API

Relationship: 1689

Title

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Binding, SH/SeH proteins involved in protection against oxidative stress leads to Oxidative Stress

Upstream event

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Binding, SH/SeH proteins involved in protection against oxidative stress

Downstream event

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Oxidative Stress

Key Event Relationship Overview

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AOPs Referencing Relationship

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Taxonomic Applicability

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Term Scientific Term Evidence Link
mouse Mus musculus High NCBI
rat Rattus norvegicus High NCBI
human Homo sapiens High NCBI
zebra fish Danio rerio High NCBI

Sex Applicability

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Sex Evidence
Unspecific High

Life Stage Applicability

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Term Evidence
During brain development, adulthood and aging High

Key Event Relationship Description

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Proteins with cysteine amino acid residues contain thiol (SH) groups, and proteins with selenocysteine amino acid residues contain selenol (SeH) are characterized as cysteine-/selenoprotein family. Thiol and selenol groups exhibit reactivity toward electrophiles and oxidants and have high binding affinities for metals (Higdon, 2012; Nagy, 2013; Winterbourn, 2008; Winther, 2014).

Figure 1. (Poole, 2015) Structures of cysteinyl and selenocysteinyl residues within proteins. The aminoacyl groups are shown to the left, with dotted lines representing peptide bonds to the next residue on either side. Both protonated (left) and deprotonated (right) forms of these amino acids are depicted with average pKa values.

The selenoprotein family composes of proteins with diverse functionality, however, several are classified as antioxidant enzymes (Reeves, 2009) and this function is of particular importance for this KER. Relevant for this KER there are two well-studied functional selenoprotein families which are described to be expressed in the brain; (i) the Glutathione Peroxidase (GPx) family, involved in detoxification of peroxidases; (ii) the Thioredoxin Reductase (TrxR) family, which is involved in the regeneration of reduced thioredoxin (Pillai, 2014). However, there is also a number of other selenoproteins with diverse functions, from selenium transport (SelP), to ER stress response (SelK, M, N, S, T and Sep15, as well as DIO2) (Pisoschi, 2015; Reeves, 2009). Due to their described functionalities (summarized in table below) an increased oxidative stress as a consequence of interference with selenoprotein function, through binding to active-site thiol-/selenol groups will primarily concern the interference with proteins of the GPx- and TrxR families, as well as SelH, K, S, R, W, and P selenoproteins.

Table1

Selenoprotein family

Protein name

Normal brain function

Disruption leading to oxidative stress

Reference

Glutathione

GSH

GSH is a major endogenous antioxidant functioning directly in neutralization of free radicals and reactive oxygen compounds. GSH is the reduced form of glutathione and its SH group of cysteine is able to reduce and/or maintain reduced form of other molecules.

Disruptions leads to increased oxidative stress and apoptosis.

(Dringen, 2000)

(Hall, 1999)

Glutathione Peroxidase (GPx) Family

GPx1

Peroxide/ROS reduction

(Promotes neuroprotection in response to oxidative challenge).

 

Brain expression levels are highest in microglia and lower levels detected in neurons.

Brains of GPx1−/− mice are more vulnerable to mitochondrial toxin treatment, ischemia/ reperfusion, and cold-induced brain injury.

Cultured neurons from GPx1−/− mice were reported to be more susceptible to Aβ-induced oxidative stress, and addition of ebselen reversed this.

(Lindenau, 1998)

(Crack, 2001;Flentjar, 2002;Klivenyi, 2000)

(Crack, 2006)

GPx4

Reduction of phospholipid

Hydroperoxides.

Only in neurons during normal conditions.

Brains of GPx4+/− mice were shown to have increased lipid peroxidation (a sign of oxidative stress).

Injury-induced GPx4 expression in astrocytes.

In vivo over expression of GPx4 protects against oxidative stress-induced apoptosis.

(Chen, 2008)

(Savaskan, 2007) and (Borchert, 2006) and (Ran, 2004)

Thioredoxin Reductase (TrxR) Family

TrxR1

Cytocsolic localization. Contributes to the reduction of hydrogen peroxide and oxidative stress, and regulates redox-sensitive

transcription factors that

control cellular transcription

mechanisms.

TrxR-1 regulates the induction of the antioxidant enzyme heme oxygenase 1 (HO-1).

Overexpression of human Trx1 and Trx2 protects retinal ganglion cells against oxidative stress-induced neurodegeneration.

(Pitts, 2014)

(Zhong, 2000)

 

(Burk, 2013)

(Arbogast, 2010;Trigona, 2006)

(Munemasa, 2008)

TrxR2

Mitochondrial localization. Contribute to the reduction of hydrogen peroxide and

oxidative stress, and regulates redox sensitive

transcription factors that

control cellular transcription

mechanisms.

