Rhodanese, but not cystathionine-γ-lyase, is associated with dextran sulfate sodium-evoked colitis in mice: A sign of impaired colonic sulfide detoxification?
Introduction
Hydrogen sulfide (H2S), like nitric oxide (NO) and carbon monoxide (CO), is now considered a gasotransmitter in the mammalian body. Endogenous H2S is synthesized from l-cysteine by two pyridoxal-5′-phosphate-dependent enzymes, cystathionine-γ-lyase (CSE) especially in the peripheral tissues and cystathionine-β-synthase (CBS) mainly in the brain (Li and Moore, 2008, Wang, 2002). Plenty of evidence implies that H2S plays emerging roles throughout the mammalian body (Li and Moore, 2008, Wang, 2002), particularly in the neuronal (Cheung et al., 2007, Kawabata et al., 2007, Kimura, 2000, Maeda et al., 2009, Tarui et al., 2009) and cardiovascular systems (Ali et al., 2006, Kubo et al., 2007, Yang et al., 2008). Roles of H2S in the alimentary system have also been well investigated. H2S protects gastric mucosa (Fiorucci et al., 2006, Yonezawa et al., 2007) and suppresses the motility of the gastrointestinal smooth muscle (Teague et al., 2002). CSE-derived H2S regulates perfusion pressure in the liver (Fiorucci et al., 2005), and is involved in the pancreatitis and/or processing of pancreatic pain (Bhatia et al., 2005, Nishimura et al., 2009).
In the colon, luminal H2S is generated abundantly by commensal sulfate-reducing bacteria (SRB). SRB-derived H2S has long been believed to participate in the etiology of inflammatory bowel disease (IBD) and/or colorectal cancer (Deplancke and Gaskins, 2003, Huycke and Gaskins, 2004, Leschelle et al., 2005, Ohge et al., 2003, Picton et al., 2002, Rose et al., 2005), although there is conflicting evidence (Fiorucci et al., 2007, Pitcher et al., 2000). Immunohistochemical studies have demonstrated that more than 90% of colonic submucous and myenteric neurons in guinea pigs and humans are co-labeled for CSE and CBS (Schicho et al., 2006), and that, in mouse colon, the external muscle layers including the myenteric plexus are labeled for CSE, but not CBS, while both of them were expressed in the mucosa (Linden et al., 2008). At least in mouse colon, CSE appears to be the relatively major enzyme responsible for enzymatic formation of H2S (Linden et al., 2008). The mechanisms by which H2S is degraded or detoxificated have been poorly investigated. Rhodanese consists of two sulfurtransferase components, thiosulfate sulfurtransferase (TST) and mercaptopyruvate sulfurtransferase (MST), with close structural and size similarities, and is involved in the mitochondrial electron transport chain and the detoxification of cyanide (Eggo et al., 2008, Nagahara et al., 1999, Nagahara et al., 2003, Westley, 1973). There is evidence that rhodanese, particularly TST, might be involved in detoxification of H2S in the colon (Picton et al., 2002, Ramasamy et al., 2006), although it is not completely clear whether rhodanese directly or indirectly degrades H2S (Eggo et al., 2008, Wilson et al., 2008). It is hypothesized that down-regulation of rhodanese, and concomitant impairment of detoxification of H2S in the colon might participate in the pathogenesis of IBD (Picton et al., 2002). Clinical studies have not necessarily provided concrete evidence for altered activity of colonic rhodanese in IBD patients, whereas increased activity of rhodanese in erythrocytes from IBD patients has been demonstrated (Picton et al., 2007). The up-regulation of erythrocytic rhodanese in IBD patients might arise from either increased luminal sulfide production or reduced colonic detoxification, and might be useful as a diagnostic parameter for IBD.
