Methylmercury neurotoxicity is associated with inhibition of the antioxidant enzyme glutathione peroxidase

被引:205
作者
Franco, Jeferson L. [1 ]
Posser, Thais [1 ]
Dunkley, Peter R. [2 ,3 ]
Dickson, Phillip W. [2 ,3 ]
Mattos, Jaco J. [1 ]
Martins, Roberta [1 ]
Bainy, Afonso C. D. [1 ]
Marques, Maria R. [1 ]
Dafre, Alcir L. [4 ]
Farina, Marcelo [1 ]
机构
[1] Univ Fed Santa Catarina, Dept Bioquim, Ctr Ciencias Biol, BR-88040900 Florianopolis, SC, Brazil
[2] Univ Newcastle, Sch Biomed Sci, Callaghan, NSW 2308, Australia
[3] Univ Newcastle, Hunter Med Res Inst, Fac Hlth, Callaghan, NSW 2308, Australia
[4] Univ Fed Santa Catarina, Dept Ciencias Fisiol, Ctr Ciencias Biol, BR-88040900 Florianopolis, SC, Brazil
关键词
Methylmercury; Glutathione peroxidase; Apoptosis; Mitochondria; SH-SY5Y cells; Free radicals; ISCHEMIA REPERFUSION INJURY; OXYGEN SPECIES FORMATION; RAT CEREBELLAR GRANULE; OXIDATIVE STRESS; HYDROGEN-PEROXIDE; METHYL MERCURY; MOUSE-BRAIN; 2,2',4,4',5,5'-HEXACHLOROBIPHENYL PCB153; CELLULAR-RESISTANCE; REDUCTIVE RESERVE;
D O I
10.1016/j.freeradbiomed.2009.05.013
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
In this study, we investigated the involvement of glutathione peroxidase-GPx in methylmercury (MeHg)induced toxicity using three models: (a) in mouse brain after treatment with MeHg (40 mg/L in drinking water), (b) in mouse brain mitochondrial-enriched fractions isolated from MeHg-treated animals, and (c) in Cultured human neuroblastoma SH-SY5Y cells. First, adult male Swiss mice exposed to MeHg for 21 days showed a significant decrease in GPx activity in the brain and ail increase in poly(ADP-ribose) polymerase cleavage, an index of apoptosis. Second, in mitochondrial-enriched fractions isolated from MeHg-treated mice, there was a significant reduction in GPx activity and a concomitant decrease in mitochondrial activity and increases in ROS formation and lipid peroxidation. Incubation of mitochondrial-enriched fractions with mercaptosuccinic acid, a GPx inhibitor, significantly augmented the toxic effects of MeHg administered in vivo. Incubation of mitochondrial-enriched fractions with exogenous GPx completely blocked MeHg-induced mitochondrial lipid peroxidation. Third, SH-SY5Y cells treated for 24 h with MeHg showed a significant reduction in GPx activity. There was a concomitant significant decrease in cell viability and increase in apoptosis. Inhibition of GPx substantially enhanced MeHg toxicity in the SH-SY5Y cells. These results suggest that GPx is an important target for MeHg-induced neurotoxicity, presumably because this enzyme is essential for counteracting the pro-oxidative effects of MeHg both in vitro and in vivo. (C) 2009 Elsevier Inc. All rights reserved.
引用
收藏
页码:449 / 457
页数:9
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