Trends in Pharmacological Sciences
ReviewPutative biological roles of hydrogen sulfide in health and disease: a breath of not so fresh air?
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 KATP 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
References (90)
A new method for the determination of sulphide in gastrointestinal contents and whole blood by microdistillation and ion chromatography
Clin. Chim. Acta
(2000)The effect of inhibitors on the oxygen kinetics of cytochrome c oxidase
Biochim. Biophys. Acta
(1977)Endogenous hydrogen sulfide regulation of myocardial injury induced by isoproterenol
Biochem. Biophys. Res. Commun.
(2004)Hydrogen sulphide: a novel inhibitor of hypochlorous acid-mediated oxidative damage in the brain?
Biochem. Biophys. Res. Commun.
(2005)Transsulfuration in mammals: microassays and tissue distribution of three enzymes in the pathway
J. Biol. Chem.
(1965)Experimentally induced type 1 diabetes is associated with impaired hydrogen sulfide biosynthesis
Biochem. Biophys. Res. Commun.
(2005)Oxidation of hydrogen sulfide and methanethiol to thiosulfate by rat tissues: a specialized function of the colonic mucosa
Biochem. Pharmacol.
(2001)The possible relaxant effect of hydrogen sulfide as an endogenous smooth muscle relaxant in synergy with nitric oxide
Biochem. Biophys. Res. Commun.
(1997)Hydrogen sulphide: a novel endogenous gasotransmitter facilitates erectile function
J. Sex. Med.
(2007)H2S generated by heart in rat and its effects on cardiac function
Biochem. Biophys. Res. Commun.
(2004)
Endogenous hydrogen sulfide contributes to the cardioprotection by metabolic inhibition preconditioning in the rat ventricular myocytes
J. Mol. Cell. Cardiol.
Hydrogen sulfide inhibits human platelet aggregation
Eur. J. Pharmacol.
Cystathionine gamma-lyase overexpression inhibits cell proliferation via a H2S-dependent modulation of ERK1/2 phosphorylation and p21Cip/WAK-1
J. Biol. Chem.
Hydrogen sulfide prevents apoptosis of human PMN via inhibition of p38 and caspase 3
Lab. Invest.
Protective effect of hydrogen sulfide in balloon injury-induced neointima hyperplasia in rat carotid arteries
Am. J. Pathol.
Effects of hydrogen sulfide on homocysteine-induced oxidative stress in vascular smooth muscle cells
Biochem. Biophys. Res. Commun.
Direct inhibition of endothelial nitric oxide synthase by hydrogen sulfide: contribution to dual modulation of vascular tension
Toxicology
The possible role of hydrogen sulfide on the pathogenesis of spontaneous hypertension in rats
Biochem. Biophys. Res. Commun.
Inhibition of hydrogen sulfide generation contributes to gastric injury caused by anti-inflammatory nonsteroidal drugs
Gastroenterology
Hydrogen sulfide – a novel mediator of inflammation
Curr. Opin. Pharmacol.
Hydrogen sulfide-releasing anti-inflammatory drugs
Trends Pharmacol. Sci.
Hydrogen sulfide induced neuronal death occurs via glutamate receptor and is associated with calpain activation and lysosomal rupture in mouse primary cortical neurons
Neuropharmacology
Hydrogen sulfide as a novel nociceptive messenger
Pain
Hydrogen sulfide is a novel prosecretory neuromodulator in the guinea pig and human colon
Gastroenterology
Streptozotocin-induced diabetes in the rat is associated with enhanced tissue hydrogen sulfide biosynthesis
Biochem. Biophys. Res. Commun.
Anti-inflammatory and gastrointestinal effects of a novel diclofenac derivative
Free Radic. Biol. Med.
Gastrointestinal safety and anti-inflammatory effects of a hydrogen sulfide-releasing diclofenac derivative in the rat
Gastroenterology
Polarographic measurement of hydrogen sulfide production and consumption by mammalian tissues
Anal. Biochem.
Hydrogen sulfide inhibits nitric oxide production and nuclear factor-κB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide
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.
Cited by (290)
A mitochondria-targeting fluorescent probe for the dual-emission fluorescence-enhanced detection of hydrogen sulfide and turn-on detection of hydrazine
2024, Sensors and Actuators B: ChemicalHydrogen sulfide donors across time: From origins to cutting-edge applications
2024, Nitric Oxide - Biology and ChemistryRegulatory effects of hydrogen sulfide on the female reproductive system
2024, European Journal of PharmacologyStrategies for gaseous neuromodulator release in chemical neuroscience: Experimental approaches and translational validation
2024, Journal of Controlled ReleaseNew tool for diseases mechanism studies: Endoplasmic reticulum-targeted fluorescent probes
2023, Dyes and PigmentsTwo-photon ratiometric imaging of endogenous reactive inorganic sulfur species in the cellular cushion toward formaldehyde
2023, Biosensors and Bioelectronics: X