Exogenously administered human rTrx ameliorates neuronal damage after transient middle cerebral artery occlusion in mice, reduces oxidative/nitrative stress and neuronal apoptosis after cerebral ischemia/reperfusion injury in mice

(Pitts, 2014) (Arbogast, 2010;Gladyshev, 1996;Papp, 2007)

(Hattori, 2004)(Ma, 2012)

Other relevant seleno- proteins

SelH

Nuclear localization. Redox sensing.

Hypersensitivity of SelH shRNA HeLa cells to paraquat- and H2O2-induced oxidative stress.

 

(Panee, 2007)(Novoselov, 2007)

(Wu, 2014)

SelK

Transmembrane protein

localized to the ER membrane.

ER homeostasis and oxidative stress response.

Protects HepG2 cells from ER stress agent-induced apoptosis.

Overexpression of SelK attenuated the intracellular reactive oxygen species level and protected cells from oxidative stress-induced toxicity in cardiomyocytes

(Shchedrina, 2011)

(Du, 2010)

(Lu, 2006)

SelS

Transmembrane protein

localized to the ER membrane. Catalyze the reduction of disulfide bonds and peroxides.

SelS overexpression increased astrocyte resistance to ER-stress and inflammatory stimuli, and suppression of SelS compromised astrocyte viability.

(Liu, 2013)

(Fradejas, 2011)

(Fradejas, 2008)

 (Gao, 2007)

MSRB1, SelR, SelX

Function in reduction of oxidized methionine residues, and actin polymerization.

Induce expression of MSRB1 protects neurons from amyloid β-protein insults in vitro and in vivo.

(Lee, 2013)

(Moskovitz, 2011)(Pillai, 2014)

SelW

Expressed in synapses. Plays an antioxidant role in cells.

Rat in vivo overexpression of SelW was shown to protect glial cells against oxidative stress caused by heavy metals and 2,20-Azobis.

Silencing of SelW made neurons more sensitive to oxidative stress.

(Reeves, 2009)

(Sun, 2001)

(Loflin, 2006)

(Raman, 2013)

(Chung, 2009)

SelP

Is important for selenium transport, distribution and retention within the brain.

Acts as a ROS-detoxifying enzyme.

Protects human astrocytes from induced oxidative.

SelP-/- mice show neurological dysfunction and that Se content and GPx activity were reduced within brain, Se supplementation to diet attenuated. neurological dysfunctions.

SelP-/- mice have reported deficits in PV-interneurons due to diminished antioxidant defense capabilities. Decreased neuronal selenoprotein synthesis may be a functional outcome of SelP

Colocalization of Sel P with amyloid plaques

 

SelP can function as an antioxidant enzyme against reactive lipid intermediates

(Steinbrenner, 2009)(Arbogast, 2010)(Zhang, 2008)

(Hill, 2003;Hill, 2004)

(Cabungcal, 2006)

(Pitts, 2012)

(Byrns, 2014)

 

 

(Schomburg, 2003)

 

(Rock, 2010)

https://aopwiki.org/system/dragonfly/production/2018/01/26/9o3c62z5ej_AOP17_KER1_Table1.pdf

Binding to thiol/sulfhydyryl groups of these proteins can firstly result in structural modifications of these proteins, which in turn negatively effects the catalytic capacity and thereby reducing or blocking the metabolic capacity to neutralize reactive oxygen species (Fernandes, 1996; Rajanna, 1995), secondly, SH/SeH binding would also the instrinsic primary antioxidant functionalities of selenoproteins (Kohen, 2002; Pisoschi, 2015).

Evidence Supporting this KER

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Biological Plausibility

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Primary antioxidants are mainly chain breakers, able to scavenge radical species by hydrogen donation. Secondary antioxidants are singlet oxygen quenchers, peroxide decomposers, metal chelators, oxidative enzyme inhibitors (Pisosci and Pop 2015).

 

Thiol- and selenol containing proteins have a high affinity for binding soft metals which contributes to the target site – brain – distribution of such toxicants (Farina, 2011).

 

GPx family

GPxs are tetrameric enzymes where their thiol groups can either act directly act as a reductant, or they catalyze reduction of hydrogen peroxide and/or phospholipid hydroperoxides through glutathione co-factors (Hanschmann, 2013; Labunskyy, 2014)

 

TrxR family

The thioredoxin reductase (TxRs) family of selenoproteins are homodimeric flavoenzymes, which mediate the reduction of oxidized Txn at the expense of NADPH (Birben et al., 2012). Inhibition of TrxR enzymes have been shown to lead to oxidative stress (Carvalho, 2008).

