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Environmental Electrophiles: Protein Adducts, Modulation of Redox Signaling and Interaction with Persulfides/Polysulfides Yoshito Kumagai, and Yumi Abiko Chem. Res. Toxicol., Just Accepted Manuscript • DOI: 10.1021/acs.chemrestox.6b00326 • Publication Date (Web): 02 Dec 2016 Downloaded from http://pubs.acs.org on December 6, 2016

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Chemical Research in Toxicology

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Environmental Electrophiles: Protein Adducts, Modulation of Redox Signaling and Interaction with Persulfides/Polysulfides Yoshito Kumagai* and Yumi Abiko Environmental Biology Section, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan Keywords: Electrophile, persulfide, polysulfide, protein modification, redox signal *

Corresponding author. Yoshito Kumagai, Faculty of Medicine, University of Tsukuba,

1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan. Tel.: +81-29-853-3297; Fax: +81-29-853-3259; E-mail: [email protected] Footnote: We have used Cys or CysSH as the abbreviation for cysteine and CysSSH for cysteine persulfide.

ACS Paragon Plus Environment


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Table of contents Ambient air

O

O

O

ishes

O

O

CH3Hg O

Cooked foods NH 2

Indoor air O

O

+

E

-

+

S

H

Rice Cd

Cigarette smoke O

O

H

H

Plants O

Drugs

H 3C(H2C)n

E-S

H

Protein adducts

Modulation of redox signaling


E

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Abstract Included among the many environmental electrophiles aromatic hydrocarbon quinones formed during combustion of gasoline, crotonaldehyde in tobacco smoke, methylmercury accumulated in fish, cadmium contaminated in rice, and acrylamide in baked foods are common examples. These electrophiles can modify nucleophilic functions such as cysteine residues in proteins forming adducts and in the process activate cellular redox signal transduction pathways such as kinases and transcription factors. However, higher concentrations of electrophiles disrupt such signaling by nonselective covalent modification of cellular proteins. Persulfide/polysulfides produced by various enzymes appear to capture of environmental electrophiles because formation of their sulfur adducts without electrophilicity. We therefore speculate that persulfide/polysulfides are candidates for regulation of redox signal transduction pathways (e.g., cell survival, cell proliferation, and adaptive response) and toxicity during exposure to environmental electrophiles.



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Contents 1. Introduction 2. Interaction of Electrophiles with Nucleophiles 2.1. Low Molecular Weight Thiol Adducts 2.2. Protein Adducts 2.3. Reversibility of Electrophile–Protein Adducts 2.4. Determination of Electrophile–Protein Adducts 3. Dual Role of Electrophiles in Redox Signal Transductions 3.1. Activation of Redox Signaling 3.2. Disruption of Redox Signaling 4. Interaction of Environmental Electrophiles and Persulfides/Polysulfides 4.1. Formation of Sulfur Adducts 4.2. Modulation of Electrophiles-mediated Activation of Redox Signaling Pathways and Toxicity by Persulfides/Polysulfides 5. Future Directions


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1. Introduction We are surrounded by numerous chemicals in all environments, which is not surprising given that the Chemical Abstracts database holds the records for 115 million small molecules. Among them, electrophiles are commonly found. Environmental electrophilic chemicals readily react with a variety of biological nucleophiles such as GSH, cysteine, histidine, and lysine residues on proteins as well as nitrogen centers in the nucleic acids to from adducts. These electrophiles include quinones generated by photooxidation of aromatic hydrocarbons1-5, formaldehyde as an indoor air pollutant6,7 and the α,β-unsaturated aldehydes, crotonaldehyde and acrolein of cigarette smoke.8 The latter two compounds are also associated with exposure to smoke from wok cooking evidenced by the urinary excretion of their mercapturic acid derivatives.8,9,10 Additional sources of electrophiles from dietary sources include a series of (E)-2-alkenals with α,β-unsaturated aldehyde moieties from edible plants such as Coriander sativum L. and Eryngium foetidum L.11,12 and the organometallic electrophile methylmercury (MeHg), found in species such as tuna and marine mammals at the top of the aquatic food chain.13,14 Electrophilic salts of cadmium accumulate in the crop biomass which, in turn, is incorporated into food crops.15-17 (Figure 1) Exposure to such environmental electrophiles at lower levels can be tolerated because of detoxification systems; most electrophiles can be detoxified and then excreted into extracellular space by phase-II xenobiotic metabolizing enzymes and phase-III transporters. However, at higher levels that exceed the capacity of the detoxification system, electrophiles can disrupt redox signaling and cause cell damage. This review discusses the interaction of sulfides with environmental electrophiles that interact with redox signal transduction pathways and postulates a regulatory mechanism of electrophile-mediated signaling by sulfide species. 2. Interaction of Electrophiles with Nucleophiles Electrophiles have an electron-deficient moiety that will form covalent bonds with nucleophiles, which are electron-rich molecules. Targets of electrophiles include nucleophilic centers such as the C8 position of guanine in DNA, and thiol groups and/or amino groups on proteins.18-20 According to the hard and soft acid and base (HSAB) concept of Pearson,21 hard electrophiles (e.g., formaldehyde) prefer hard nucleophiles such as amino groups, whereas soft electrophiles (e.g., α,β-unsaturated carbonyl) prefer



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to react with soft nucleophiles (e.g., thiolate anions).18,22 Jones23 states that about 214,000 Cys residues are encoded in the human genome and 10–20% of the protein thiols can be oxidized or modified by electrophiles. This review focuses on the soft–soft reaction, or the electrophilic modification of thiol groups by α,β-unsaturated carbonyl/aldehydes and methylmercury. In studies of chemical carcinogenesis, Yamagiwa and Ichikawa24 demonstrated that coal tar contained aromatic hydrocarbons such as benzo[a]pyrene, which was metabolically converted to an electrophile that covalently binds to 2-amino group of guanine on nucleic acids and will be a carcinogen.25-28 Miller et al.29-31 also reported that electrophiles, which can covalently modify proteins, would be carcinogen. The electrophile, bis(2-chloroethyl)sulfide, causes necrosis through alkylation of nucleic acids and proteins.32 The toxicity of electrophiles are minimized by conjugation with GSH in the absence and presence of GSH S-transferases (GSTs)33,34 (phase-II reaction) and are excreted from cells by phase-III transporters that were regulated by a transcription factor, NF-E2-related factor 2 (Nrf2) (See Section 3.1 for the mechanism of the Nrf2 activation).35,36 We have found that Nrf2 deletion enhanced MeHg toxicity in vitro37 and in vivo,38 indicating that Nrf2 is a key molecule in the detoxification of MeHg. 2.1. Low Molecular Weight Thiol Adducts Under conditions such as oxidative stress and inflammation, endogenous compounds such as dopamine, estrogens, prostaglandins (PGs), polyunsaturated fatty acids, and cGMP are converted to dopamine quinone, catechol estrogens, dehydro PGs, nitrated fatty acids and 8-nitro-cGMP electrophiles which are conjugated with GSH.39-48 The same reaction with GSH has also been reported for exogenous electrophiles.19,34 For example, the bromobenzene−SG adduct was found in the bile of rats treated with bromobenzene49 and we previously identified (8S)-(glutathion-S-yl)-dihydromorphinone as a novel metabolite in the bile of guinea pigs given morphin,50 which was subsequently shown to be the product of a reaction of the electrophilic metabolite morphinone with GSH.50,51 Acetaminophen, which is a mild analgesic drug, is oxidized by cytochrome P450s (CYPs) to form N-acetyl-p-benzoquinoneimine (NAPQI) (phase-I reaction),52-54 which is further biotransformed to its GSH adduct.55 Ambient electrophiles such as benzoquinones (BQs), naphthoquinones (NQs), acrolein, and


