H2S (hydrogen sulfide) physiology

H2S (hydrogen sulphide) is typically most well-known as a toxic environmental gas which binds to cytochrome oxidase and inhibits energy metabolism. However H2S is also produced in small amounts in the body where the last 15 years of research have shown that it functions as an important gaseous signalling molecule, alongside the other two currently known gaseous mediators - NO (nitric oxide) and CO (carbon monoxide). However it is also produced in small amounts in the body where the last 15 years of research have shown that it functions as an important gaseous signalling molecule, alongside the other two currently known gaseous mediators - NO (nitric oxide) and CO (carbon monoxide). H2S plays a role in processes such as neurotransmission, inflammation, nociception, insulin release, vasodilation and redox. In general, H2S has many benefits at healthy physiological levels, but becomes harmful at higher levels. Raised H2S levels have been reported in CFS ([1] unpublished) and have been hypothesised to play a role in CFS symptomatology and pathogenesis [2]. Excessive levels of H2S in many with CFS might result from various sources such as: (i) gut-bacterial origin; (ii) endogenous metabolic dysfunction; (iii) excessive endogenous signalling stimulating H2S synthesis/release. Option (i) has been proposed by some, but for it to be of gut-bacterial origin, it seems likely that there would have to be excessive breakdown of sulphur containing foods in the gut, and perhaps a resulting deficiency of sulphur containing amino acids in the blood. Personally I favour options (ii) and (iii). Below is an objective summary of the latest research on the functions of H2S in the body under normal physiological conditions, some of which may bring answers questions about the role of H2S in CFS, whilst some may bring more questions.

H2S metabolism

H2S is produced from cysteine or homocysteine by the P5P-dependant transsulfuration enzymes, CBS (cystathionine beta-synthase) and CGL (cystathionine gamma-lyase, aka CSE), as well as by the enzymes 3MST (3-mercaptopyruvate sulfurtransferase) and CAT (cysteine aminotransferase) and possibly others (e.g. 3MP) [3]. Murine studies have shown that in the liver, CBS is only responsible for 3% of H2S production by the transsulfuration pathway, whereas in the kidney and brain the majority of H2S comes from the CBS reaction [4], the extent of which is dependent upon its allosteric activation by SAMe [5]; notably CBS dominance in the brain is also suggested by higher relative levels of cystathionine in the rodent and primate brain [6]. Production of H2S is likely to be altered under hyperhomocysteinemic conditions where the relative contribution of CBS to H2S formation is likely to decrease and CGL to increase [5]. H2S is released either directly after enzymatic production or from sulfur stores in response to acidic conditions or reducing agents [3]. H2S is metabolised or detoxified mainly through oxidation where it is converted first to sulphite by the enzyme sulfite reductase, then to sulphate by the enzyme sulphite oxidase (molybdenum cofactor), and finally excreted in urine.

H2S Functions

In the body H2S is a smooth muscle relaxant and shares similar vasodilation effects to nitric oxide, although via a different mechanism - activation of KATP channels [7,8]. As such H2S is involved in blood pressure regulation; CGL is expressed in vascular tissue and CGL knockout mice exhibit hypertension [3]. CBS and CGL are also expressed in the penis where H2S is involved in the vasodilation mediating an erection [9]. Studies have shown that H2S acts synergistically with NO to relax vascular smooth muscle; NO stimulates CGL and H2S production, and H2S stimulated vascular relaxation is attenuated by NOS antagonists [3]. Recent research is increasingly showing that H2S modulates both pro-inflammatory [10] and anti-inflammatory pathways [11-14], possibly suggesting cell and situation specific inflammatory modulation. With regards to anti-inflammatory activity, H2S has been shown to attenuate interleukin-1β, 6, 8, and TNF-α, whilst increasing HO-1 and interleukin-10 [11-14].

