International Journal of Molecular Sciences Review Hydrogen Sulfide Metabolite, Sodium Thiosulfate: Clinical Applications and Underlying Molecular Mechanisms Max Y. Zhang 1,2, George J. Dugbartey 1,2,3, Smriti Juriasingani 1,3 and Alp Sener 1,2,3,4,* 1 Matthew Mailing Center for Translational Transplant Studies, London Health Sciences Center, Western University, London, ON N6A 5A5, Canada; [email protected] (M.Y.Z.); [email protected] (G.J.D.); [email protected] (S.J.) 2 London Health Sciences Center, Multi-Organ Transplant Program, Western University, London, ON N6A 5A5, Canada 3 London Health Sciences Center, Department of Surgery, Division of Urology, Western University, London, ON N6A 5A5, Canada 4 Department of Microbiology & Immunology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON N6A 3K7, Canada * Correspondence: [email protected]; Tel.: +1(519) 6633352 Abstract: Thiosulfate in the form of sodium thiosulfate (STS) is a major oxidation product of hydrogen sulfide (H2S), an endogenous signaling molecule and the third member of the gasotransmitter family. STS is currently used in the clinical treatment of acute cyanide poisoning, cisplatin toxicities in cancer therapy, and calciphylaxis in dialysis patients. Burgeoning evidence show that STS has antioxidant and anti-inflammatory properties, making it a potential therapeutic candidate molecule that can target multiple molecular pathways in various diseases and drug-induced toxicities. This review Citation: Zhang, M.Y.; Dugbartey, discusses the biochemical and molecular pathways in the generation of STS from H2S, its clinical G.J.; Juriasingani, S.; Sener, A. usefulness, and potential clinical applications, as well as the molecular mechanisms underlying these Hydrogen Sulfide Metabolite, clinical applications and a future perspective in kidney transplantation. Sodium Thiosulfate: Clinical Applications and Underlying Keywords: sodium thiosulfate (STS); thiosulfate; hydrogen sulfide (H2S); ischemia–reperfusion injury Molecular Mechanisms. Int. J. Mol. (IRI); sulfide oxidation pathway Sci. 2021, 22, 6452. https:// doi.org/10.3390/ijms22126452 Academic Editor: 1. Introduction Marcin Magierowski Sodium thiosulfate (STS) is an odorless, inorganic, and water-soluble compound Received: 28 May 2021 with the chemical formula Na2S2O3 and a molecular weight of 158.11g/mol. It is a major Accepted: 11 June 2021 oxidation production of hydrogen sulfide (H2S) and is typically available as a white crys- Published: 16 June 2021 talline or powdered substance in the form of pentahydrate (Na2S2O3·5H2O) [1]. Currently on the World Health Organization’s list of essential medicines, STS has several other Publisher’s Note: MDPI stays neutral uses including as a common food preservative, a water dechlorinator, a photographic with regard to jurisdictional claims in fixative, and a bleaching agent for paper pulp [2]. It possesses therapeutic properties such published maps and institutional affil- as antioxidant, anti-inflammatory, and antihypertensive properties [3–7]. It is approved iations. by Food and Drugs Administration (FDA) and is currently clinically useful in the treat- ment of acute cyanide poisoning, carbon monoxide toxicity, cisplatin toxicities in cancer therapy, and calcific uremic arteriolopathy (calciphylaxis) in dialysis patients [8–11]. STS is administered intravenously or topically because it is rapidly degraded in the stomach. Copyright: © 2021 by the authors. Emerging reports also suggest its potential application in ischemia–reperfusion injury (IRI) Licensee MDPI, Basel, Switzerland. in solid organ transplantation [12–14]. In this review, we first present hydrogen sulfide This article is an open access article (H2S) as an endogenous signaling molecule and a third member of the gasotransmitter distributed under the terms and family. Next, we describe the biochemical and molecular pathways of H2S from which conditions of the Creative Commons thiosulfate is generated. Finally, we discuss the clinical usefulness and potential clinical Attribution (CC BY) license (https:// applications of STS and its underlying molecular mechanisms, with a future perspective creativecommons.org/licenses/by/ on kidney transplantation. 4.0/). Int. J. Mol. Sci. 2021, 22, 6452. https://doi.org/10.3390/ijms22126452 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 14 potential clinical applications of STS and its underlying molecular mechanisms, with a future perspective on kidney transplantation. 