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crotonaldehyde are able to react directly with GSH56-59 and their mercapturic acids, formed by removal of glutamyl and glycine moieties, followed by N-acetylation,60 are excreted in the urine.61-65 Mercapturic acids have been validated as biomarkers of environmental exposure for evaluation of health risk.10,66-68 High levels of electrophiles cause substantial GSH depletion, which is associated with oxidative stress.32,39,69 However, although GSH conjugates are generally thought to be low-toxicity metabolites, some electrophile−SG adducts still have significant reactivity.70 As examples, a menadione−SG adduct undergoes redox cycling to generate reactive oxygen species71 and the acetaminophen−SG adduct is readily oxidized to a free radical.72 2.2. Protein Adducts Protein adduct formation is associated with inhibition of enzyme activity and alteration of protein structure. For instance, endogenous electrophiles such as 8-nitro-cGMP, catechol

estrogens,

PGA2,

15-deoxy-Δ12,14-PGJ2

(15d-PGJ2),

9-

and

10-nitrooctadecenoic acid, and 4-hydroxynonenal (4-HNE) modify the thiol group of Kelch-like ECH-associated protein 1 (Keap1) protein, leading to activation of Nrf2 (see Section 3).73-77 Dihydroxyphenylalanine and dopamine inhibit tyrosine hydroxylase, presumably through covalent modification by quinoid products of autoxidation.78 It is well known that toxicity of xenobiotics such as bromobenzene, acrolein, and acetaminophen are associated with covalent attachment to cellular proteins.53,79-82 We have demonstrated that the quinones 1,2-NQ, 1,4-NQ, and tert-butyl-1,4-benzoquinone (TBQ) and airborne samples containing 1,2-NQ and 1,4-NQ1 can modify cellular proteins containing reactive thiols; such as the arylhydrocarbon receptor (AhR),83 Keap1,84,85 glyceraldehyde-3-phosphate dehydrogenase (GAPDH),86,87 protein tyrosine phosphatase 1B (PTP1B),88 peroxiredoxin 6,89 ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1),90 heat shock protein 90 (HSP90),91 cAMP response element-binding protein (CREB),92,93 IkappaB kinase β (IKKβ),94 and phosphatase and tensin homolog (PTEN)95. Similarly, electrophilic MeHg is also capable of covalently modifying Keap1,37 CREB,96 PTEN,96 sorbitol dehydrogenase,97 Mn-superoxide dismutase,98,99 arginase-I,100 and UCH-L1,101 resulting in changes in their function (Table 1). Although most of the proteins modified by 1,2-NQ involved cysteine residues, PTP1B, peroxiredoxin 6, and UCH-L1 were found to undergo N-arylation by 1,2-NQ through histidine or lysine groups.88-90 However, reflecting the high association constant of



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MeHg for thiols (1015−1016) we have found its cellular protein modification sites to be limited to cysteine.102 Table 1 summarizes covalent protein modifications linked to inhibition of enzyme activities, declining protein function, or altered protein structures (except for AhR).

2.3. Reversibility of Electrophile–Protein Adducts In terms of chemical bonding, the C−S bond is stable and thus covalent protein modifications mediated by environmental electrophiles are thought to be irreversible. For example, acrylamide is a soft, but weak, electrophile of the type-2 alkene chemical class that causes enzyme inhibition and toxicity by irreversibly forming Michael-type adducts with cysteine (e.g., Cys151 of GAPDH determined in vitro)103. Nevertheless, there are several reports on the instability of electrophile–protein interactions. For example, GSH conjugates of methyl isocyanate can easily be converted to other thiol conjugates104 and electrophilic modification of a GAPDH thiol by low concentrations of 9- and 10-nitrooctadecenoic acid is reversible in the presence of GSH.43 Rudolph and Freeman105 have suggested that the redox signaling (See Section 4) mediated by endogenous electrophiles such as 9- and 10-nitrooctadecenoic acid is regulated by GSH. Quinones react with protein thiolates through a 1,4-Michael addition reaction to form hydroquinone–S-protein adducts, which is no longer electrophilic19 (Figure 2). However, as Smithgall et al.106 reported that 1,2-dihydroxynaphthalene 4-glutathionyl ether of the reaction product of 1,2-NQ and GSH, is readily autooxidized under aerobic conditions. We postulated that these quinone–protein adducts could undergo a second Micheal reaction with GSH, followed by a retro-Michael reaction, resulting in the formation of a quinone−SG adduct and recovery of protein modified by 1,2-NQ (Figure 2). To test this hypothesis, we prepared adducts of 1,2-NQ with GAPDH, TBQ with Keap1 and 1,2-NQ with UCH-L1, and found that these protein adducts undergo a S-transarylation reaction with GSH, resulting in the removal of 1,2-NQ, TBQ, and UCH-L1 from the modified proteins and restoration of diminished protein activity87,90,107 (Figures 2). These findings suggest that some environmental quinones may trigger redox signal transduction pathways through reversal of the reaction between electrophiles and protein thiols. Consistent with this notion, TBQ was shown to cause a transient activation of Nrf2 due to S-arylation of its negative regulator, Keap1.107 In case


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of UCH-L1, however, we found that although 1,2-NQ is covalently bound to this protein through Cys152 and Lys4, the covalent modification of Lys4 was unaffected by GSH-dependent

S-transarylation.90

Furthermore,

1,2-NQ

modification

of

peptidyl-prolyl cis-trans isomerase A through amino groups did not show reversibility by addition of thiol compounds such as GSH, cysteine, N-acetylcysteine, dithiothreitol, and 2-mercaptoethanol (Abiko Y., unpublished observation). In general, it appears that C−N based adducts are more stable than those with C−S bonds, consistent with the binding energies of the C−N and C−S bonds (bond strengths in diatomic molecules are 748.0 D°298kJ/mol and 714.1 D°298kJ/mol, respectively108). The S−N bond formed through S-nitrosylation to thiol groups is readily removed by GSH.109,110 S-Mercuration of cellular proteins during exposure to MeHg is a major factor in its toxicity.111 Some of the MeHg, however, is conjugated with GSH by glutamate cysteine ligase (GCL) in the absence and presence of GSTs to yield its GSH adduct. The adduct is then excreted into extracellular space through multidrug resistance associated proteins (MRPs)111,112 (Figure 3). Since GCL, GST, and MRPs are cooperatively regulated by transcription factor Nrf235,36,113-116, we hypothesized that Nrf2 would play a crucial role in decreased MeHg toxicity, which was confirmed in vitro and in vivo.37,38 The formation of metal–protein adducts is thought to be reversible in the presence of excess thiols because unlike the C−S bond, the Hg−S bond is unstable in the presence of nucleophiles.117,118 Thus, a combination of isoelectric focusing-agarose gel electrophoresis and synchrotron radiation X-ray fluorescence analysis revealed that GSH is able to release MeHg from Mn–superoxide dismutase modified by MeHg.98 We also considered the MeHg−SG adduct to be a labile species, capable of reaction with protein thiols (Figure 3). We thought that if MeHg−SG adduct is not rapidly excreted into intracellular space, it could cause cytotoxicity. As expected, S-mercuration of cellular proteins was enhanced upon MRP blockage following exposure of SH-SY5Y cells to the synthetic ethyl monoester of MeHg−SG adduct, resulting in increased toxicity while MeHg−SG adduct activated Nrf2 presumably through modification of cellular Keap1 in the cells.119 On the basis of observations of redox signaling based toxicity associated with the exchange reactions between: (1) GSH and proteins modified by the metals, and (2) heavy metal−SG adducts and protein thiols (Figure 3), we speculate that electrophilic metals such as cadmium and lead may act similarly.



