Putative biological roles of hydrogen sulfide in health and disease: a breath of not so fresh air?

doi:10.1016/j.tips.2007.11.003

Trends in Pharmacological Sciences

Volume 29, Issue 2, February 2008, Pages 84-90

https://doi.org/10.1016/j.tips.2007.11.003 Get rights and content

The past two decades have seen an upsurge in interest in the biology of naturally occurring gases, starting with nitric oxide and extending through to carbon monoxide. The latest addition to the list of biologically relevant gases is hydrogen sulfide. In the past few years, hydrogen sulfide has transited rapidly from environmental pollutant to biologically relevant mediator with potential roles in several physiological processes and disease states. Further, interest is now being shown in developing drugs which either mimic its effects or block its biosynthesis. Similarly to its gaseous cousins, the biology of hydrogen sulfide is proving to be complex and difficult to unravel.

Introduction

The past two decades have witnessed increasing interest in the biology of endogenous gases. It is becoming increasingly clear that nitric oxide (NO) is not the only such biologically active gas, and that molecules such as carbon monoxide (CO) and hydrogen sulfide (H₂S), and perhaps others, are also important. Cells are constantly enveloped in an atmosphere containing many different gases, and it is not surprising that at least some of those gases have evolved over the ages into potent regulators of cell function. The latest such ‘candidate gas’ is H₂S, once viewed solely as an environmental pollutant but now seen more and more as a biologically significant molecule in its own right. Compared with NO and CO, the study of the biology of H₂S is still in its infancy. Nevertheless, much research has already been devoted to a better understanding of the physiological and pathophysiological significance of this gas and the way in which it interacts with NO and CO. Here, we describe recent advances in our understanding of the biology of H₂S, centring on its most important biological effects (Figure 1), and also whether drugs interfering with the synthesis or effects of H₂S might be of therapeutic interest.

Section snippets

Physical and chemical properties of H₂S

H₂S is a colourless, flammable gas with a characteristic odour of rotten eggs. It is soluble in water (1 g in 242 ml at 20°C). In water or plasma, H₂S is a weak acid which dissociates as follows: H₂S ↔ HS⁻ + H⁺. The pKa at 37°C is 6.76; therefore, when either sodium hydrosulfide (NaHS) or H₂S is dissolved in physiological solution (pH 7.4, 37°C), it will form approximately 18.5% H₂S and 81.5% hydrosulfide anion (HS), as predicted by the Henderson–Hasselbach equation [1]. H₂S is a highly lipophilic

Occurrence of H₂S in the body

In the past few years, much attention has been focused on measuring H₂S in plasma, brain and many other tissues. Remarkably high levels of H₂S have been reported. For example, both rat and human plasma contain approximately 50 μM H₂S [2], and rat brain homogenate contains concentrations in excess of 100 μM [3]. These figures imply that the body is awash with H₂S and are difficult to correlate with the potent inhibitory effect of this gas on mitochondrial cytochrome c oxidase [4]. Indeed, at these

Biosynthesis and catabolism of H₂S

H₂S is formed in mammalian cells largely by the activity of two pyridoxal phosphate-dependent enzymes, cystathionine γ lyase (CSE, EC 4.4.1.1) and cystathionine β synthetase (CBS, EC 4.2.1.22) (Figure 2). These enzymes are widespread in mammalian tissues and cells [12] and also in many invertebrates and bacteria. In mammals, large amounts of CBS occur in the brain (particularly in Purkinje cells and hippocampus [13], whereas CSE activity is highest in peripheral tissues – notably liver, kidney

H₂S in the cardiovascular system

H₂S dilates blood vessels. Examples of blood vessels relaxed by H₂S in vitro (either as the gas in water or using NaHS to donate H₂S) include the isolated rat aorta and portal vein 2, 28, 29, rabbit corpus cavernosum [30] and the perfused rat mesenteric [31] and hepatic [32], but not coronary [33], vascular beds. In whole animals, intravenous injection of NaHS elicits short-lived but dose-related falls in blood pressure 2, 29. Blood vessels are not alone in responding to H₂S with relaxation;

H₂S and inflammation

The precise role of H₂S in inflammation is still far from clear and has also been the subject of several recent reviews 60, 61. Perhaps more than any other topic, the pro- versus anti-inflammatory effectof H₂S has proved to be the most contentious, with both pro- and anti-inflammatory effects reported. Interestingly, a similar situation exists with NO, which can also cause both pro- and anti-inflammatory activity. Table 1 provides a summary of the evidence for a role of H₂S in inflammation.