 

SelP

Downregulation of intracellular SelP by use of small interfering RNA (siRNA) impaired the viability of human astrocytes and made them more susceptible to hydroperoxide-induced oxidative stress, pointing to a direct contribution of SeP to ROS clearance (Steinbrenner, 2006)

Empirical Evidence

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Mercury

The selenol group (-SeH) of selenocysteines is generally more reactive than thiols (-SH) towards mercury (Sugiura 1976, Khan, 2009). Methyl mercury (MeHg) can target both the GPx and TrxR proteins thereby causing induction of oxidative stress and neurotoxicity (Branco, 2017; Carvalho, 2008; Farina, 2011).

Table 2

KEup

Interference with SH/SeH

KEdown

Oxidative stress induction

species; in vivo / in vitro

Stressor

Dose/ conc. +

Duration of exp.

Protective/ aggravating evidence

Reference

Post-transcriptional effects on GPx1 and TrxR1 expression and activity.

 

TrxR1 – 2-fold

GPx1 – 0.6-fold

Disturbance of redox-response and induction of oxidative stress.

 

 

SOD – 2-fold

ROS – increased

Mouse myoblast C2C12,

 

MeHg

0.4 µM

 

9 h

Treatment with ebselen suppressed MeHg-induced oxidative

stress

(Usuki, 2011)

Inhibition of TrxR and GSH activities.

 

 

TrxR1&2 – 0.6-fold

GSH – 0.7-fold

Oxidative stress shown by shift in GSSG/GSH ratio.

 

GSSG/GSH – 1.5-fold

Human neuroblastoma cells (SH-SY5Y)

MeHg

1 µM

 

 

Se supplementation gave some extent of oxidative stress protection.

(Branco, 2017)

Decreased activity of TrxR and GPx.

 

TrxR – 0.5-fold

GPx – 0.5-fold

Oxidative stress.

 

 

No fold reported.

Zebra fish brain

Hg2+, MeHg

1.8 molar (measured in brain tissue),

28 days

 

(Branco, 2012)

Inhibition of GPx activity.

 

 

 

GPx – 0.4-fold

Increased ROS formation and lipid peroxidation

 

 

ROS – 1.75-fold

Total peroxidase – 4.5-fold

Lipid perox. – 3-fold

Mouse brain

MeHg

40 mg/L in drinking

water

 

21-days

Incubation of mitochondrial-enriched fractions with exogenous GPx completely blocked MeHg-induced

mitochondrial lipid peroxidation.

(Franco, 2009)

Inhibition of GPx activity.

 

 

GPx – 0.7-fold

Increased ROS formation and lipid peroxidation.

 

Total H2O2 – 1.5-fold

Human neuro-blastoma SH-SY5Y cells.

MeHg

1 µM (nominal)

Inhibition of GPx substantially enhanced MeHg toxicity.

(Franco, 2009)

Decreased GPx1, activity in cerebral

cortex and hippocampus.

 

 

 

 

GPx1 – 0.5-fold

Induction of oxidative stress (oxidative damage product from the reaction of ROS and deoxy-thymidine in DNA)

 

No fold-change reported.

Male C57BL/6NJcl mice

MeHg

1.5 mg kg−1 day−1

 

6-weeks

 

(Fujimura, 2017)

Downregulation of antioxidant selenoprotein gene expression, and reduced GPx activity.

 

Gpx1a – 0.2-fold

Gpx4a – 0.2-fold

TxnRd1 – 0.5-fold

GPx – 0.2-fold

Indirect effects reported – larvae hypoactivity

Zebra fish

MeHg

0.05 mg/kg DM

 

20-days

0.7 mg/kg DM Se-supplementation partially restored GPx activity

 

 

 

 

GPx activity upregulated from 0.2-fold to 0.7-fold.

(Penglase, 2014)

Depletion of GSH levels.

 

 

 

 

 

 

 

 

 

 

 

GSH-activity:

10µM – 0.75-fold

30µM – 0.6-fold

100µM – 0,5-fold

Increased glutathione oxidation, hydroperoxide formation (xylenol orange assay) and lipid peroxidation

end-products (thiobarbituric acid reactive substances, TBARS).

 

Mitochondrial viability:

10µM – 0.75-fold

30µM – 0.6-fold

100µM – 0,5-fold

Total hydroperoxidases:

10µM – 1.0-fold

30µM – 1.2-fold

100µM – 1.75-fold

Mouse brain mito-chondrial-enriched

fractions

MeHg

10, 30, and 100 μM

 

30 minutes

The co-incubation with diphenyl diselenide (100 μM)

completely prevented the disruption of mitochondrial activity as well as the increase in TBARS levels. thiol peroxidase activity of organoselenium compounds accounts for their protective actions against methylmercury-induced oxidative stress

(Meinerz, 2011)

Depletion of mono- and disulfide

glutathione in neuronal, glial and mixed cultures

 

 

 

GSH activity – 0.83-fold

increased reactive oxygen species (ROS) formation measured by dichlorodihydro-fluorescein

(DCF) fluorescence

 

DCF – 1.2-1.5-fold

Mouse primary cortical cultures

MeHg

5 µM

 

24h

glutathione monoethyl ester (GSHME) (100 µM) supplementation protected against oxidative stress formation

(Rush, 2012)

Reduced glutathione (GSH) content decreased in liver, kidney and brain.