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2.4. Determination of Electrophile–Protein Adducts Detection of electrophilic protein modification is key to identifying target proteins linked to adaptive changing of protein functions. In the 1970s and early 1980s, radiolabeled compounds were used extensively to allow tracing of radioactive molecules by liquid scintillation counting.120 In 1985, Satoh et al. determined trifluoroacetylated hepatocyte and trifluoroacetylated CYP from halothane-treated rats using anti-trifluoroacetylated rabbit serum albumin antibody, which recognized trifluoroacetylated-lysine adducts of proteins.121,122 Indirect methods to detect electrophilic modification were also developed instead of antibodies. Thus, Uchida and co-workers detected thioredoxin (Trx), actin, and Keap1 as target proteins of 15d-PGJ2 using biotinylated 15d-PGJ2.123-125 We developed the biotin-PEAC5-labeling (BPM) assay to detect chemical modification of protein by electrophilic environmental metals126 and organic compounds127. Using BPM labeling ELISA, the existence of electrophiles in environmental samples can be detected easily without specific antibodies against electrophiles.127 Then, LC-MS/MS can reveal the modification sites and/or proteomic profiling of modified proteins. Liebler, Marnett, and co-workers captured heat shock protein 90 with a geldanamycin–polyethylene glycol–biotin probe and analyzed its modification site by 4-HNE using LC-MS/MS.128,129 Biotinylated electrophile probes allow broad analysis of modified proteins.130,131 Measurement of covalent adducts of proteins is useful in evaluating environmental chemical exposure through electrophilic metabolites. Rappaport and his collaborators have profiled electrophile-protein adducts such as electrophile-Cys34 adducts of human serum albumin using fixed-step selected reaction monitoring employed LC-MS/MS132,133 to characterize exposures to environmental electrophiles or their parent compounds. They call this the exposome. 3. Dual Role of Electrophiles in Redox Signal Transductions Although excess reactive oxygen species (ROS) derived from environmental exposure causes DNA damage and oxidation of proteins, ROS such as hydrogen peroxide produced physiologically can activate redox signal transduction pathways involved in adaptive responses, cell survival, cell proliferation, and quality control of damaged proteins [e.g., HSP90/heat shock factor 1(HSF1),134,135 Keap1/Nrf2,36 PTEN/Akt,136,137 and PTP1B/epidermal growth factor receptor (EGFR)138,139 signaling] and subsequent


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apoptotic signaling [e.g., Trx/apoptosis signal-regulating kinase 1 (ASK1)140 signaling] associated with cell death.19,141 Interestingly, these signals operate through effector molecules such as kinases and transcription factors and sensor proteins that negatively regulate the effector molecules. HSP90, Keap1, PTEN, PTP1B, and Trx act as sensor proteins and negative regulators for HSF1, Nrf2, Akt, EGFR, and ASK1, respectively. These sensor proteins have low pKa thiols that convert into thiolate ions (S–) at physiological pH and thus undergo oxidative and covalent modification by ROS and electrophiles. Although the pKa of cysteine is 8–9,142,143 the pKa values of active or sensitive sites of sensor proteins such as PTP signature motif HCXXGXXRS(T) in PTP superfamily,144 Cys215 on PTP1B,145 Cys151 on Keap1 (Miura T. et al, unpublished observation determined by PROPKA146), and Cys32 on Trx147 are 4.5–5.5, 5.4, 7.2, and 6.7, respectively. Thiolate ions on protein (P–S−) are oxidized to the sulfenic acid (P–SOH), then to the sulfinic acid (P–SO2H), and ultimately to sulfonic acid (P–SO3H) states. P–SOH is reduced by GSH or GSH-dependent reductase and P–SO2H

(e.g., peroxiredoxin) can be reduced by

enzymes such as sulfiredoxin.148-151 In contrast, there are no enzymes that reduce P– SO3H back to P-SH,19 suggesting that such this oxidation state is associated with pathophysiological and toxicological changes in the affected protein. For instance, Trx has an XCXXC motif, and undergoes reversible oxidation to form the sulfenic acid at Cys32, followed by a disulfide formation with the vicinal thiols.152,153 This indicates that reversibility of redox sensor proteins with reactive thiols including Trx would promote transient activation of cellular redox signaling. In contrast, it can be hypothesized that irreversible modification of the sensor thiols (i.e., P–SO3H or P–S– electrophile adducts) trigger permanent activation of effector molecules, resulting in cell damage and toxicity. Overall, the current consensus is that, whereas ROS can activate redox signaling via reversible oxidation of reactive thiolates on sensor proteins, they can cause cell injury and apoptotic cell death by irreversible modification of thiols, oxidation of amino groups to carbonyls and DNA damage. Based on these considerations, we suggest that environmental electrophiles may affect redox based signal transduction pathways by covalent modification of sensor protein nucleophiles. 3.1 Activation of Redox Signaling There are at least three ways to regulate redox signaling pathways: (1) redox changes of



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sensor proteins that negatively regulate effector molecules (de-repression); (2) redox change of effector molecules themselves, and (3), by changes in the redox status of small molecules such as GSH.142 This perspective article focuses on possibility 1. Receptor tyrosine kinases regulate many signaling cascades. For example, EGFR signal transduction is regulated by PTPs, which have reactive Cys thiols in their active sites (see Section 2.3).154,155 Among them, PTP1B is a negative repressor for EGFR,138,156 because knockout of PTP1B significantly enhances EGF-dependent EGFR activation.157 Lee et al.139 found that oxidative modification of the active site thiolate of PTP1B Cys215, by H2O2, causes substantially increased EGFR phosphorylation. We have found that 1,2-NQ, an electrophile found in ambient air samples collected in Riverside, California,1 causes concentration-dependent contractions of guinea pig tracheal rings with an EC50 value of 18.7 µM.158 This action was linked to activation of phospholipase A2/lipoxygenase/transient receptor potential cation channel subfamily V member 1.158 The relevant finding was that the 1,2-NQ-mediated constriction required EGFR activation and covalent modification of unidentified proteins, presumably in the epithelial cells.158 These observations led us to consider that EGFR activation caused by 1,2-NQ exposure may be due to covalent binding of 1,2-NQ to PTPs through thiol groups and in a study of human epithelial A431cells to 1,2-NQ was found to inhibit cellular PTP and activate the EGFR (Table 2).88,158 Overexpression of a variety of PTP isoforms such as LAR, PTP1B, PTP20, TC-PTP, PTPα, PTPε, SHP-1 and SHP-2 in the cells revealed that PTP1B is an abundant isozyme of the PTPs that represses EGFR autoxidation (Iwamoto N. et al., unpublished observation). An immunoprecipitation study with anti-PTP1B and Western blot analysis with specific antibody against 1,2-NQ indicated that 1,2-NQ clearly modifies cellular PTP1B in A431 cells.88 Recombinant human PTP1B studies showed that PTP1B undergoes S-arylation via Cys121 by 1,2-NQ, resulting in reduction of its catalytic activity,88 suggesting that EGFR activation caused by 1,2-NQ in A431 cells is attributable to its covalent attachment PTP1B. Mutation of the cysteine to serine did not affect dephosphorylation activity, suggesting that Cys121 is not a catalytic amino acid, whereas the S-arylation of Cys121 led to a substantial decline of PTP1B activity.88 Taken together, we suggest that the modification of the cysteine residue by 1,2-NQ may alter PTP1B structure with consequent activation of EGFR. To our knowledge, this is first report to show atmospheric electrophile-mediated PTP1B/EGFR signaling associated with cell proliferation. In our preliminary study, we


