title: Mitochondrial thioredoxin reductase inhibition, selenium status, and Nrf-2 activation are determinant factors modulating the toxicity of mercury compounds.
abstract: The thioredoxin system has essential functions in the maintenance of cellular redox homeostasis in the cytosol, nucleus, and mitochondria. Thioredoxin (Trx) and thioredoxin reductase (TrxR) are targets for mercury compounds in vitro and in vivo. This study aimed at understanding mechanistically how the mitochondrial and cytosolic thioredoxin systems were affected by mercurials, including the regulation of TrxR transcription. The effects of coexposure to selenite and mercurials on the thioredoxin system were also addressed. Results in HepG2 cells showed that TrxR1 expression was enhanced by Hg(2+), whereas exposure to MeHg decreased expression. Selenite exposure also increased the expression of TrxR1 and resulted in higher specific activity. Coexposure to 2 µM selenite and up to 5 µM Hg(2+) increased even further TrxR1 expression. This synergistic effect was not verified for MeHg, because TrxR1 expression and activity were reduced. Analysis of Nrf-2 translocation to the nucleus and TrxR mRNA suggests that induction of TrxR1 transcription was slower upon exposure to MeHg in comparison to Hg(2+). Subcellular fractions showed that MeHg affected the activity of the thioredoxin system equally in the mitochondria and cytosol, whereas Hg(2+) inhibited primarily the activity of TrxR2. The expression of TrxR2 was not upregulated by any treatment. These results show important differences between the mechanisms of toxicity of Hg(2+) and MeHg and stress the narrow range of selenite concentrations capable of antagonizing mercury toxicity. The results also highlight the relevance of the mitochondrial thioredoxin system (TrxR2 and Trx2) in the development of mercury toxicity.
authors.affiliation: Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisboa, Portugal.
authors.forename: Vasco
authors.initials: V
authors.lastname: Branco
authors.affiliation: Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisboa, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Godinho-Santos
authors.affiliation: Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisboa, Portugal.
authors.forename: João
authors.initials: J
authors.lastname: Gonçalves
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden.
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden.
authors.forename: Arne
authors.initials: A
authors.lastname: Holmgren
authors.affiliation: Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisboa, Portugal. Electronic address: cristina.carvalho@ff.ul.pt.
authors.forename: Cristina
authors.initials: C
authors.lastname: Carvalho
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation; D056945:Hep G2 Cells; D006801:Humans; D017669:Mercury Compounds / Q000633:toxicity*; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000096:biosynthesis; D012643:Selenium / Q000378:metabolism; D054481:Thioredoxin Reductase 1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D054482:Thioredoxin Reductase 2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D013879:Thioredoxins / Q000096:biosynthesis
chemical_list: D017669:Mercury Compounds; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D012333:RNA, Messenger; D013879:Thioredoxins; C516124:TXNRD1 protein, human; C516127:TXNRD2 protein, human; D054481:Thioredoxin Reductase 1; D054482:Thioredoxin Reductase 2; D012643:Selenium
keywords: Free radicals; Mercury; Methylmercury; Mitochondria; Nrf-2; Selenium; Thioredoxin; Thioredoxin reductase; mRNA