Toxicological effects of thiomersal and ethylmercury: Inhibition of the thioredoxin system and NADP{sup +}-dependent dehydrogenases of the pentose phosphate pathway

Rodrigues, Juan; Branco, Vasco; Lu, Jun; Holmgren, Arne; Carvalho, Cristina

doi:10.1016/J.TAAP.2015.05.002

Title: Toxicological effects of thiomersal and ethylmercury: Inhibition of the thioredoxin system and NADP{sup +}-dependent dehydrogenases of the pentose phosphate pathway

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Abstract

Mercury (Hg) is a strong toxicant affecting mainly the central nervous, renal, cardiovascular and immune systems. Thiomersal (TM) is still in use in medical practice as a topical antiseptic and as a preservative in multiple dose vaccines, routinely given to young children in some developing countries, while other forms of mercury such as methylmercury represent an environmental and food hazard. The aim of the present study was to determine the effects of thiomersal (TM) and its breakdown product ethylmercury (EtHg) on the thioredoxin system and NADP{sup +}-dependent dehydrogenases of the pentose phosphate pathway. Results show that TM and EtHg inhibited the thioredoxin system enzymes in purified suspensions, being EtHg comparable to methylmercury (MeHg). Also, treatment of neuroblastoma and liver cells with TM or EtHg decreased cell viability (GI{sub 50}: 1.5 to 20 μM) and caused a significant (p < 0.05) decrease in the overall activities of thioredoxin (Trx) and thioredoxin reductase (TrxR) in a concentration- and time-dependent manner in cell lysates. Compared to control, the activities of Trx and TrxR in neuroblastoma cells after EtHg incubation were reduced up to 60% and 80% respectively, whereas in hepatoma cells the reduction was almost 100%. In addition, the activities of glucose-6-phosphate dehydrogenasemore »« less

Authors:

Rodrigues, Juan ^[1]; Branco, Vasco ^[1]; Lu, Jun; Holmgren, Arne ^[2]; Carvalho, Cristina ^[1]

Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa (Portugal)
Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet (Sweden)

Publication Date:: Sat Aug 01 00:00:00 EDT 2015

OSTI Identifier:: 22465797

Resource Type:: Journal Article

Journal Name:: Toxicology and Applied Pharmacology

Additional Journal Information:: Journal Volume: 286; Journal Issue: 3; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X

Country of Publication:: United States

Language:: English

Subject:: 60 APPLIED LIFE SCIENCES; ANTISEPTICS; CHILDREN; CONCENTRATION RATIO; DEVELOPING COUNTRIES; DOSES; FOOD; HAZARDS; HEPATOMAS; INCUBATION; KIDNEYS; LIVER CELLS; MERCURY; METHYLMERCURY; NADP; OXIDOREDUCTASES; SELENIUM; SELENIUM IONS; TIME DEPENDENCE; TOXICITY; VACCINES

Citation Formats


                    Rodrigues, Juan, Laboratory of Biochemistry, Faculty of Pharmacy, Central University of Venezuela, Branco, Vasco, Lu, Jun, Holmgren, Arne, and Carvalho, Cristina. Toxicological effects of thiomersal and ethylmercury: Inhibition of the thioredoxin system and NADP{sup +}-dependent dehydrogenases of the pentose phosphate pathway.  United States: N. p., 2015. 
        Web.  doi:10.1016/J.TAAP.2015.05.002.

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                    Rodrigues, Juan, Laboratory of Biochemistry, Faculty of Pharmacy, Central University of Venezuela, Branco, Vasco, Lu, Jun, Holmgren, Arne, & Carvalho, Cristina. Toxicological effects of thiomersal and ethylmercury: Inhibition of the thioredoxin system and NADP{sup +}-dependent dehydrogenases of the pentose phosphate pathway.  United States.  https://doi.org/10.1016/J.TAAP.2015.05.002

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                    Rodrigues, Juan, Laboratory of Biochemistry, Faculty of Pharmacy, Central University of Venezuela, Branco, Vasco, Lu, Jun, Holmgren, Arne, and Carvalho, Cristina. 2015.  
        "Toxicological effects of thiomersal and ethylmercury: Inhibition of the thioredoxin system and NADP{sup +}-dependent dehydrogenases of the pentose phosphate pathway".  United States.  https://doi.org/10.1016/J.TAAP.2015.05.002.

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@article{osti_22465797,

  title        = {Toxicological effects of thiomersal and ethylmercury: Inhibition of the thioredoxin system and NADP{sup +}-dependent dehydrogenases of the pentose phosphate pathway},

  author       = {Rodrigues, Juan and Laboratory of Biochemistry, Faculty of Pharmacy, Central University of Venezuela and Branco, Vasco and Lu, Jun and Holmgren, Arne and Carvalho, Cristina},

  abstractNote = {Mercury (Hg) is a strong toxicant affecting mainly the central nervous, renal, cardiovascular and immune systems. Thiomersal (TM) is still in use in medical practice as a topical antiseptic and as a preservative in multiple dose vaccines, routinely given to young children in some developing countries, while other forms of mercury such as methylmercury represent an environmental and food hazard. The aim of the present study was to determine the effects of thiomersal (TM) and its breakdown product ethylmercury (EtHg) on the thioredoxin system and NADP{sup +}-dependent dehydrogenases of the pentose phosphate pathway. Results show that TM and EtHg inhibited the thioredoxin system enzymes in purified suspensions, being EtHg comparable to methylmercury (MeHg). Also, treatment of neuroblastoma and liver cells with TM or EtHg decreased cell viability (GI{sub 50}: 1.5 to 20 μM) and caused a significant (p < 0.05) decrease in the overall activities of thioredoxin (Trx) and thioredoxin reductase (TrxR) in a concentration- and time-dependent manner in cell lysates. Compared to control, the activities of Trx and TrxR in neuroblastoma cells after EtHg incubation were reduced up to 60% and 80% respectively, whereas in hepatoma cells the reduction was almost 100%. In addition, the activities of glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase were also significantly inhibited by all mercurials, with inhibition intensity of Hg{sup 2+} > MeHg ≈ EtHg > TM (p < 0.05). Cell incubation with sodium selenite alleviated the inhibitory effects on TrxR and glucose-6-phosphate dehydrogenase. Thus, the molecular mechanism of toxicity of TM and especially of its metabolite EtHg encompasses the blockage of the electrons from NADPH via the thioredoxin system. - Highlights: • TM and EtHg inhibit Trx and TrxR both in purified suspensions and cell lysates. • TM and EtHg also inhibit the activities of G6PDH and 6PGDH in cell lysates, • Co-exposure to selenite alleviates the inhibitory effects of TM/EtHg on TrxR and G6PDH. • EtHg is more toxic than the parent compound TM.},

  doi          = {10.1016/J.TAAP.2015.05.002},

  url          = {https://www.osti.gov/biblio/22465797},
  journal      = {Toxicology and Applied Pharmacology},

  issn         = {0041-008X},

  number       = 3,

  volume       = 286,

  place        = {United States},

  year         = {Sat Aug 01 00:00:00 EDT 2015},

  month        = {Sat Aug 01 00:00:00 EDT 2015}

}

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