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also found that the electrophiles N-ethylmaleimide, 1,4-NQ, 15d-PGJ2, and monomethylarsenite (a metabolite of arsenite) also inhibited recombinant PTP1B activity in a concentration-dependent manner. In contrast, there was little appreciable inhibitory effect of these compounds on the enzyme activity of the serine mutant of PTP1B Cys121. It was also shown that N-ethylmaleimide, 1,4-NQ, 15d-PGJ2, and monomethylarsenite repressed cellular PTP activity and activated EGFR in A431 cells (Iwamoto N. et al., unpublished observation). These observations suggest that activation of PTP1B/EGFR signaling by electrophiles may be a common event. The Keap1/Nrf2 pathway regulates the gene expression of antioxidant proteins, phase-II xenobiotic metabolizing enzymes, and phase-III transporters.35,36 Under basal conditions, Nrf2 undergoes rapid degradation by the ubiquitin–proteasome system, resulting in minimal Nrf2 levels in a variety of cells because this transcription factor is negatively regulated by Keap1, which interacts with Cul3.159,160 When oxidants and/or electrophiles invade the cells, the reactive thiols of Keap1 undergo oxidative and/or covalent modifications by these substances, and block its attachment to Nrf2.75,159,161 As a result, released Nrf2 translocates to the nucleus and together with small Maf, forms a hetero-dimer complex that binds to the antioxidant/electrophile responsive element (ARE/EpRE), upregulating its downstream genes [e.g., hemeoxygenase-1, GCL, GSTs, UDP-glucuronosyltransferases (UGTs), MRPs etc.]36,160,162 (Table 2). In this manner one of the Keap1/Nrf2 pathway functions as an adaptive response against oxidative and electrophilic stresses. Environmental electrophiles such as 1,2-NQ,84 1,4-NQ,163 TBQ,85 (E)-2-alkenals,164 Cd,165 and MeHg37 are able to modify Keap1 protein through reactive thiols (thiolate ions), thereby activating Nrf2 (Table 2). We also found that knockout of Nrf2 enhances cellular toxicities during exposure to environmental electrophiles, supporting the notion of Nrf2 as a cytoprotective regulator of environmental electrophiles as shown in Figure 1.37,84 HSP90 is also a molecular target of ROS and electrophiles.129,166,167 Under basal conditions, HSP90 is complexed with HSF1; oxidative or electrophilic stress stimulates the dissociation of HSF1 from HSP90, which translocates into the nucleus and upregulates HSPs by binding to the heat shock elements.168,169 4-HNE and 6-methylsulfinylhexyl isothiocyanate activate the HSPs/HSF1 signaling pathway by disruption of the HSPs-HSF1 complex by modification of HSP90.129,170 Our current studies indicate that environmental electrophiles such as 1,4-NQ and cadmium are able



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to modify HSP90 at Cys412 and Cys564 and facilitate nuclear translocation of HSF1 to A431 cells and bovine aortic endothelial cells through transactivation of heat shock element (HSE), leading to regulation of HSPs (Table 2) (Abiko Y et al., submitted).91 Knockdown of HSF1 significantly increased 1,4-NQ and Cd-dependent cytotoxicities in A431 and bovine aortic endothelial cells, respectively (Abiko Y et al., submitted and Shinkai et al., submitted), suggesting that such a HSF1 activation caused by environmental electrophiles plays a role in the diminishment of cytotoxicity during exposure of them. Proteins whose functions have been altered by environmental electrophiles are shown in Table 1. While the endogenous electrophile 15d-PGJ2 suppressed IKKβ/nuclear factor κB (NF-κB) signaling based inflammatory signaling by inactivation of IKKβ,171 1,2-NQ was also capable of covalently modifying IKK and suppressing lipopolysaccharide-mediated activation of IKKβ/NF-κB signaling.94 As an exception to the notion of electrophile action in protein regulation, we found that activation of the transcription factor AhR stimulates the AhR/XRE signaling pathway without S-arylation of its negative regulator HSP90.83 It is well recognized that activation of AhR requires a ligand (small molecule)–receptor (AhR) interaction.172 Previous studies have indicated that naphthalene, a bicyclic aromatic hydrocarbon, neither activates AhR nor induces CYP1A1, which is a downstream protein of AhR173 but electrophilic metabolites of monocyclic and bicyclic quinones, 1,4-BQ, TBQ, 1,2-NQ, and 1,4-NQ, are able to facilitate translocation of AhR to the nucleus, and upregulate CYP1A1 in A549 cells, Hepa1c1c7 cells, HepG2 cells, and mouse primary hepatocytes through transactivation of XRE.83,174 We also showed that 1,2-NQ upregulates CYP1A1 in vivo.83 Given that the pKa of a Cys thiol is decreased when it is proximal to basic amino acids such as lysine, histidine, or arginine,23 it is possible that a variety of quinones can covalently bind to AhR through the Cys residues, leading to induction of CYP1A1 because little appreciable modification of HSP90 was detected under the conditions. As mentioned above, our group has demonstrated that the activation of effector molecules is coupled to the covalent attachment of environmental electrophiles to sensor proteins.19,37,84,85,88,96,164,175 AhR activation by 1,2-NQ is the first example of activation of a redox signal transduction through direct arylation of the transcription factor by environmental quinones.


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15

3.2. Disruption of Redox Signaling Akt is negatively regulated by phosphatase and PTEN,176 which would be a sensor protein as described above. Activation of Akt leads to increased phosphorylation of transcription factor CREB, and upregulates one of its downstream genes for an anti-apoptotic protein, B-cell lymphoma 2 (Bcl-2).177-179 We postulated that environmental electrophiles could modify the reactive thiols of PTEN, thereby increasing Akt phosphorylation as an effector molecule, which activates CREB. To test this hypothesis, we used MeHg as an environmental electrophile. This was a challenging project for us because many toxicologists believed that MeHg is a highly toxic metal species that causes cell apoptosis.180-183 The compound was identified as the causative agent of “Minamata disease”, based deaths in Minamata City on the Japanese island of Kyushu. Exposure of SH-SY5Y cells to MeHg at nontoxic concentrations resulted in S-mercuration of PTEN and a decrease in its enzyme activity. Under these conditions, Akt and CREB were activated,96 leading to upregulation of Bcl-2, consistent with a previous observation.184 Experiments with inhibitors of phosphatidylinositol 3-kinase (PI3K)/Akt indicated that Akt activation caused by MeHg was associated with blockage of MeHg-mediated cytotoxicity96 (Table 2). However, increasing MeHg concentration caused S-mercuration of not only PTEN but also CREB through Cys286, thereby inhibiting interaction of CREB with CRE on DNA in the cells, thus downregulating Bcl-2 expression involved in substantial apoptotic cell death96 (Table 2). Disruption of CREB binding on CRE through covalent modification of CREB was also detected with 1,2-NQ in our previous study.92,93 Based on these findings, we suggest that SH-SY5Y cells respond, at least in part, to MeHg at lower concentrations by activation of PTEN/Akt/CREB/Bcl-2 signaling, whereas excess covalent modification of cellular proteins including CREB by high levels of MeHg seems to trigger disruption of this redox signaling that is associated with cell survival. Although

several

researchers

have

reported

on

environmental

electrophile-mediated induction of cellular signaling related to apoptotic cell death,185,186 detailed mechanisms of the process remain unclear. Ichijo and co-workers found Trx/ASK1 to be a redox based apoptosis signal.140,187 Thus, while the reduced form of Trx at Cys32 and Cys35 maintains ASK1 in the inactive state by binding to the N-terminal of ASK1,140 oxidative modification of Trx thiols facilitates its dissociation;



