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

doi:10.1016/j.tet.2012.09.025

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 journal › Article

14 Scopus citations

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 language	English (US)
Pages (from-to)	10437-10443
Number of pages	7
Journal	Tetrahedron
Volume	68
Issue number	51
DOIs	https://doi.org/10.1016/j.tet.2012.09.025
State	Published - Dec 23 2012
Externally published	Yes

Keywords

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

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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Dalla Corte, C. L., Soares, F. A. A., Aschner, M., & Rocha, J. B. T. (2012). Diphenyl diselenide prevents methylmercury-induced mitochondrial dysfunction in rat liver slices. Tetrahedron, 68(51), 10437-10443. https://doi.org/10.1016/j.tet.2012.09.025

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title = "Diphenyl diselenide prevents methylmercury-induced mitochondrial dysfunction in rat liver slices",

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.",

keywords = "Methylmercury, Mitochondrial dysfunction, Mitochondrial permeability transition pore, ROS production, Seleno-organic compounds",

author = "{Dalla Corte}, {Cristiane L.} and Soares, {F{\'e}lix A A} and Michael Aschner and Rocha, {Jo{\~a}o B T}",

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T1 - Diphenyl diselenide prevents methylmercury-induced mitochondrial dysfunction in rat liver slices

AU - Dalla Corte, Cristiane L.

AU - Soares, Félix A A

AU - Aschner, Michael

AU - Rocha, João B T

PY - 2012/12/23

Y1 - 2012/12/23

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.

AB - 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.

KW - Methylmercury

KW - Mitochondrial dysfunction

KW - Mitochondrial permeability transition pore

KW - ROS production

KW - Seleno-organic compounds

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