Apart from SRB-derived H2S, enzymatic formation and detoxification of H2S in the colonic tissue may be associated with the pathophysiology of IBD, but have not been investigated in animal models for IBD. In this context, we aimed at characterizing the activity and protein levels of enzymes responsible for production and degradation of H2S in the colon and/or erythrocytes of a murine model for IBD. Here our study provides novel evidence for the down-regulation of colonic rhodanese and the up-regulation of erythrocytic rhodanese in the mice with colitis induced by dextran sulfate sodium (DSS).
Section snippets
Animals
Male Wistar rats (6–8 weeks old) and male ddY mice (4–6 weeks old) were purchased from Japan SLC, Inc. (Shizuoka, Japan). All animals were used with approval by the Committee for the Care and Use of Laboratory Animals at Kinki University and were in accordance with the Guide for the care and use of laboratory animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996).
Induction and evaluation of colitis in mice
Colitis was induced by using the drinking water containing 5% (w/v) dextran sulfate
H2S formation and the activity and protein expression of CSE in mouse and rat colon
H2S was formed in mouse and rat colonic homogenates, as in their renal homogenates (Fig. 1A). PPG, an inhibitor of CSE, but not AOAA, an inhibitor of CBS, significantly attenuated H2S production in both rat colon and kidney (Fig. 1B). Rat feces produced H2S in a manner resistant to either of PPG or AOAA (Fig. 1A and B). The CSE activity in the colon exhibited no remarkable species difference between mice and rats, whereas the renal CSE activity in mice was much less than that in rats (Fig. 1C).
Discussion
Our data from the experiments using naïve mice and rats indicate that CSE, but not CBS, is a major enzyme responsible for H2S formation from l-cysteine in mouse or rat colon, in agreement with an independent study (Linden et al., 2008), and that rhodanese activity and protein are detectable in the rodents’ colon as well as kidney. In the mice drinking DSS, CSE does not appear to play a major role in the development of colitis, considering that CSE inhibition by PPG only slightly improved the
Conflicts of interest
The authors declare that there are no conflicts of interest.
Acknowledgements
This work was financially supported in part by “Antiaging Center Project” for Private Universities from Ministry of Education, Culture, Sports, Science and Technology, 2008–2012.
References (47)
- et al.
Comparative studies on the distribution of rhodanese in different tissues of domestic animals
Comp. Biochem. Physiol. B
(1991) - et al.
Hydrogen sulfide induced neuronal death occurs via glutamate receptor and is associated with calpain activation and lysosomal rupture in mouse primary cortical neurons
Neuropharmacology
(2007) - et al.
The emerging roles of hydrogen sulfide in the gastrointestinal tract and liver
Gastroenterology
(2006) - et al.
Hydrogen sulfide as a novel nociceptive messenger
Pain
(2007) Hydrogen sulfide induces cyclic AMP and modulates the NMDA receptor
Biochem. Biophys. Res. Commun.
(2000)- et al.
Direct inhibition of endothelial nitric oxide synthase by hydrogen sulfide: contribution to dual modulation of vascular tension
Toxicology
(2007) - et al.
Inhibition of glutathione synthesis with propargylglycine enhances N-acetylmethionine protection and methylation in bromobenzene-treated Syrian hamsters
J. Nutr.
(1999) - et al.
Adaptative metabolic response of human colonic epithelial cells to the adverse effects of the luminal compound sulfide
Biochim. Biophys. Acta
(2005) - et al.
Putative biological roles of hydrogen sulfide in health and disease: a breath of not so fresh air?
Trends Pharmacol. Sci.
(2008) - et al.
Hyperalgesia induced by spinal and peripheral hydrogen sulfide: evidence for involvement of Cav3.2 T-type calcium channels
Pain
(2009)
Identification of probasin-related antigen as cystathionine gamma-lyase by molecular cloning
J. Biol. Chem.
The effect of antibiotics and bismuth on fecal hydrogen sulfide and sulfate-reducing bacteria in the rat
FEMS Microbiol. Lett.
Hydrogen sulfide is a novel prosecretory neuromodulator in the Guinea-pig and human colon
Gastroenterology
The possible role of hydrogen sulfide on the pathogenesis of spontaneous hypertension in rats
Biochem. Biophys. Res. Commun.
