The Role of Selenium in the Pathophysiology of Mercury Toxicity

Clinical Toxicology ISSN: 1556-3650 (Print) 1556-9519 (Online) Journal homepage: http://www.tandfonline.com/loi/ictx20 Rethinking mercury: the role of selenium in the pathophysiology of mercury toxicity Henry A. Spiller To cite this article: Henry A. Spiller (2017): Rethinking mercury: the role of selenium in the pathophysiology of mercury toxicity, Clinical Toxicology, DOI: 10.1080/15563650.2017.1400555 To link to this article: http://dx.doi.org/10.1080/15563650.2017.1400555 Published online: 10 Nov 2017. Submit your article to this journal Article views: 3 View related articles View Crossmark data Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ictx20 Download by: [American Academy of Clinical Toxicology] Date: 13 November 2017, At: 08:04 CLINICAL TOXICOLOGY, 2017 https://doi.org/10.1080/15563650.2017.1400555 REVIEW ARTICLE Rethinking mercury: the role of selenium in the pathophysiology of mercury toxicity Henry A. Spillera,b aCentral Ohio Poison Center, Columbus, OH, USA; bDepartment of Pediatrics, College of Medicine, Ohio State University, Columbus, OH, USA ABSTRACT ARTICLE HISTORY Introduction: There is increasing evidence that the pathophysiological target of mercury is in fact sel- Received 17 July 2017 enium, rather than the covalent binding of mercury to sulfur in the body’s ubiquitous sulfhydryl Accepted 31 October 2017 groups. The role of selenium in mercury poisoning is multifaceted, bidirectional, and central to under- Published online 9 November standing the target organ toxicity of mercury. 2017 Methods: An initial search was performed using Medline/PubMed, Toxline, Google Scholar, and Google KEYWORDS for published work on mercury and selenium. These searches yielded 2018 citations. Publications that Mercury; methylmercury; did not evaluate selenium status or evaluated environmental status (e.g., lake or ocean sediment) were selenium; poisoning; excluded, leaving approximately 500 citations. This initial selection was scrutinized carefully and 117 of selenoprotein; toxicity the most relevant and representative references were selected for use in this review. Binding of mercury to thiol/sulfhydryl groups: Mercury has a lower affinity for thiol groups and higher affinity for selenium containing groups by several orders of magnitude, allowing for binding in a multifaceted way. The established binding of mercury to thiol moieties appears to primarily involve the transport across membranes, tissue distribution, and enhanced excretion, but does not explain the oxidative stress, calcium dyshomeostasis, or specific organ injury seen with mercury. Effects of mercury on selenium and the role this plays in the pathophysiology of mercury toxicity: Mercury impairs control of intracellular redox homeostasis with subsequent increased intracellular oxidative stress. Recent work has provided convincing evidence that the primary cellular targets are the selenoproteins of the thioredoxin system (thioredoxin reductase 1 and thioredoxin reductase 2) and the glutathione-glutaredoxin system (glutathione peroxidase). Mercury binds to the selenium site on these proteins and permanently inhibits their function, disrupting the intracellular redox environment. A number of other important possible target selenoproteins have been identified, including selenoprotein P, K, and T. Impairment of the thioredoxin and glutaredoxin systems allows for proliferation intracellular reactive oxygen species which leads to glutamate excitosis, calcium dyshomeostasis, mito- chondrial injury/loss, lipid peroxidation, impairment of protein repair, and apoptosis. Methylmercury is a more potent inhibitor of the thioredoxin system, partially explaining its increased neurotoxicity. A second important mechanism is due to the high affinity of mercury for selenium and the subsequent depletion of selenium stores needed for insertion into de novo generation of replacement selenoproteins. This mercury-induced selenium deficiency state inhibits regeneration of the selenoproteins to restore the cellular redox environment. The effects of selenium on mercury and the role this plays in biological response to mercury: Early research suggested selenium may provide a protective role in mercury poisoning, and with limitations this is true. The roles selenium plays in this reduction of mercury toxicity partially depends on the form of mercury and may be multifaceted including: 1) facilitating demethylation of organic mercury to inorganic mercury; 2) redistribution of mercury to less sensitive target organs; 3) binding to inorganic mercury and forming an insoluble, stable and inert Hg:Se complex; 4) reduction of mercury absorption from the GI tract; 5) repletion of selenium stores (reverse selenium deficiency); and 