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activated ASK1 promotes apoptosis signalling.140 Endogenous electrophiles 15d-PGJ2 and 4-HNE are reported to modify Trx through the reactive thiols,123,188 whereas we found that 1,2-NQ binds to Lys85 without S-arylation of Cys32 and/or Cys35 on Trx.189 Interestingly, 1,2-NQ bound to Trx at Lys85 was able to cause redox cycling with Trx Cys32 and/or Cys35 to generate ROS, leading to oxidation of Trx, poly(ADP-ribose) polymerase cleavage, and cell death.189 Thus, environmental electrophiles can induce cell death signaling, at least in part, through disruption of anti-apoptotic Akt/CREB/Bcl-2 signaling and activation of apoptosis Trx/ASK1 signaling. Based on the observations above, we speculate that 1,2-NQ, 1,4-NQ, crotonaldehyde, MeHg, cadmium, and other environmental electrophiles (e.g., acrylamide, benzoquinone, lead etc.) activate a variety of redox signal transduction pathways at low concentrations. However, at higher concentrations electrophiles cause nonselective protein modification, disrupting these signals. As a result, there appears to be repression of their downstream gene expressions, leading to unexpected apoptosis, necrosis, and mortality during excess and/or chronic exposure to the compounds. 4. Interaction of Environmental Electrophiles and Persulfides/Polysulfides GSH is a cysteine containing tripeptide and is present in various tissues at concentrations of more than 1 mM and large numbers of GSH adducts with electrophiles have been identified following exposure to the electrophiles themselves or to xenobiotics capable of forming electrophilic metabolites.34,54 However, it should be pointed out that the thiolate ion of the thiol is the nucleophile that forms covalent bonds with electrophiles.190 The pKa values of GSH, Cys, and hydrogen sulfide (H2S) are 9.12191, 8.6143, and 6.83192, respectively, indicating that GSH and cysteine largely exist as the relatively unreactive thiols at physiological pH. However, the reactions of electrophiles with GSH are greatly facilitated by GSTs which lower its apparent pKa. Abe and Kimura193 reported for the first time that H2S modulates synaptic activities regulated by steroid hormones and neurotransmitters. Subsequently, numerous reports have described the beneficial effects of H2S on cardiovascular and neuronal diseases.194-196 However, approximately 80% of H2S, with a pKa1 value of 6.83 exists as its deprotonated form (HS–) under physiological conditions,192 indicating the likely reaction product of endogenous and exogenous electrophiles with HS– are sulfur


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17

adducts. HS– also will react with oxidized thiols to form persulfides, which have lower pKa values because of the adjacent sulfur atom (so-called α-effect197,198). H2S can also generate per/polysulfide species.197,199 The thiol of cysteine persulfide (CysSSH) has been calculated to be 4.34 by Cuevasanta et al.200, suggesting that this compound should be a highly reactive thiol based nucleophile compared to cysteine, GSH and even H2S. Although there are other reasons for greater nucleophilicity particularly protein thiols.18,201 Among the enzymes involved in reactive sulfur species (RSS), cystathionine β-synthase

(CBS),

cystathionine

γ-lyase

(CSE),

and

3-mercaptopyruvate

sulfurtransferase (3MST) are well known as enzymes responsible for formation of H2S.202-204 In a collaborative study with the Akaike group we were surprised to find that CBS and CSE also catalyze CysSSH formation with cystine (CysSSCys) as a substrate and that tissue concentrations of CysSSH were approximately 2 µM (brain), 4 µM (heart) and 1 µM (liver) of mice.205 More importantly, we noted that a sulfur of CysSSH is a sulfane-like197,206 “mobilized sulfur atom”, capable of reaction with GSH to yield GSH persulfide (GSSH) which, in turn, reacts with oxidized GSH (GSSG) to form GSH polysulfide (GSSSG) as shown in Figure 4. In terms of physiological relevance, GSSSG is a substrate for GSH reductase, which regenerates GSSH from its oxidized form (Figure 4). The study showed that GSSH concentrations were approximately 150 µM (brain) and 50 µM (liver and heart) of mice205. We also found that there are many proteins that undergo S-polythiolation in A549 cells as assessed by a Tag-switch-Tag assay205. The presence of abundant S-polythiolated proteins in mouse liver was also confirmed by a bismethylmercury sulfide [(MeHg)2S] assay207 (see Section 4.1). Taken together these results suggest that endogenous persulfide/polysulfide species produced in vivo in the body also interact with electrophiles. A molecular orbital calculations by Steudel indicated that the gas-phase acidities of hydrogen polysulfides increase with increasing numbers of sulfur atoms in the persulfide.208 In support of this calculation, an experimental study showed that pKa values of hydrogen persulfide (H2S2) and its polysulfides were: pKa1, 5.0; pKa2, 9.7 (H2S2); pKa1, 4.2; pKa2, 7.5 (H2S3); pKa1, 3.8; pKa2, 6.3 (H2S4).192,208 These results suggest that HSS− is the dominant form rather than S22–, whereas both HSSS– (HSSSS–)



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18

and S32– (S42–) would exist under physiological conditions. We speculated that endogenous CysSSH/GSSH and their hydropolysulfides (CysSSSnH/GSSSnH) would show similar chemical properties and that these hydropersulfide/polysulfides could form of sulfur adducts with environmental electrophiles and inactivate them.

4.1. Formation of Sulfur Adducts Our collaborative studies with the Nishida and Akaike groups revealed that there are at least three fates for electrophiles after reaction with sodium hydrosulfide (NaHS).209 Group I electrophiles (endogenous 8-NO2-cGMP and 15d-PGJ2) undergo sulfhydration, followed by desulfhydration (8-NO2-cGMP), and further oxidation to yield sulfinic acid (15d-PGJ2). Group II electrophiles (endogenous nitrated fatty acids and exogenous 1,2-NQ, 1,4-NQ, TBQ, etc.) form electrophile−S−electrophile adducts by sulfhydration and group III electrophiles (endogenous 4-HNE and acrolein) are degraded to unknown compounds.175,209 Of note, although 8-NO2-cGMP was a fairly inert electrophile in terms of reactivity with HS- in a cell-free system, addition of metal and CysSH to the reaction mixture facilitated cGMP–SH adduct formation, strongly suggesting that the reaction actually involves CysSSH, a superior nucleophile compared to H2S, which is produced by oxidation of CysSH to CysSSCys, We previously reported that overexpression of CBS in SH-SY5Y cells blocked MeHg cytotoxicity, whereas knockdown of this enzyme enhanced MeHg-mediated toxicity.210 These results suggest that RSS produced by CBS trap MeHg, by forming its sulfur adduct. To test this notion, we synthesized (MeHg)2S and found unknown metabolites from SH-SY5Y cells exposed to MeHg were identical to authentic (MeHg)2S generated from rat liver homogenate and from MeHg using a HPLC–atomic absorption spectroscopy.210 Analysis by electron-impact ionization mass spectrometry confirmed that the isolated metabolite was (MeHg)2S. Furthermore, an in vivo study showed that (MeHg)2S is a detoxificated metabolite of MeHg. As we described earlier (see Sections 2.3 and 3.1), the transcription factor, Nrf2, plays a critical role in the detoxification and excretion of MeHg because it regulates GCL, GST, and MRP which are associated with formation of MeHg–SG adduct and rapid elimination of this polar metabolite into extracellular space (Figure 3). The reaction of MeHg with RSS to form


