The thioredoxin system as a target for mercury compounds

• Published in: Biochimica et biophysica acta. General subjects Vol. 1863; no. 12; p. 129255
• Main Authors: Branco, Vasco, Carvalho, Cristina
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.12.2019
• Subjects: active sites; Animals; biomarkers; cell death; Cell Proliferation - drug effects; dietary supplements; glutathione; Humans; Mercury; mercury compounds; Mercury Compounds - toxicity; Nrf-2; risk assessment process; Selenium; Selenoproteins; Thioredoxin; Thioredoxin reductase; Thioredoxin-Disulfide Reductase - antagonists & inhibitors; thioredoxins; Thioredoxins - antagonists & inhibitors; toxicity; Selenium; Selenoproteins; Thioredoxin; Mercury; Thioredoxin reductase; Nrf-2
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2018.11.007

Mercury interaction with selenium in vivo has been recognized for >50 years. Several researchers attempted to use selenium to mitigate the detrimental effects of mercurial compounds but the results were controversial. Selenium pools in living organisms are quite low and the high affinity of mercury to bind selenols pointed out selenoproteins as possible targets of toxicity. Such was the case of the selenoenzyme thioredoxin reductase (TrxR) which is an integrant part of the thioredoxin system. Given the important role of this redox system for cellular functioning and the high affinity of mercury for TrxR's active site, this interaction can be key to understand the mechanism by which Hg causes cell death. This review discusses the current state of knowledge concerning the interaction between mercury compounds and the thioredoxin system, its implications for the development of toxicity and the effects of selenium co-exposure. The mechanism of toxicity of mercurials is a complex chain of events starting with inhibition of the selenoenzyme, TrxR. Selenium supplementation protects TrxR from the toxicity of inorganic forms of mercury (i.e., Hg(II)) to a certain extent, but not from methylmercury. When TrxR is inhibited, thioredoxin is reduced by alternative mechanisms involving glutathione and glutaredoxin and only when this pathway is hampered does cell death occur. Understanding the molecular mechanism of mercury toxicity and the mechanisms of enzymatic compensation allows the design of mitigation strategies and, since TxrR and Trx exist in the plasma, puts forward the possibility for future use of changes in activity/expression of these enzymes as biomarkers of mercury toxicity, thus refining the risk assessment process. [Display omitted] •The selenoenzyme TrxR is a primary target for Hg compounds in vitro and in vivo.•Selenite recovers TrxR inhibited by Hg2+ but not by MeHg.•Selenite counteracts Hg2+ toxicity through Nrf2 signaling increasing TrxR1 synthesis but not TrxR2.•GSH and glutaredoxin serve as backups for TrxR by keeping Trx reduced.•High level of exposure to Hg oxidizes Trx causing apoptosis via the ASK-1 pathway.