INTRODUCTION

There is increasing evidence that the pathophysiological target of mercury is in fact selenium, rather than the covalent binding of mercury to sulfur in the body's ubiquitous sulfhydryl groups. The role of selenium in mercury poisoning is multifaceted, bidirectional, and central to understanding the target organ toxicity of mercury.

METHODS

An initial search was performed using Medline/PubMed, Toxline, Google Scholar, and Google for published work on mercury and selenium. These searches yielded 2018 citations. Publications that did not evaluate selenium status or evaluated environmental status (e.g., lake or ocean sediment) were excluded, leaving approximately 500 citations. This initial selection was scrutinized carefully and 117 of 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, mitochondrial 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) restoration of target selenoprotein activity and restoring the intracellular redox environment. There is conflicting 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 significant limitations including: the form of mercury (methylmercury toxicity is less responsive to amelioration) 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.