title: Toxicological effects of thiomersal and ethylmercury: Inhibition of the thioredoxin system and NADP(+)-dependent dehydrogenases of the pentose phosphate pathway.
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(+)-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 (GI50: 1.5 to 20μM) 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(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.
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal; Laboratory of Biochemistry, Faculty of Pharmacy, Central University of Venezuela, Venezuela. Electronic address: juanricardorodrigues@gmail.com.
authors.forename: Juan
authors.initials: J
authors.lastname: Rodrigues
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal.
authors.forename: Vasco
authors.initials: V
authors.lastname: Branco
authors.affiliation: Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Sweden.
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.affiliation: Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Sweden.
authors.forename: Arne
authors.initials: A
authors.lastname: Holmgren
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal. Electronic address: cristina.carvalho@ff.ulisboa.pt.
authors.forename: Cristina
authors.initials: C
authors.lastname: Carvalho
mesh_terms: D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D005035:Ethylmercury Compounds / Q000633:toxicity*; D056945:Hep G2 Cells; D006801:Humans; D009252:NADPH Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010427:Pentose Phosphate Pathway / Q000187:drug effects* / Q000502:physiology; D013849:Thimerosal / Q000633:toxicity*; D013879:Thioredoxins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D005035:Ethylmercury Compounds; D013849:Thimerosal; D013879:Thioredoxins; D009252:NADPH Dehydrogenase
keywords: Ethylmercury; Mercury; Pentose phosphate pathway; Selenium; Thiomersal; Thioredoxin system