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19

(MeHg)2S is an alternative inactivation process as studies with SH-SY5Y cells showed an increased toxicity of MeHg upon blocking the MRP because the cellular protein modification due to S-transmercuration of the GSH adduct increased cytotoxicity119 (Figure 3). Although we synthesized authentic (MeHg)2S by reaction of MeHg with NaHS,210 subsequent reports indicated that MeHg reacts with GSSH, GSSSG, and even protein-bound persulfides/polysulfides (e.g., GSTP1) to yield (MeHg)2S in all cases. This suggests that (MeHg)2S produced in vitro and in vivo207 results from capture of MeHg by small molecule and protein-bound persulfides/polysulfides. We also found that MeHg is capable of interacting with sodium tetrasulfide (Na2S4)207 to form (MeHg)2S, indicating that MeHg is able to capture a sulfur atom of Na2S4. The reactivity of MeHg toward RSS led us to consider that (MeHg)2S formation could be used to identify protein-bound RSS. Our rationale was that when MeHg is mixed with fractions obtained during separation of proteins by column chromatography, the fraction can be considered to contain protein-bound RSS if (MeHg)2S is detected. Isolation of mouse hepatic proteins bound to RSS by column chromatography on Cibacron Blue 3GA indicated that many proteins undergo S-polythiolation. Of particular note, approximately 50% of the protein-bound RSS was eluted by 10 mM NADH despite about 1% of the total protein being applied in this fraction, suggesting a connection between pyridine-binding proteins and protein-bound RSS. Subsequent column chromatography of the partially isolated protein preparation with Sephacryl S-100 resin showed a highly purified protein with a subunit molecule of 25 kDa on SDS-PAGE which was identified as GSTP1. With this recombinant protein we confirmed that GSTP1 did indeed contain RSS as evaluated by (MeHg)2S formation. Our recent product analyses for the chemical reaction of 1,4-NQ with Na2S4 and enzymatic reaction of 1,4-NQ by recombinant CSE with pyridoxal phosphate indicated that 1,4-NQ–SH, (1,4-NQ)2S, and 1,4-NQ–SCys adducts were formed (Abiko Y. et al., submitted). We have also found that incubation of acrylamide with Na2S4 formed C6O2N2H13S, presumably as the acrylamide–S–acrylamide adduct (Abiko Y. et al, unpublished observation). The liver injury by covalent binding to hepatic proteins by NAPQI, an electrophilic CYP based metabolite of is well established as its detoxification by



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20

conjugation NAPQI with GSH.55,211 However, we have reported that pretreatment with NaHS significantly blocked acetaminophen-mediated hepatotoxicity in CSE KO mice,212 suggesting: direct reaction of HS− with NAPQI to form sulfur metabolites; or increased levels of persulfides/polysulfides in the liver tissues. Consistent with this, we recently identified NAPQIH2–SSSCys and NAPQIH2–SSG adducts as novel metabolites of acetaminophen from the urine of C57BL/6J mice treated with this drug in vivo.213 A cell-free study suggested that formation of these sulfur metabolites due to reaction with GSSH and enzymatic production of mediated by a RSS-producing enzyme such as CSE. In a cell free study, these metabolites were found to be the product of an enzymatic reaction with CysSSCys, producing CySSH and its related polysulfide(s) by a RSS-producing enzyme such as CSE. Thus these studies from our laboratory indicate that environmental and medicinal xenobiotics can be metabolized to electrophilic metabolites that are captured by RSS in the body to form sulfur adducts as part of the detoxification process.

4.2. Modulation of Electrophile-Mediated Activation of Redox Signaling Pathways and Toxicity by Persulfides/Polysulfides In other studies we showed that the 8-nitro-cGMP activated H-Ras that is mediated by S-guanylation of H-Ras Cys184 was suppressed by pretreatment with NaHS,175 suggesting that persulfides/polysulfides produced by CBS/CSE could regulate redox signal transduction pathways during exposure to electrophiles. As expected, we recently found that knockdown of CBS/CSE enhanced covalent modification of cellular proteins and activation of HSP90/HSF1 signaling during exposure of A431 cells to 1,4-NQ (see Section 3.1). In contrast, treatment with Na2S4 repressed these effects (Abiko Y. et al., submitted), with the formation of sulfur adducts of proteins thereby activating the redox signal transduction pathway mediated by 1,4-NQ (Abiko Y. et al., submitted). Furthermore, it is evident that 1,4-NQ can activate PTEN/Akt/CREB, which is negatively regulated by RSS.95 Overall, we propose a concept of environmental electrophile-mediated activation (low concentration) and disruption (high concentration) of redox signaling by sensor proteins with low pKa thiols and effector molecules that could be repressed by: (1)


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21

endogenous persulfides/polysulfides

produced by enzymes such as CBS, CSE, and

3MST; or (2) exogenous polysulfide(s) as shown in Figure 5 (left panel). Thus, we suggest that because of their electrophile capturing abilities, persulfides (and polysulfides) are crucial molecules that elevate a threshold of redox signaling and toxicity during exposure to environmental electrophiles and their precursors (Figure 5, right panel). Conversely, a reduction of small-molecule and protein RSS levels would be cause susceptibility to environmental electrophiles.

5. Future Directions The presence of sulfur in compounds provides at least two types of valence states, that include sulfide sulfur such as R-S-R (8 electrons, S2–) and sulfane sulfur (6 electrons S0), with nuances that are not clearly understood214. Although the sulfane sulfur has is both a nucleophile and an electrophile215, the sulfur atom(s) in polysulfides/persulfides also have electrophilic and nucleophilic character and are participate in S-transsulfuration reactions.197,206,216 As a result, some proteins may have longsulfur side chains. Dóka et al.217

suggest

that

thioredoxin

reductase1

(TrxR1)

may

regulate

protein

persulfides/polysulfides in cells (Figure 6). Knockdown of TrxR1 or thioredoxin-related protein-14 (TRP14) induced persulfide protein levels and enhanced the cytotoxicity of polysulfide in HEK293 cells. Since Trx/TrxR1 catalyzes the reduction of protein disulfide bonds to thiols,217 it is likely that it plays a role in the reduction of protein persulfides and polysulfides associated with redox balance (Figure 6). Similar phenomena, which is reported by Dóka et al.217, has been observed by others.218 The mobilized sulfur atom(s) may be utilized for formation of small-molecule persulfides/polysulfides. If so, this will be a novel redox homeostasis strategy. Stable isotope based LC–MS/MS analyses for bimane-RSS adducts and bis-S-bimane adduct revealed that recombinant CBS/CSE mainly produced CysSSH and its polysulfides (CysSSSH and CysSSSSH) formed from CysSSCys with negligible amounts of H2S-like species.205 However, H2S and HSSH were formed in a variety of mouse tissues.219 A reasonable explanation for this discrepancy between purified enzyme preparation and tissues is that observed H2S-like species in vivo may be reduction products of protein-bound persulfides/polysulfides mediated by Trx/TrxR1 and unidentified enzymes, but require further studies are needed.



