Review articleHydrogen sulfide in pharmacology and medicine – An update
Introduction
It was first proposed by Abe and Kimura in 1996 that hydrogen sulfide (H2S) is the endogenously generated neuromodulator [1]. During almost two decades since their seminal paper was published, a large body of data about H2S in biological systems has been accumulated. Currently, there is little doubt that hydrogen sulfide is the third “gasotransmitter” in addition to nitric oxide (NO) and carbon monoxide (CO) [2], [3], [4]. In 2007 we published a review article about H2S in pharmacology in this journal [5]. Herein, I briefly review the progress made in the field since that time. Because H2S literature is now very huge, I will not comprehensively cover its effects in all experimental systems but will focus on general aspects of H2S biochemistry and molecular signaling mechanisms as well as its potential application in pharmacotherapy.
Section snippets
General properties of H2S
H2S is a colorless flammable gas with a strong odor of rotten eggs. It is easily soluble in both water and lipids. At physiological pH (7.4) less than 20% of H2S exists in the solution as the undissociated compound and the rest is dissociated to HS− (hydrosulfide anion) and H+. Further dissociation of HS− to sulfide anion (S2−) occurs only at high pH and is insignificant at physiological conditions. Since both H2S and HS− always coexist in aqueous solution, it is not possible to separate their
Endogenous H2S synthesis
Four enzymatic pathways of H2S production have been described so far. Two of them are catalyzed by cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE) which are pyridoxal 5′-phosphate (vitamin B6)-dependent cytosolic enzymes of the transsulfuration pathway in which homocysteine is metabolized to cysteine. In the transsulfuration pathway l-homocysteine is condensed by CBS with l-serine to produce l-cystathionine and H2O. However, l-serine may be replaced in this reaction by l-cysteine
H2S concentration in plasma and tissues
Early studies suggested that H2S is present in plasma and tissues at relatively high concentrations; values up to 50–60 μM have been reported in plasma and even >100 μM in the brain. However, it was the artifact resulting from using colorimetric methylene blue method which has multiple disadvantages [6]. This method measures not only free H2S/HS− but also other sulfide pools in the sample including sulfane sulfur and acid-labile sulfur; the latter mostly includes iron–sulfur clusters in proteins
H2S metabolism
H2S has been known for decades as one of the most important poisons in human toxicology. The main mechanism of its toxicity is inhibition of mitochondrial respiratory chain by binding to cytochrome c oxidase. Indeed, H2S is the second most potent inhibitor of this enzyme after cyanide [25]. However, one of the most exciting findings of the recent years in the H2S field was that it may also be enzymatically metabolized in mitochondria. H2S is the first and until now the only known inorganic
Mechanisms of H2S signaling in the cells
Biological effects of H2S result from its interactions with three groups of targets: (1) thiols, (2) reactive oxygen and nitrogen species as well as oxidation products of macromolecules, (3) metals and metalloproteins. Below these three targets are briefly characterized.
H2S as a target for pharmacotherapy
Although excess H2S may contribute to the pathogenesis of some diseases such as cancer [88], [89], septic shock [90] or acute pancreatitis [91] and pharmacological or genetic inhibition of H2S production is protective in some models, application of H2S donors and/or augmenting endogenous H2S attracts most attention as the possible therapeutic approach for several reasons. First, protective effects of H2S or its donors were demonstrated more convincingly in many experimental models. Potential
Conclusions and future directions
A significant progress has been made in recent years in the H2S field. The mechanisms of H2S synthesis by CBS and CSE were explained and it was demonstrated that it can be formed not only from cysteine but also from homocysteine. The new 3-MST-dependent pathways of H2S production have been described and its mitochondrial metabolism is now quite well characterized. Several molecular signaling mechanisms have been demonstrated. Many new methods of H2S measurements such as polarographic sensors,
Conflict of interest
None declared.
Acknowledgements
Author's own studies cited in this paper were supported by grant DS 476 from Medical University, Lublin, Poland, as well as by EU Project “The equipment of innovative laboratories doing research on new medicines used in the therapy of civilization and neoplastic diseases” within the Operational Program Development of Eastern Poland 2007–2013, Priority Axis I Modern Economy, Operations I.3 Innovation Promotion.
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