In the nervous system, H2S production is induced in response to neuronal excitation in a Ca2+/calmodulin-dependent manner; specifically Ca2+ influx through NMDARs induces CBS activity and thus H2S production [15]. H2S selectively enhances NMDAR-mediated responses and facilitates LTP (memory and learning) in the hippocampus [3]. Whilst the other gaseous mediators (NO and CO) also facilitate LTP, and do so by activating the second messenger cGMP, H2S acts directly on NMDARs and presumably in a similar manner to other reducing agents such as DTT and glutathione, which have also been shown to enhance NMDAR activity [16]. H2S also induces Ca2+ waves in astrocytes, which may be mediated by activation of TRP channels [3,17]. H2S is neuro- and cardio-protective via its activation of Cl­- and KATP channels which stabilise membrane potentials and protect against excitotoxicity [3]. Finally, H2S has been shown to lower sympathetic tone by reducing noradrenaline and adrenaline release [18].

Research has demonstrated a robust cytoprotective role for H2S via its direct and indirect modulation of redox. In the nervous system H2S boosts neuronal glutathione levels through enhanced cystine and cysteine transport, and also enhanced γ-GCS activity [3,19]. H2S as a reducing agent has also demonstrated direct protective effects against cytosolic and mitochondrial oxidative stress [3], and it has been suggested that H2S may directly scavenge the peroxynitrite radical [20]. Notably brain H2S is severely depressed in Alzheimer’s disease [21], which is consistent with disturbance to most other methylation-related parameters and hypomethylation in Alzheimer’s [22]. Finally H2S-induced cardioprotection was recently demonstrated to be NOS dependant, once again illustrating the synergy between these two gases [23].

Concluding speculation

With regards to illnesses featuring methylation dysfunction and specifically lowered SAMe, one theory based upon the above information may be that lowered SAMe stimulation of CBS activity leads to lowered H2S levels in the kidney and brain, whilst increased homocysteine levels stimulate CGL activity (subject to B6 availability) and H2S levels in the liver and vasculature. This might occur because the CGL enzyme has been shown to be far more responsive to hyperhomocysteine conditions than CBS, and this CGL stimulation by homocysteine leads to up-regulation of H2S producing reactions (upward arrows on diagram) [5]. However increased H2S levels in illnesses such as CFS might also arise from disrupted redox, excessive inflammation and NO production and the resulting stimulation of CGL activity. Given that H2S is generally associated with positive modulation of redox and inflammation, whereas CFS is associated with increased oxidative stress and inflammation, this may support the notion that excessive H2S production results from disturbance of these processes.

References

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[2]         M.D. Lemle, Hypothesis: chronic fatigue syndrome is caused by dysregulation of hydrogen sulfide metabolism., Medical Hypotheses. 72 (2009) 108-9.

[3]         H. Kimura, Hydrogen sulfide : its production , release and functions, Amino Acids. (2010).

[4]         O. Kabil, V. Vitvitsky, P. Xie, R. Banerjee, The quantitative significance of the transsulfuration enzymes for H2S production in murine tissues., Antioxidants & Redox Signaling. 15 (2011) 363-72.

[5]         S. Singh, D. Padovani, R.A. Leslie, T. Chiku, R. Banerjee, Relative contributions of cystathionine beta-synthase and gamma-cystathionase to H2S biogenesis via alternative trans-sulfuration reactions., The Journal of Biological Chemistry. 284 (2009) 22457-66.

[6]         V. Vitvitsky, M. Thomas, A. Ghorpade, H.E. Gendelman, R. Banerjee, A functional transsulfuration pathway in the brain links to glutathione homeostasis., The Journal of Biological Chemistry. 281 (2006) 35785-93.

[7]         G.S. Dawe, S.P. Han, J.S. Bian, P.K. Moore, Hydrogen sulphide in the hypothalamus causes an ATP-sensitive K+ channel-dependent decrease in blood pressure in freely moving rats., Neuroscience. 152 (2008) 169-77.

[8]         G. Tang, L. Wu, R. Wang, Interaction of hydrogen sulfide with ion channels., Clinical and Experimental Pharmacology & Physiology. 37 (2010) 753-63.