H₂S in the nervous system

H₂S, synthesized by CBS, is found in the brain and peripheral nerves, and evidence is growing that, similarly to NO, this gas has a role either as a neuromodulator or a neurotransmitter. Deranged biosynthesis of H₂S is a feature of animal (middle cerebral artery occlusion) models of stroke in the rat [62] and perhaps also Alzheimer's disease [63]. The biological effects of H₂S in the nervous system are complex. For example, some reports show that H₂S triggers primary cortical neurone death

H₂S and the endocrine system

Recently, there has been interest in the possible roles of H₂S in regulating endocrine function. Much of this work is centred on the well known role of K_ATP channels in controlling the function of insulin-secreting pancreatic β cells. Exogenously applied H₂S and transfection of rat insulinoma cells with CSE both resulted in reduced glucose-induced insulin release from the cells, whereas PAG increased release [74]. Similar results were shown using isolated mouse pancreatic islets [75]. As such,

Pharmacological targeting of the H₂S system

It is still early days in identifying drug candidates which manipulate the cysteine–H₂S system. Previous studies relied heavily on simple sulfide salts as H₂S donors. These included NaHS, which, when dissolved in water, dissociates instantly to yield HS⁻ and H⁺; these then recombine to form H₂S. Most researchers have opted to used NaHS in their experiments rather than using H₂S gas dissolved in water, even though there might be differences in the potency of the two [31]. Inhibitors of CSE

Conclusion

H₂S, similarly to NO and CO, exhibits complex biological effects in many mammalian and non-mammalian systems. Contraction versus relaxation of blood vessels, and apoptotic versus anti-apoptotic, neurodegenerative versus neuroprotective, pro-inflammatory versus anti-inflammatory and hyperalgesic versus analgesic activity have all been described in the literature. The conundrum is clear: how does one molecule exert such widely differing effects? Do different concentrations of H₂S exert different

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Trends in Pharmacological Sciences

ReviewPutative biological roles of hydrogen sulfide in health and disease: a breath of not so fresh air?

Introduction

Section snippets

Physical and chemical properties of H2S

Occurrence of H2S in the body

Biosynthesis and catabolism of H2S

H2S in the cardiovascular system

H2S and inflammation

H2S in the nervous system

H2S and the endocrine system

Pharmacological targeting of the H2S system

Conclusion

Clin. Chim. Acta

Biochim. Biophys. Acta

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Biochem. Pharmacol.

Biochem. Biophys. Res. Commun.

J. Sex. Med.

Biochem. Biophys. Res. Commun.

J. Mol. Cell. Cardiol.

Eur. J. Pharmacol.

J. Biol. Chem.

Lab. Invest.

Am. J. Pathol.

Biochem. Biophys. Res. Commun.

Toxicology

Biochem. Biophys. Res. Commun.

Gastroenterology

Curr. Opin. Pharmacol.

Trends Pharmacol. Sci.

Neuropharmacology

Pain

Gastroenterology

Biochem. Biophys. Res. Commun.

Free Radic. Biol. Med.

Gastroenterology

Anal. Biochem.

Free Radic. Biol. Med.

Hydrogen sulfide as an endogenous regulator of vascular smooth muscle tone in trout

Am. J. Physiol. Regul. Integr. Comp. Physiol.

The vasorelaxant effect of H2S as a novel endogenous gaseous KATP channel opener

EMBO J.

Inhibition of respiratory and bioenergetic mechanisms by hydrogen sulfide in mammalian brain

J. Toxicol. Environ. Health A.

Monoamine oxidase inhibition as a sequel of hydrogen sulfide intoxication: increases in brain catecholamine and 5-hydroxytryptamine levels

Arch. Toxicol.

Toxicology of hydrogen sulfide

Annu. Rev. Pharmacol. Toxicol.

Oxidative stress dependent conversion of hydrogen sulfide to sulfite by activated neutrophils

Shock

The novel neuromodulator hydrogen sulfide: an endogenous peroxynitrite ‘scavenger’?

J. Neurochem.

Endogenous production of hydrogen sulfide in mammals

Amino Acids

Expression of the cystathionine beta synthase (CBS) gene during mouse development and immunolocalization in adult brain

J. Histochem. Cytochem.

Murine cystathionine gamma-lyase: complete cDNA and genomic sequences, promoter activity, tissue distribution and developmental expression

Biochem. J.

Modulation of endogenous production of H2S in rat tissues

Can. J. Physiol. Pharmacol.

Human cystathionine gamma-lyase: developmental and in vitro expression of two isoforms

Biochem. J.

Hydrogen sulfide is a novel mediator of endotoxic shock

FASEB J.

Role of hydrogen sulphide in acute pancreatitis in the mouse and rat

FASEB J.

Transcriptional regulation of the human cystathionine beta-synthase-1b basal promoter: synergistic transactivation by transcription factors NF-Y and Sp1/Sp3

Biochem. J.

S-adenosylmethionine stabilizes cystathionine beta-synthase and modulates redox capacity

Proc. Natl. Acad. Sci. U. S. A.

Review
Putative biological roles of hydrogen sulfide in health and disease: a breath of not so fresh air?

Physical and chemical properties of H₂S

Occurrence of H₂S in the body

Biosynthesis and catabolism of H₂S

H₂S in the cardiovascular system

H₂S and inflammation

H₂S in the nervous system

H₂S and the endocrine system

Pharmacological targeting of the H₂S system

The vasorelaxant effect of H₂S as a novel endogenous gaseous K_ATP channel opener

Modulation of endogenous production of H₂S in rat tissues