2. Hydrogen Sulfide as a Gasotransmitter Hydrogen sulfide (H2S) is a colorless, flammable, and water-soluble gas with the Int. J. Mol. Sci. 2021, 22, 6452 2 of 13 characteristic smell of rotten eggs [15,16]. For several centuries, H2S was notoriously known for its toxic effects and death among agricultural and industrial workers at high concentrations. The mechanism underlying the toxic effect of H2S involves reversible antagonism2. Hydrogen of Sulfide cytochrome as a Gasotransmitter c oxidase (complex IV), the terminal complex of the mitochondrialHydrogen electron sulfide (H transport2S) is a colorless, chain flammable, [17]. In andthe water-solublepast two decades, gas with thehowever, charac- this obnoxiousteristic smell-smelling of rotten, membrane eggs [15,16].-permeable For several centuries,gas has risen H2S wasabove notoriously its negative known public for its image andtoxic is now effects known and death to play among several agricultural important and industrial functions workers in physiological at high concentrations. processes The at low concentrations.mechanism underlying Additionally, the toxic it effect exhibits of H2 Sdiverse involves therapeutic reversible antagonism potential of with cytochrome the ability c to oxidase (complex IV), the terminal complex of the mitochondrial electron transport chain [17]. target several molecular pathways in several diseases and drug-induced toxicities [18–22]. In the past two decades, however, this obnoxious-smelling, membrane-permeable gas has H2risenS is abovealso itsestablished negative public among image researchers and is now knownas the to playthird several member important of the functions family of gasotransmittersin physiological, processes endogenous at low concentrations.gaseous signaling Additionally, molecules it exhibits, next diverse to nitric therapeutic oxide and carbonpotential monoxide with the [ ability15]. It to has target the several ability molecular to alter pathwaysactivity of in severalproteins diseases from andmany drug- cellular signalinginduced toxicitiespathways [18 involved–22]. H2S isin also apoptosis, established angiogenesis, among researchers inflammation, as the third membermetabolism, proliferationof the family, and of gasotransmitters, oxygen sensing. endogenous It can also gaseous play signalinga detoxifying molecules, role nextduring to nitric oxidative stressoxide by and increasing carbon monoxide the development [15]. It has of the glutathione ability to alter [23– activity25], the of most proteins abundant from many naturally occurringcellular signalingantioxidant pathways in the involved body, and in apoptosis, by reacting angiogenesis, directly inflammation,with peroxynitrite metabolism, (ONOO−) proliferation, and oxygen sensing. It can also play a detoxifying role during oxidative stress as a direct scavenging property of H2S toward cellular ROS. H2S is endogenously by increasing the development of glutathione [23–25], the most abundant naturally occurring producedantioxidant in inall the mamm body, andalian by cells reacting through directly metabolic with peroxynitrite pathways (ONOO that− )use as athe direct sulfur- containingscavenging amino property acid of L H-2cysteineS toward and cellular 3-mercaptopruvate ROS. H2S is endogenously via 3 enzymes: produced cystathionine in all mam- β- synthasemalian cells(CBS), through cystathionine metabolic pathways γ-lyase that(CSE), use theand sulfur-containing 3-mercaptopyruvate amino acid sulfurtransferase L-cysteine (3-andMST) 3-mercaptopruvate (Figure 1). It ha vias also 3 enzymes: been found cystathionine that H2Sβ can-synthase be produced (CBS), cystathionine from D-cysteineγ-lyase using the(CSE), peroxisomal and 3-mercaptopyruvate enzyme, D-amino sulfurtransferase acid oxidase (3-MST) [26]. Besides (Figure1 its). It endogenous has also been production, found H2thatS is H also2S can administered be produced from exogenously D-cysteine using through the peroxisomal a number enzyme, of its D-aminodonor acidcompounds oxi- , includingdase [26]. STS Besides and itsGYY4137 endogenous [27– production,29]. H2S is also administered exogenously through a number of its donor compounds, including STS and GYY4137 [27–29]. Figure 1. Generation of thiosulfate from H S in the mitochondrial sulfide oxidation pathways. Hydrogen sulfide (H S) is Figure 1. Generation of thiosulfate from H2S2 in the mitochondrial sulfide oxidation pathways. Hydrogen sulfide2 (H2S) is producedproduced by enzymes by enzymes cystathione cystathione γ-γlyase-lyase (CSE) (CSE) and and cystathionine β β-synthase-synthase (CBS) (CBS) in thein the trans-sulfuration trans-sulfuration pathway. pathway. A A third enzyme, 3-mercaptopyruvate sulfurtransferase (MST), also produces endogenous H S in the presence of the substrate third enzyme, 3-mercaptopyruvate sulfurtransferase (MST), also produces endogenous2 H2S in the presence of the sub- 3-mercaptopyruvate. A membrane-bound sulfide, quinone oxidoreductase (SQR), oxidizes H S to persulfide, which