[9]         R. d’ Emmanuele di Villa Bianca, R. Sorrentino, P. Maffia, V. Mirone, C. Imbimbo, F. Fusco, et al., Hydrogen sulfide as a mediator of human corpus cavernosum smooth-muscle relaxation., Proceedings of the National Academy of Sciences of the United States of America. 106 (2009) 4513-8.

[10]      L. Zhi, A.D. Ang, H. Zhang, P.K. Moore, M. Bhatia, Hydrogen sulfide induces the synthesis of proinflammatory cytokines in human monocyte cell line U937 via the ERK-NF-kappaB pathway., Journal of Leukocyte Biology. 81 (2007) 1322-32.

[11]      L.-L. Pan, X.-H. Liu, Q.-H. Gong, D. Wu, Y.-Z. Zhu, Hydrogen sulfide attenuated tumor necrosis factor-α-induced inflammatory signaling and dysfunction in vascular endothelial cells., PloS One. 6 (2011) e19766.

[12]      A. Esechie, L. Kiss, G. Olah, E.M. Horváth, H. Hawkins, C. Szabo, et al., Protective effect of hydrogen sulfide in a murine model of acute lung injury induced by combined burn and smoke inhalation., Clinical Science (London, England : 1979). 115 (2008) 91-7.

[13]      T. Li, B. Zhao, C. Wang, H. Wang, Z. Liu, W. Li, et al., Regulatory effects of hydrogen sulfide on IL-6, IL-8 and IL-10 levels in the plasma and pulmonary tissue of rats with acute lung injury., Experimental Biology and Medicine (Maywood, N.J.). 233 (2008) 1081-7.

[14]      K. Kang, H.-chi Jiang, M.-yan Zhao, X.-ying Sun, S.-ha Pan, [Protection of CSE/H2S system in hepatic ischemia reperfusion injury in rats]., Zhonghua Wai Ke Za Zhi [Chinese Journal of Surgery]. 48 (2010) 924-8.

[15]      K. Eto, M. Ogasawara, K. Umemura, Y. Nagai, H. Kimura, Hydrogen sulfide is produced in response to neuronal excitation., The Journal of Neuroscience : The Official Journal of the Society for Neuroscience. 22 (2002) 3386-91.

[16]      K. Bodhinathan, A. Kumar, T.C. Foster, Intracellular redox state alters NMDA receptor response during aging through Ca2+/calmodulin-dependent protein kinase II., The Journal of Neuroscience : The Official Journal of the Society for Neuroscience. 30 (2010) 1914-24.

[17]      Y. Nagai, M. Tsugane, J.-I. Oka, H. Kimura, Hydrogen sulfide induces calcium waves in astrocytes., The FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology. 18 (2004) 557-9.

[18]      K.H. Kulkarni, E.M. Monjok, R. Zeyssig, G. Kouamou, O.N. Bongmba, C.A. Opere, et al., Effect of hydrogen sulfide on sympathetic neurotransmission and catecholamine levels in isolated porcine iris-ciliary body., Neurochemical Research. 34 (2009) 400-6.

[19]      Y. Kimura, Y.-I. Goto, H. Kimura, Hydrogen sulfide increases glutathione production and suppresses oxidative stress in mitochondria., Antioxidants & Redox Signaling. 12 (2010) 1-13.

[20]      M. Whiteman, J.S. Armstrong, S.H. Chu, S. Jia-Ling, B.-S. Wong, N.S. Cheung, et al., The novel neuromodulator hydrogen sulfide: an endogenous peroxynitrite “scavenger”?, Journal of Neurochemistry. 90 (2004) 765-8.

[21]      K. Eto, Brain hydrogen sulfide is severely decreased in Alzheimer’s disease, Biochemical and Biophysical Research Communications. 293 (2002) 1485-1488.

[22]      F. Coppedè, One-carbon metabolism and Alzheimer’s disease: focus on epigenetics., Current Genomics. 11 (2010) 246-60.

[23]      B. Sojitra, Y. Bulani, U.K. Putcha, A. Kanwal, P. Gupta, M. Kuncha, et al., Nitric oxide synthase inhibition abrogates hydrogen sulfide-induced cardioprotection in mice., Molecular and Cellular Biochemistry. (2011).