non-vascular smooth muscle. Other sources of H 2 S include enterobacterial flora and inorganic sources. H 2 S exerts numerous biological effects on various biological targets, leading to responses that range from cytotoxic effects (due to free radical and oxidant generation) to cytoprotective (antinecrotic or anti-apoptotic) actions. In particular, H 2 S has been specifically shown to exert a pharmacological effect on potassium-opened ATP (K ATP ) channels. These opposing effects have been demonstrated in various animal models. Inhibition of sulphide in animal models of haemorrhagic shock has been demonstrated to accelerate the recovery of mean arterial pressure. H 2 S can also induce a suspended-animated-like state in mice — whether this can be achieved in larger animals remains to be seen. Protection from lethal hypoxic insult, myocardial injury and inflammation has also been shown. The options that could be explored to utilize this knowledge for therapeutic purposes are discussed. Two main pathways are considered viable: the development of inhibitors of CBS or CSE, and the development of H 2 S or H 2 S-releasing compounds. In this rapidly emerging field, there are still many unknowns — including the relationship of H 2 S with the other two gasotransmitters — however, further studies are likely to yield a number of therapeutic possibilities, and early stage drug candidates are already in development.