In vivo and in vitro inhibition of mice thioredoxin reductase by methylmercury.
The thioredoxin (Trx) system, involving redox active Trxs and thioredoxin reductases (TrxRs), sustain a number of important Trx-dependent pathways. These redox active proteins support several processes crucial for cell function, cell proliferation, antioxidant defense, and redox-regulated signaling cascades. Methylmercury (MeHg) is an important environmental toxicant that has a high affinity for thiol groups and can cause oxidative stress. The Trx system is the major system responsible for maintaining the redox state of cells and this function involves thiol reduction mediated by selenol groups in TrxRs. MeHg has a great affinity to thiols and selenols, thus the potential toxic effects of MeHg on TrxR inhibition were determined in the current study. A single administration of MeHg (1, 5, and 10 mg/Kg) caused a marked inhibition of kidney TrxR activity, while significant inhibition was observed in the liver after exposure to 5 and 10 mg/Kg of MeHg. TrxR activity was determined 24 h after MeHg. In the brain, MeHg did not inhibit TrxR activity. In vitro exposure to MeHg indicated that MeHg inhibits cerebral (IC(50), 0.158 μM), hepatic (IC(50), 0.071 μM), and renal TrxR activity (IC(50), 0.078 μM). The results presented herein demonstrated for the first time that renal and hepatic TrxRs can serve as an in vivo target for MeHg. This study suggests that MeHg can bind to selenocysteine residues present in the catalytic site of TrxR, in turn causing enzyme inhibition that can compromise the redox state of cells.
Wagner
Caroline
C
Centro de Ciências Naturais e Exatas, Programa de Pós-Graduação em Bioquímica Toxicológica, Departamento de Química, Universidade Federal de Santa Maria, Santa Maria, RS, 97105-900, Brazil. carolwagner@ibest.com.br
Sudati
Jéssie H
JH
Nogueira
Cristina W
CW
Rocha
João B T
JB
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008767:Methylmercury Compounds / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D017279:Selenocysteine / Q000378:metabolism; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D008767:Methylmercury Compounds; D017279:Selenocysteine; D013880:Thioredoxin-Disulfide Reductase; C004925:methylmercuric chloride