Serveur d'exploration sur la glutarédoxine

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Methylmercury alters glutathione homeostasis by inhibiting glutaredoxin 1 and enhancing glutathione biosynthesis in cultured human astrocytoma cells.

Identifieur interne : 000444 ( Main/Exploration ); précédent : 000443; suivant : 000445

Methylmercury alters glutathione homeostasis by inhibiting glutaredoxin 1 and enhancing glutathione biosynthesis in cultured human astrocytoma cells.

Auteurs : Stephan Robitaille [Canada] ; Ryan J. Mailloux [Canada] ; Hing Man Chan [Canada]

Source :

RBID : pubmed:27180086

Descripteurs français

English descriptors

Abstract

Methylmercury (MeHg) is a neurotoxin that binds strongly to thiol residues on protein and low molecular weight molecules like reduced glutathione (GSH). The mechanism of its effects on GSH homeostasis particularly at environmentally relevant low doses is not fully known. We hypothesized that exposure to MeHg would lead to a depletion of reduced glutathione (GSH) and an accumulation of glutathione disulfide (GSSG) leading to alterations in S-glutathionylation of proteins. Our results showed exposure to low concentrations of MeHg (1μM) did not significantly alter GSH levels but increased GSSG levels by ∼12-fold. This effect was associated with a significant increase in total cellular glutathione content and a decrease in GSH/GSSG. Immunoblot analyses revealed that proteins involved in glutathione synthesis were upregulated accounting for the increase in cellular glutathione. This was associated an increase in cellular Nrf2 protein levels which is required to induce the expression of antioxidant genes in response to cellular stress. Intriguingly, we noted that a key enzyme involved in reversing protein S-glutathionylation and maintaining glutathione homeostasis, glutaredoxin-1 (Grx1), was inhibited by ∼50%. MeHg treatment also increased the S-glutathionylation of a high molecular weight protein. This observation is consistent with the inhibition of Grx1 and elevated H2O2 production however; contrary to our original hypothesis we found few S-glutathionylated proteins in the astrocytoma cells. Collectively, MeHg affects multiple arms of glutathione homeostasis ranging from pool management to protein S-glutathionylation and Grx1 activity.

DOI: 10.1016/j.toxlet.2016.05.013
PubMed: 27180086


Affiliations:


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Le document en format XML

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<term>Astrocytoma (enzymology)</term>
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<term>Cell Line, Tumor (MeSH)</term>
<term>Central Nervous System Neoplasms (enzymology)</term>
<term>Central Nervous System Neoplasms (pathology)</term>
<term>Dose-Response Relationship, Drug (MeSH)</term>
<term>Glutaredoxins (antagonists & inhibitors)</term>
<term>Glutaredoxins (metabolism)</term>
<term>Glutathione (biosynthesis)</term>
<term>Glutathione Disulfide (MeSH)</term>
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<term>Humans (MeSH)</term>
<term>Mercury Poisoning, Nervous System (enzymology)</term>
<term>Mercury Poisoning, Nervous System (metabolism)</term>
<term>Methylmercury Compounds (toxicity)</term>
<term>Neurons (drug effects)</term>
<term>Neurons (enzymology)</term>
<term>Neurons (pathology)</term>
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<term>Oxidative Stress (drug effects)</term>
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<term>Astrocytome (anatomopathologie)</term>
<term>Astrocytome (enzymologie)</term>
<term>Composés méthylés du mercure (toxicité)</term>
<term>Disulfure de glutathion (MeSH)</term>
<term>Glutarédoxines (antagonistes et inhibiteurs)</term>
<term>Glutarédoxines (métabolisme)</term>
<term>Glutathion (biosynthèse)</term>
<term>Homéostasie (MeSH)</term>
<term>Humains (MeSH)</term>
<term>Lignée cellulaire tumorale (MeSH)</term>
<term>Maturation post-traductionnelle des protéines (MeSH)</term>
<term>Neurones (anatomopathologie)</term>
<term>Neurones (effets des médicaments et des substances chimiques)</term>
<term>Neurones (enzymologie)</term>
<term>Oxydoréduction (MeSH)</term>
<term>Relation dose-effet des médicaments (MeSH)</term>
<term>Stress oxydatif (effets des médicaments et des substances chimiques)</term>
<term>Troubles neurologiques de l'intoxication par le mercure (enzymologie)</term>
<term>Troubles neurologiques de l'intoxication par le mercure (métabolisme)</term>
<term>Tumeurs du système nerveux central (anatomopathologie)</term>
<term>Tumeurs du système nerveux central (enzymologie)</term>
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<term>Neurones</term>
<term>Tumeurs du système nerveux central</term>
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<term>Glutarédoxines</term>
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<term>Glutathion</term>
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<term>Neurones</term>
<term>Troubles neurologiques de l'intoxication par le mercure</term>
<term>Tumeurs du système nerveux central</term>
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<term>Mercury Poisoning, Nervous System</term>
<term>Neurons</term>
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<term>Glutaredoxins</term>
<term>Mercury Poisoning, Nervous System</term>
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<term>Troubles neurologiques de l'intoxication par le mercure</term>
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<term>Astrocytoma</term>
<term>Central Nervous System Neoplasms</term>
<term>Neurons</term>
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<term>Methylmercury Compounds</term>
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<term>Composés méthylés du mercure</term>
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<div type="abstract" xml:lang="en">Methylmercury (MeHg) is a neurotoxin that binds strongly to thiol residues on protein and low molecular weight molecules like reduced glutathione (GSH). The mechanism of its effects on GSH homeostasis particularly at environmentally relevant low doses is not fully known. We hypothesized that exposure to MeHg would lead to a depletion of reduced glutathione (GSH) and an accumulation of glutathione disulfide (GSSG) leading to alterations in S-glutathionylation of proteins. Our results showed exposure to low concentrations of MeHg (1μM) did not significantly alter GSH levels but increased GSSG levels by ∼12-fold. This effect was associated with a significant increase in total cellular glutathione content and a decrease in GSH/GSSG. Immunoblot analyses revealed that proteins involved in glutathione synthesis were upregulated accounting for the increase in cellular glutathione. This was associated an increase in cellular Nrf2 protein levels which is required to induce the expression of antioxidant genes in response to cellular stress. Intriguingly, we noted that a key enzyme involved in reversing protein S-glutathionylation and maintaining glutathione homeostasis, glutaredoxin-1 (Grx1), was inhibited by ∼50%. MeHg treatment also increased the S-glutathionylation of a high molecular weight protein. This observation is consistent with the inhibition of Grx1 and elevated H2O2 production however; contrary to our original hypothesis we found few S-glutathionylated proteins in the astrocytoma cells. Collectively, MeHg affects multiple arms of glutathione homeostasis ranging from pool management to protein S-glutathionylation and Grx1 activity. </div>
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}}

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HfdIndexSelect -h $EXPLOR_AREA/Data/Main/Exploration/RBID.i   -Sk "pubmed:27180086" \
       | HfdSelect -Kh $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd   \
       | NlmPubMed2Wicri -a GlutaredoxinV1 

Wicri

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Data generation: Wed Nov 18 15:13:42 2020. Site generation: Wed Nov 18 15:16:12 2020