Increased lipid peroxidation and generation of

reactive oxygen species

Adult male albino Sprague-Dawley rat

Dimethylmercury (DMM)

10 mg/kg bw

 

3-days

Supplementation with Se (2 mmol/kg and 0.5 mg/kg partially protected against DMM-induced tissue damage.

(Deepmala, 2013)

Reduced glutathione (GSH) level and acetyl cholinesterase activity, as well as reduced antioxidant enzyme glutathione peroxidase (GPx)

Increased lipid peroxidation level and DNA damage.

Adult male Sprague-Dawley rats

MeHg

1 mg kg−1 orally

 

6 months

 

(Joshi, 2014)

Depleted GSH levels.

Antioxidant imbalance and lipid peroxidation.

Adult male Wistar rats

mercuricchloride

30ppm in drinking water

 

(Agrawal, 2015)

GSH levels decreased in astrocytes.

Severe damage

to the cell membranes, as well as to mitochondria.

Primary mouse neuron and astrocyte co-cultures

MeHg

10, 25, or 50 µM nominal

 

24h exposure

 

(Morken, 2005)

GPx1 significantly decreased prior to neurotoxic effects being visible.

 

GPx1 – 0.7-fold

Increased lipid

Peroxidation and later neuronal cell death.

 

Lipid peroxidation - 1.75-fold

Primary cultured mouse cerebellar granule cells

MeHg

300nM nominal

 

24h

Overexpression of GPx-1 prevented MeHg-induced

neuronal death

(Farina, 2009)

Reduction of GPx activity and increased glutathione reductase activity

 

 

 

 

GPx – 0.7-fold

Increased oxidative stress – shown by increased TBA-RS and 8-OHdG content, as well as reduction of complexes I, II, and IV activities

 

H2O2 – 1.6-fold

 

MeHg

3–5 µg/g brain tissue

 

21-days

 

 

Treatment with diphenyl diselenide (PhSe)2 (5 µmol/kg) reversed MeHg’s inhibitory effect on mitochondrial

activities, as well as the increased oxidative stress parameters.

(Glaser, 2013)

 

Oxidative stress (increased H2O2 production)

Rat astro-glioma C6 cell line

MeHg

10 and 50 µM

 

1h

Cell viability protective effect of 1 µM of the organic selenium compound (PhSe)2

(Glaser, 2013)

 

Protein oxidation (increase of protein carbonyls)

Mouse primary cortical neurons, and cerebellar granule cells

MeHg

10-600 nM

All effects were prevented by co-treatment with the antioxidant probucol.

(Caballero, 2017)

Reduced glutathione peroxidase activity was found in the fetal side of human placental samples.

 

Human placenta tissue samples – INMA Valencia

mother-infant cohort (Spain)

MeHg

20-40 µg/mL blood plasma

 

(Caballero, 2017)

https://aopwiki.org/system/dragonfly/production/2018/01/26/94pzx39utv_AOP17_KER1_Table2.pdf

 

Acrylamide (acrylamide is a common food contaminant generated by heat processing)

No literature supporting the link “SH/she binding leads to oxidative stress” for acrylamide as stressor in brain/neural tissue can be found.

 

Acrolein

No literature supporting the link “SH/she binding leads to oxidative stress” for acrolein as stressor in brain/neural tissue can be found.

Uncertainties and Inconsistencies

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Another important group of thiol-containing proteins are the metal-binging detoxifying metallothioneins. This protein family bind mercury and lead, and this binding thus serves as a protective mechanism and also protects against metal toxicity and oxidative stress (Aschner, 2006).

Lactational exposure to methylmercury (10 mg/L in drinking water) significantly increased cerebellar GSH level and GR activity. Possibly a compensatory response to mercury-induced oxidative stress (Franco et al., 2006)

Methylmercury cytotoxicity in PC12 cells is mediated by primary glutathione depletion independent of excess reactive oxygen species generation (Gatti et al., 2004).

Quantitative Understanding of the Linkage

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cf Table 2

Response-response Relationship

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Time-scale

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Known modulating factors

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Known Feedforward/Feedback loops influencing this KER

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Domain of Applicability

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Mechanistic support for the link between interference of SH/SeH groups of proteins and induction of oxidative stress can be found in Zebrafish, rodents (mouse and rat) and to some extent in man (see Table 2).

References

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