A protective role of hydrogen sulfide against oxidative stress in rat gastric mucosal epithelium
Toxicology
Regulation of vascular nitric oxide in vitro and in vivo; a new role for endogenous hydrogen sulphide?
Br. J. Pharmacol.
Role of hydrogen sulfide in acute pancreatitis and associated lung injury
FASEB J.
Hydrogen sulfide induces serum-independent cell cycle entry in nontransformed rat intestinal epithelial cells
FASEB J.
Is thiosulfate sulfurtransferase the colonic sulfide oxidase?
Dig. Dis. Sci.
The third gas: H2S regulates perfusion pressure in both the isolated and perfused normal rat liver and in cirrhosis
Hepatology
Enhanced activity of a hydrogen sulphide-releasing derivative of mesalamine (ATB-429) in a mouse model of colitis
Br. J. Pharmacol.
Binding of hydrogen sulfide by bismuth does not prevent dextran sulfate-induced colitis in rats
Dig. Dis. Sci.
Commensal bacteria, redox stress, and colorectal cancer: mechanisms and models
Exp. Biol. Med. (Maywood)
Cited by (31)
Thiosulfate sulfurtransferase: a model of essential enzyme with potential applications in medicine and biotechnology
2023, Sulfurtransferases: Essential Enzymes for LifeUnraveling the role of thiosulfate sulfurtransferase in metabolic diseases
2020, Biochimica et Biophysica Acta - Molecular Basis of DiseaseCitation Excerpt :Expression of TST in colon mucosa is often markedly reduced in patients with ulcerative colitis and colon cancer when compared to normal mucosa, although the evidence is not completely consistent [72]. This decrease in TST activity corresponds with the development of colitis, and is followed by an elevation of TST activity in erythrocytes [71–73]. Conversely, mucosal healing was associated with an increased TST gene expression.
Polymorphic variants of human rhodanese exhibit differences in thermal stability and sulfur transfer kinetics
2015, Journal of Biological ChemistryCitation Excerpt :H2S levels are high in the lumen of the colon, where it is a product of commensal sulfate reducing bacteria (26). Colonic rhodanese levels and activity are down-regulated in colitis (27), and dysregulation of H2S homeostasis at the host-microbe interface could be important in the etiology of inflammatory bowel disease and colorectal cancer (18, 27–30). Identification of single nucleotide polymorphisms correlated with disease resistance or susceptibility is an area of intense current interest.
H<inf>2</inf>S and its role in redox signaling
2014, Biochimica et Biophysica Acta - Proteins and ProteomicsCitation Excerpt :Sulfide oxidation was reportedly ~ 3-fold lower at sites of mucosal ulceration in hapten-induced colitis in rats versus in healthy controls while H2S production was increased and mirrored in enhanced expression of CSE and MST (10- and 3-fold respectively), and diminished expression of SQR (~ 3-fold) [210]. Rhodanese expression and activity were diminished in colonic tissues in dextran sulfate sodium-induced colitis in mice, consistent with a role for impaired sulfide clearance in inflammatory bowel disease [211]. Administration of high concentrations of methionine or S-adenosylmethionine 1,4 butane disulfonate to rat colonocytes ablated the effects of sulfide toxicity and was proposed to be due to sulfide methylation [212].
Hydrogen sulfide is an endogenous potentiator of T cell activation
2012, Journal of Biological ChemistryCitation Excerpt :Inflammatory bowel disease is a chronic inflammatory disease caused by the generation and persistence of colitogenic CD4+ effector and memory T cells that react to antigens of commensal bacteria. H2S is continually produced by luminal sulfate-reducing commensal bacteria in the colon and is normally detoxified by rhodanese in the surrounding mucosal cells to thiosulfate (65, 66). An increase in the steady state H2S levels either from overproduction or reduced consumption is thought to play a role in the etiology of inflammatory bowel disease and related cancers (67).