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As shown in Figure 6, MeHg is an environmental electrophile that is able to capture mobilized sulfur atoms, resulting in S-mercuration of protein CysSH residues, inhibition of enzyme activity, and alteration of protein structure.96,97,100,101,220 If the biochemical function of protein S-polythiolation is protection of protein CysSH residues, as recently proposed by Fukuto and colleagues,216 and supplementation of mobilized sulfur of protein-bound persulfides/polysulfides, environmental MeHg may act as a sink for mobilized sulfur atoms, thereby disrupting redox homeostasis. Thus, we should address other environmental electrophile-mediated toxicities based on the interaction with small and high molecular RSS. Our major concern is resolving the biochemical fate of (MeHg)2S produced from MeHg. In 1978, Craig and Bartlett221 suggested that (MeHg)2S generated in the environment undergoes slow degradation to form mercury sulfide and dimethylmercury, but to our knowledge, there are no reports that demonstrate this possibility in a biological system. As mentioned above in both cell free and intact mice, we found that (MeHg)2S is formed during the interaction of MeHg with H2S, GSSH, and GSSSG generated from CysSSCys, which is a substrate for CBS/CSE.205,207 Therefore, it is likely that the decomposition of (MeHg)2S takes place in the body. To address this possibility, we are analyzing tissue homogenates from mice treated with authentic (MeHg)2S. It is well established that after xenobiotics absorbed and distributed in the body, they are extensively bio-transformed by CYP to form, for example, hydroxylated metabolites in cells (phase I reaction). Most of the hydroxylated metabolites are detoxification products of the parent substances. However, some drugs and environmental chemicals undergo metabolic activation to electrophilic species by CYPs and other enzymes that cause tissue injury through covalent modification.4,106,222,223 These hydroxylated and electrophilic metabolites undergo UGTs and GSTs mediated conjugation reactions to glucuronides and GSH adducts (phase II reaction).224-226 Finally, these polar metabolites are recognized by ATP-dependent MRPs and are excreted (phase III reaction).227,228 A

point

to

emphasize

here

is

that

CysSH

and

GSH

and

their

persulfides/polysulfides are constitutively excreted into extracellular space from cultured cells such as A431 cells and primary mouse hepatocytes. These RSS can indeed interact with Na2S4 exogenously added to these cultured cells, leading to a


Page 23 of 60

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23

marked increase in RSS levels (Shinkai Y. and Unoki T. et al. unpublished observation). This suggests that Na2S4 can increase endogenous persulfide/polysulfide levels, in addition to its ability to capture MeHg directly to form (MeHg)2S.207 As shown in Figure 7, some environmental electrophiles would be effectively trapped by endogenous RSS prior to invasion of cells. We also speculate that some proteins may act as reservoirs of per/polysulfide species to fight electrophiles. We propose to describe this process as the “phase-zero reaction” for inactivation of environmental electrophiles. To promote

this

phase-zero

reaction,

we

suggest

that

the

addition

of

persulfides/polysulfides in foods or supplements is an effective preventive medicine strategy to trap environmental electrophiles. While it has been reported that garlic contains a substrate for CSE,229 our preliminary examination has indicated that there are many other RSS components when evaluated by our (MeHg)2S assay (Abiko Y. et al., unpublished observation). More interestingly, co-treatment of MeHg with a hexane extract of garlic significantly blocked its toxicity in vivo (Akiyama M. et al., unpublished observation). Identification of active components from the garlic extract is in progress in our laboratory. ACKOWLEDGEMENT We are grateful to Prof. Author K. Cho, UCLA School of Medicine, and Prof. Jon M. Fukuto, Sonoma State University, for their critical reading and useful comments to this manuscript. FUNDING INFORMATION This work was supported by a Grant-in-Aid (#JP25220103 to Y.K. and #JP15K18906 to Y.A.) for scientific research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. ABBREVIATIONS AhR, arylhydrocarbon receptor; ARE/EpRE, antioxidant/electrophile responsive element; ASK1, apoptosis signal-regulating kinase 1; Bcl-2, B-cell lymphoma 2; BPM, biotin-PEAC5-labeling; BQ, benzoquinone; CBS, cystathionine β-synthase; CREB, cAMP response element-binding protein; CSE, cystathionine γ-lyase; CYP, cytochrome P450; Cys or CysSH, cysteine; CysSSCys, cysteine; CysSSH, Cysteine persulfide;



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EGFR, epidermal growth factor receptor; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GCL, glutamate cysteine ligase; GSH, Glutathione; GSSG, oxidized GSH; GSSH, GSH persulfide; GSSSH, GSH polysulfide; GST, GSH S-transferases; HSAB, hard and soft acid and base; HSE, heat shock element; HSF1, heat shock factor 1; HSP90, heat shock protein 90; IKKβ, IkappaB kinase β; Keap1, Kelch-like ECH-associated protein 1; MeHg, methylmercury; MRP, multidrug resistance associated protein; NAPQI, N-acetyl-p-benzoquinoneimine; NF-κB, nuclear factor κB; NQ, naphthoquinone; Nrf2, NF-E2-related factor 2; PG, prostaglandin; PI3K, phosphatidylinositol 3-kinase; PTEN, phosphatase and tensin homolog; PTP1B, protein tyrosine

phosphatase

1B;

ROS,

reactive

oxygen

species;

TBQ,

tert-butyl-1,4-benzoquinone; TRP14, thioredoxin-related protein-14; Trx, thioredoxin; TrxR1, thioredoxin reductase1; UCH-L1, ubiquitin carboxyl-terminal hydrolase L1; UGT, UDP-glucuronosyltransferase; XRE, xenobiotics responsive element; 3MST, 3-mercaptopyruvate

sulfurtransferase;

4-HNE,

4-hydroxynonenal;

15d-PGJ2,

15-deoxy-Δ12,14-PGJ2.

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47

Yoshito Kumagai is a Professor in the Faculty of Medicine at University of Tsukuba, Japan. He received his B.S. degree in Pharmaceutical Sciences in 1982, M.S. and Ph.D. in Drug Metabolism and Toxicology in 1984 and 1988, respectively, from Fukuoka University. Then, he worked as postdoctoral fellow in Department of Molecular Pharmacology, UCLA School of Medicine from 1989 to 1992. He started his



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48

professional career as a researcher at the National Institute for Environmental Studies, Tsukuba, Japan, and then moved to University of Tsukuba in 1994. Finally, he got a full professor position in 2003 in University of Tsukuba.

Yumi Abiko is an Assistant professor in the Faculty of Medicine at University of Tsukuba, Japan. She received her B.S. in Health Sciences from Shinshu University School of Medicine in 2008. She earned her M.S. in Environmental Sciences and Ph.D. in Medicine from the University of Tsukuba in 2010 and 2013, respectively, where she worked under the advisement of Prof. Yoshito Kumagai to study the defense systems against environmental chemicals. After continuing as a JSPS research fellow with Prof. Kumagai, she began as an assistant professor at the University of Tsukuba form 2014.


