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  • Review Article
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Hydrogen sulphide and its therapeutic potential

Nature Reviews Drug Discovery volume 6, pages 917–935 (2007)Cite this article

Key Points

  • Hydrogen sulphide (H2S), together with nitric oxide and carbon monoxide, belongs to a family of labile biological mediators called gasotransmitters.

  • H2S 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.

  • H2S 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 H2S-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 H2S include enterobacterial flora and inorganic sources.

  • H2S 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, H2S has been specifically shown to exert a pharmacological effect on potassium-opened ATP (KATP) 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. H2S 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 H2S or H2S-releasing compounds. In this rapidly emerging field, there are still many unknowns — including the relationship of H2S 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.

Abstract

Hydrogen sulphide (H2S) is increasingly being recognized as an important signalling molecule in the cardiovascular and nervous systems. The production of H2S from L-cysteine is catalysed primarily by two enzymes, cystathionine γ-lyase and cystathionine β-synthase. Evidence is accumulating to demonstrate that inhibitors of H2S production or therapeutic H2S donor compounds exert significant effects in various animal models of inflammation, reperfusion injury and circulatory shock. H2S can also induce a reversible state of hypothermia and suspended-animation-like state in rodents. This article overviews the physiology and biochemistry of H2S, summarizes the effects of H2S inhibitors or H2S donors in animal models of disease and outlines the potential options for the therapeutic exploitation of H2S.

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Figure 1: Enzymatic pathways of H2S production in mammalian cells.
Figure 2: Some biological effects of H2S in mammalian cells.
Figure 3: Structures of PAG and BCA.
Figure 4: Induction of a suspended animation-like state in mice by H2S inhalation.
Figure 5: Protective effects of sulphide donors in disease models.
Figure 6: Potential mechanisms of protective effects of H2S.

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Acknowledgements

The author thanks K. Tomaselli, T. Deckwerth, C. Toombs, E. Wintner and M. Roth for helpful discussions. Also, the author is grateful for T. Deckwerth and E. Wintner for preparing figures 1 and 2, respectively, and F. Su and C. Toombs for providing the data for figure 5b.

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    Csaba Szabó

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C.S. is an employee and stock holder to Ikaria, a for-profit organization involved in the development of H2S-related technologies.

Supplementary information

Supplementary information S1 (table)

Some pharmacological and toxicological effects of H2S in animals. (PDF 119 kb)

Supplementary information S2 (table)

Some pharmacological or toxicological effects of H2S in humans (PDF 126 kb)

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DATABASES

SwissProt ENZYME

Amine oxidase

carbonate dehydratase

cystathionine β-synthase

cystathionine γ-lyase

cystathionine γ-synthase

cytochrome c oxidase

glutamate cysteine ligase

thiosulphate sulphurtransferase

FURTHER INFORMATION

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Glossary

Sulphide

In this article, the term sulphide is used to collectively describe all biologically active sulphide-related species, including HS−. When referring to the chemical compounds, the chemical terms H2S, Na2S or NaHS are used.

Endotoxin

A toxin produced by Gram-negative bacteria and released from the bacterial cell.

Long-term potentiation

The prolonged strengthening of synaptic communication, which is induced by patterned input and is thought to be involved in learning and memory formation.

Haem proteins

Haem proteins contain an iron complex of porphyrin, usually protoporphyrin IX, and function as catalysts in many biological processes.

Cytochrome c oxidase

A component of the oxidative phosphorylation machinery within the cell that normally binds oxygen.

Suspended animation

A state of temporary and reversible slowing down or cessation of life functions by external means.

Cecal ligation and puncture

An experimental model of polymicrobial sepsis that is generally considered more relevant to the human disease than rodents injected with bacterial lipopolysaccharide (endotoxin).

Hibernation

It is well known that various organisms can reversibly arrest their essential life processes, in some cases for several years at a time. This phenomenon is known as quiescence, torpor or hibernation. An important aspect of this process is a significant reduction in both energy production and energy consumption. Organisms in this state are resistant to environmental stresses including temperature extremes and oxygen deprivation.

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Szabó, C. Hydrogen sulphide and its therapeutic potential. Nat Rev Drug Discov 6, 917–935 (2007). https://doi.org/10.1038/nrd2425

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