6) res- toration of target selenoprotein activity and restoring the intracellular redox environment. There is con- Downloaded by [American Academy of Clinical Toxicology] at 08:04 13 November 2017 flicting evidence as to whether selenium increases or hinders mercury elimination, but increased mercury elimination does not appear to be a major role of selenium. Selenium supplementation has been shown to restore selenoprotein function and reduce the toxicity of mercury, with several signifi- cant limitations including: the form of mercury (methylmercury toxicity is less responsive to amelior- ation) and mercury dose. Conclusions: The interaction with selenium is a central feature in mercury toxicity. This interaction is complex depending on a number of features such as the form of mercury, the form of selenium, the organ and dose. The previously suggested “protective effect” of selenium against mercury toxicity may in fact be backwards. The effect of mercury is to produce a selenium deficiency state and a direct inhibition of selenium’s role in controlling the intracellular redox environment in organisms. Selenium supplementation, with limitations, may have a beneficial role in restoring adequate selenium status from the deficiency state and mitigating the toxicity of mercury. CONTACT Henry A. Spiller [email protected], www.linkedin.com/in/henryspiller/ Central Ohio Poison Center, 700 Childrens Dr, Columbus, OH 43205, USA ß 2017 Informa UK Limited, trading as Taylor & Francis Group 2 H. A. SPILLER Introduction selenocystine, and selenocysteine. These searches yielded 2018 citations. Publications that did not evaluate selenium There has been an important shift in the understanding of status or evaluated environmental status (e.g., lake or ocean the mechanisms of toxicity of mercury both at the cellular sediment) were excluded, leaving approximately 500 cita- and organism level. The shift in a large part has occurred tions. This initial selection was scrutinized carefully and 124 from a long-held focus on the covalent binding of mercury of the most relevant and representative references were to sulfur in the body’s ubiquitous sulfhydryl groups [1,2]. selected for use in this review. There is increasing and convincing evidence that the pathophysiological target of mercury is not the in vivo binding of sulfur, but rather selenium [3–5]. This may not be surprising Binding of mercury to thiol/sulfhydryl groups since the binding affinity between mercury and selenium is several orders of magnitude greater than the affinity of mer- Decades of work have focused on the interaction between cury and sulfur [5,6–9]. Previous reviews of mercury toxicity mercury and sulfhydryl moieties, including cysteine, homo- have been published and this review is not intended to cysteine, s-adenosylmethionine, metalothionine, and glutathi- readdress well established kinetics, clinical effects or out- one [1]. The primary outcome of the binding to sulfhydryl comes. Rather, this review will focus on growing understand- groups appears to be increased transport across membranes and enhanced excretion. Early work on the monovalent orga- ing of the role selenium plays in the pathophysiology of þ mercury toxicity. nomercury methylmercury (MeHg ) suggested binding of the The role of selenium in mercury poisoning is multifaceted, sulfur moiety on cysteine allowed the MeHg-cysteine com- bidirectional and central to understanding the target organ plex to become a substrate for the L-type large neutral toxicity of mercury. An addition critical feature of mercury amino acid transporters 1 and 2 (LAT-1 and LAT-2) [13,14]. toxicity and of the interaction with selenium is the chemical The MeHg-cysteine complex mimics methionine as a sub- state of mercury (e.g., Hg0,Hgþ, and Hgþ2). The mechanism strate for L-type large neutral amino acid transporters allow- of toxicity of mercury is based on its ability to bind to and in ing it to readily cross the blood brain and placental barrier certain cases inhibit moieties containing sulfur and selenium and cell membrane [15]. [3–5,10]. Mercury has a lower affinity for thiol groups and However, the divalent inorganic form of mercury (e.g., þ2 higher affinity for selenium containing groups, allowing for mercuric chloride, Hg ) has difficulty penetrating the CNS or binding in a multifaceted way. The relative ease with which crossing cell membranes suggesting L-type large neutral þ2 mercury can move from one thiol group to another allows amino acid transporters are not involved in Hg transport. for movement from one binding group to another, transport Kageyama et al. [16] suggested intracellular sulfhydryl group across membranes, and potentially temporarily impairment of inhibition

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