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49

TABLES Table 1. Modification of proteins by environmental electrophiles and resulting biochemical effects Electrophile

Target protein

Effect

Reference

(E)-2-Alkenal

Keap1

Disruption of its function

164

tert-Butyl-1,4-benzoquinone

AhR

Activation

83,174

Keap1


85

Cadmium

Keap1


165

Methylmercury

Arginase I

Reduction of arginase activity

100

CREB


96

Keap1


37

Mn-SOD

Aggregation and release of zinc ion

98,99

PTEN

Reduction of phosphatase activity

96

SDH

Aggregation

97

UCH-L1


101

AhR

Activation

83,174

CREB


92,93

GAPDH

Reduction of GAPDH activity

87

IKKβ

Reduction of its activity

94

Keap1


84

Peroxiredoxin 6

Reduction of phospholipase A2 activity

89

PTP1B

Reduction of the phosphatase activity

88

UCHL-1


90

AhR

Activation

83,174

HSF1


91, Abiko (submitted)

PTEN

Reduction of phosphatase activity

95

1,2-Naphthoquinone

1,4-Naphthoquinone



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Table 2. Activation of redox signaling pathways by environmental electrophiles examined in our laboratory

Electrophiles

Electrophilic

Sensor

Effector

signal

protein

molecule

1,2-NQ, TBQ, MeHg, Cd,

Response

References

Upregulation of phase-II drug Keap1/Nrf2

Keap1

Nrf2

Crotonaldehyde

metabolizing enzymes and

37,84,85,164,165

phase-III transporters

Quinones such as 1,2-NQ, 1,4-NQ

AhR/XRE

AhR

AhR

Upregulation of CYP1A1

PTEN/Akt

PTEN

Akt

1,2-NQ

PTP1B/EGFR

PTP1B

EGFR

Phospholyration of ERK cascade

Cd, 1,4-NQ

HSF1/HSP90

HSF1

HSP90

Upregulation of HSPs

83,174

and TBQ MeHg, 1,4-NQ

Phosphorylation of CREB, Upregulation of Bcl-2


96, 95 88 Abiko (submitted), Shinkai (unpublished)

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51

FIGURE LEGENDS Figure 1. Structures of environmental electrophiles. Figure 2. S-Arylation of 1,2-naphthoquinone (1,2-NQ) to sensor protein and GSH-dependent S-transarylation of modified protein bound to 1,2-NQ. First, thiolate ion in sensor proteins (e.g., GAPDH, Keap1 and UCH-L1) attacks 1,2-NQ to form the 1,2-NQH2–protein adducts, whose molecular weight is +158.02 Da through 1,4-Michael addition reaction. The 1,2-NQH2–protein adducts rapidly undergo autoxidation to form the 1,2-NQ–protein adducts, whose molecular weight is +156.02 Da. A second Michael reaction leads to production of dithiolated moiety of 1,2-NQ in the presence of GSH, and then undergoes a retro-Michael reaction. As a result, 1,2-NQ– SG adduct and unmodified proteins are formed. Figure 3. Biotransformation of MeHg involved in GSH conjugation and sulfur adduct formation. Figure 4. Generation of persulfides/polysulfides by CSE and/or CBS and formation of (MeHg)2S in vivo. A, low molecular weight reactive persulfides/polysulfides; B, protein-bound reactive persulfides/polysulfides. Figure 5. Modulation of environmental electrophile-mediated activation of redox signaling pathways and health risk negatively regulated by persulfides/polysulfides.

Figure 6. Possible regulation of protein bound polysulfide by Trx system and depriving of the polysulfide by MeHg. The Trx system might regulate elongation of polysulfide chain in protein, which is formed as a result of enzymatic reaction of CBS/CSE and/or other enzymes, in vivo.217 MeHg mimics function of the Trx system to deprive sulfur atom to yield (MeHg)2S, resulting in formation of MeHg–protein adduct. Figure 7. Contribution of reactive persulfides/polysulfides to xenobiotic-metabolizing



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52

system to detoxify electrophiles. CYPs, cytochrome P450s; GSTs, glutathione S-transferases; MRPs, multidrug resistance

associated

proteins;

RSS,

reactive

UDP-glucuronosyltransferases.


sulfur

species;

UGTs,

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Table of Contents (TOC) graphic 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42

Ambient air

O

O

O

Fishes

O

O

CH3Hg O

Cooked foods NH 2

Indoor air O

O

+

E

-

+

S

H

Rice Cd

Cigarette smoke O

O

H

H

Plants O

Drugs

H 3C(H2C)n

E-S

H

Protein adducts

ACS Paragon Environment Modulation of Plus redox signaling

E


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42

Page 54 of 60

Figure 1

O

O O O

O

1,4-Benzoquinone

O

O

1,4-Naphthoquinone

NH 2

O

O

H

H

H

Formaldehyde

O

1,2-Naphthoquinone

Acrolein

Crotonaldehyde

Acrylamide

O H 3C(H2C)n

(E)-2-Alkenals

H

CH3Hg

Cd

Methylmercury

Cadmium


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Figure 2

S-arylation O

O

OH

O

O

OH

α

S

β

δM=158.02

H

S

H S

SH

rotein

Protein

Protein [O]

S-transarylation O

O

O O H

O

retro-Michael SG reaction

O

GSH S

SG

pKa=9.12

protein


δM=156.02

S

protein


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42

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Figure 3

Disruption of protein function

Protein S HgMe S-trans mercuration

S-mercuration

Persulfides/ polysulfides

MeHg

GS–

Protein S– MRP

MeHg-SG

Phase-II

MeHg-SH

MeHg-S–

Detoxification & Nrf2 excretion of MeHg

Phase-III

Nrf2

MeHg (MeHg)2S

Capture & inactivation of MeHg

Bismethylmercury sulfide


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Figure 4

A CBS CSE CysS-SCys ystine

H2

S/HS-

(MeHg)2S

(MeHg)2S

MeHg

pKa=6.76

GR

CysS-SH

GS-SH

Cysteine persulfide

Glutathione persulfide

pKa=4.34

GSH

[O]

MeHg GS-S-SG Glutathione polysulfide

GS-SG

pKa=9.12

B Protein SH

Persulfides/ polysulfides

Protein -S-SSH(R) e.g., GSTP1


MeHg

(MeHg)2S


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Figure 5

S

E

Lower dose

Transcriptional induction Maintenance of homeostasis

Inactivation

E Effecter molecule

Activation

Higher dose

Transcriptional repression Failure to maintain Homeostasis


Disruption of redox signaling

Increased risk

Persulfides/ polysulfides Sensor protein

Effecter molecule

SH

Environmental electrophiles +Persulfides

–Persulfides

S

E Formation of Sulfur adducts

Environmental electrophiles

Increased risk

Sensor protein

Signal transduction

Activation of redox signaling

Signal transduction

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Figure 6 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42

* Thioredoxin (Trx) + Trx reductase + TRP14

Trx system*

Trx system* Protein S SH

Protein SH

?

+

S

CBS CSE Protein S S SH Persulfides/ Protein SH polysulfides

(MeHg)2S MeHg

+ Protein S SH

(MeHg)2S

+

MeHg Protein

SH

MeHg Protein S HgMe S-Mercuration of protein



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Figure 7 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42

Extracellular space

Intracellular space Phase-I reaction

+

E

CYPs Chemicals

GSTs UGTs

+

+

E

E Environmental electrophiles

E

S

S

GSH CysSH

Phase-II reaction

RSS

RSS

Phasezero reaction ?

Electrophilic metabolites

E

CSE, CBS 3MST, CARS

E Sulfur adducts ACS Paragon Plus Environment

Polar groups

MRP Phase-III reaction

Protein Adducts, Modulation of Redox Signaling ... - ACS Publications

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