Diphenyl diselenide prevents methylmercury-induced mitochondrial dysfunction in rat liver slices

Cristiane L. Dalla Corte, Félix A A Soares, Michael Aschner, João B T Rocha

Research output: Contribution to journalArticle

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Abstract

Methylmercury (MeHg) is a strong soft electrophile chemical form ubiquitously found in environment and it can exhibit highly toxic effects in multiple organs. Previously, we observed that diphenyl diselenide [(PhSe) 2] reduced the deposition and toxicity of MeHg in brain, liver and kidney of mice. The present study was designed to investigate the possible interaction of (PhSe)2 with MeHg-induced mitochondrial dysfunction in rat liver slices in vitro. The liver slices were treated with MeHg (25 μM) and/or (PhSe)2 (0.5, 1, and 5 μM) for 30 min at 37 °C, then mitochondria were isolated from these slices, and the reactive oxygen species (ROS) formation, oxygen consumption, membrane potential (ΔΨm), mitochondrial metabolic function, nonprotein and total thiol content, and Glutathione peroxidase (GPx) activity were assessed. MeHg decreased the mitochondrial function by increasing ROS production, impairing oxygen consumption, and collapsing the ΔΨm. (PhSe)2 protected against the MeHg-induced ROS generation and prevented the decrease in the respiratory rate and in the mitochondrial metabolic function [measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction]. (PhSe)2 (0.5 μM) blunted the MeHg-induced ΔΨm collapse; however at 5 μM, (PhSe)2 alone decreased ΔΨm, yet partially protected the mitochondria from MeHg-induced depolarization. MeHg and (PhSe)2 (0.5 μM) alone or in combination had no effect on nonprotein and total thiol levels and on the GPx activity in mitochondria isolated from liver slices. The protection afforded by (PhSe)2 against the MeHg-induced mitochondrial dysfunction can be associated with (PhSe)2 metabolism to a selenol intermediate, forming inert complex(es) with MeHg, thus effectively decreasing its toxicity. Furthermore, the selenol intermediate of (PhSe)2 (selenophenol) may have direct antioxidant properties against peroxides induced by MeHg. In conclusion, the results demonstrate that low (PhSe)2 concentrations effectively prevent the MeHg-induced mitochondrial dysfunction in vitro.

Original languageEnglish (US)
Pages (from-to)10437-10443
Number of pages7
JournalTetrahedron
Volume68
Issue number51
DOIs
StatePublished - Dec 23 2012
Externally publishedYes

Fingerprint

Liver
Mitochondria
Rats
Reactive Oxygen Species
Glutathione Peroxidase
Sulfhydryl Compounds
Oxygen Consumption
Toxicity
Liver Mitochondrion
Mitochondrial Membrane Potential
Poisons
Peroxides
Respiratory Rate
Oxygen
Depolarization
Antioxidants
Metabolism
Kidney
Brain
Membranes

Keywords

  • Methylmercury
  • Mitochondrial dysfunction
  • Mitochondrial permeability transition pore
  • ROS production
  • Seleno-organic compounds

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

Cite this

Diphenyl diselenide prevents methylmercury-induced mitochondrial dysfunction in rat liver slices. / Dalla Corte, Cristiane L.; Soares, Félix A A; Aschner, Michael; Rocha, João B T.

In: Tetrahedron, Vol. 68, No. 51, 23.12.2012, p. 10437-10443.

Research output: Contribution to journalArticle

Dalla Corte, Cristiane L. ; Soares, Félix A A ; Aschner, Michael ; Rocha, João B T. / Diphenyl diselenide prevents methylmercury-induced mitochondrial dysfunction in rat liver slices. In: Tetrahedron. 2012 ; Vol. 68, No. 51. pp. 10437-10443.
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N2 - Methylmercury (MeHg) is a strong soft electrophile chemical form ubiquitously found in environment and it can exhibit highly toxic effects in multiple organs. Previously, we observed that diphenyl diselenide [(PhSe) 2] reduced the deposition and toxicity of MeHg in brain, liver and kidney of mice. The present study was designed to investigate the possible interaction of (PhSe)2 with MeHg-induced mitochondrial dysfunction in rat liver slices in vitro. The liver slices were treated with MeHg (25 μM) and/or (PhSe)2 (0.5, 1, and 5 μM) for 30 min at 37 °C, then mitochondria were isolated from these slices, and the reactive oxygen species (ROS) formation, oxygen consumption, membrane potential (ΔΨm), mitochondrial metabolic function, nonprotein and total thiol content, and Glutathione peroxidase (GPx) activity were assessed. MeHg decreased the mitochondrial function by increasing ROS production, impairing oxygen consumption, and collapsing the ΔΨm. (PhSe)2 protected against the MeHg-induced ROS generation and prevented the decrease in the respiratory rate and in the mitochondrial metabolic function [measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction]. (PhSe)2 (0.5 μM) blunted the MeHg-induced ΔΨm collapse; however at 5 μM, (PhSe)2 alone decreased ΔΨm, yet partially protected the mitochondria from MeHg-induced depolarization. MeHg and (PhSe)2 (0.5 μM) alone or in combination had no effect on nonprotein and total thiol levels and on the GPx activity in mitochondria isolated from liver slices. The protection afforded by (PhSe)2 against the MeHg-induced mitochondrial dysfunction can be associated with (PhSe)2 metabolism to a selenol intermediate, forming inert complex(es) with MeHg, thus effectively decreasing its toxicity. Furthermore, the selenol intermediate of (PhSe)2 (selenophenol) may have direct antioxidant properties against peroxides induced by MeHg. In conclusion, the results demonstrate that low (PhSe)2 concentrations effectively prevent the MeHg-induced mitochondrial dysfunction in vitro.

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