Environmental Electrophiles: Protein Adducts, Modulation of Redox Signaling, and Interaction with Persulfides/Polysulfides

Abstract

Included among the many environmental electrophiles are 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. 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 environmental electrophiles because of the formation of their sulfur adducts without electrophilicity. We therefore speculate that persulfide/polysulfides are candidates for the regulation of redox signal transduction pathways (e.g., cell survival, cell proliferation, and adaptive response) and toxicity during exposure to environmental electrophiles.

Polysulfide Na2S4 regulates the activation of PTEN/Akt/CREB signaling and cytotoxicity mediated by 1,4-naphthoquinone through formation of sulfur adducts

“…S4). We previously reported detection of a variety of sulfur adducts of environmental electrophiles, including an acrylamide-S-acrylamide adduct (Abiko Y et al ., unpublished observations) 31 , 1,2-NQ–S–1,2-NQ adduct 32 , tert -butyl-1,4-benzoquinone–S– tert -butyl-1,4-benzoquinone adduct 32 , N -acetyl- p -benzoquinoneimine (NAPQI)–S–NAPQI adduct 33 , potentially unreactive to cellular nucleophiles like (MeHg) 2 S, and, now, the 1,4-NQ-sulfur adduct identified in this study. These results strongly indicated that highly reactive nucleophilic sulfur species, such as Na 2 S 4 , can scavenge environmental electrophiles to form their sulfur adducts that lack electrophilic characteristics.…”

Biological hydropersulfides and related polysulfides – a new concept and perspective in redox biology

“…One aspect of the interaction of hydropersulfides with metals in a biological system that has been examined is the effect of persulfides on electrophilic heavy metal toxicity [59]. Abiko and coworkers [60] found that detoxification of methyl mercury can occur via interaction with H 2 S, hydropersulfides and polysulfides.…”

Nrf2 Activation and Its Coordination with the Protective Defense Systems in Response to Electrophilic Stress

“…In vivo studies have shown that CSE deletion in mice causes increased sensitivity to acetaminophen-induced hepatotoxicity, Cd-induced hepatotoxicity and MeHg-induced toxicity [20,77,84]. Overall, this suggests that CSE is a crucial factor engaged in the protection against electrophiles because this enzyme is involved in the production of RSS, thereby capturing electrophiles to yield their sulfur adducts [5,85] (Figure 3). Xenobiotic electrophiles selectively modify sensor proteins through thiolate ions at low doses and thus inhibit their activities.…”

“…As noted above, electrophiles can be captured by RSS, leading to the formation of their sulfur adducts. For example, we previously reported that MeHg, Cd, 1,4-NQ and NAPQI, which is the toxic metabolite of acetaminophen, can react with RSS, such as H 2 S, CysSSH, GSSH, GSSSG or the model polysulfide Na 2 S 4 , leading to the formation of bismethylmercury sulfide [(MeHg) 2 S], cadmium sulfide (CdS), CdS 2 O 3 , 1,4-NQ-SH, 1,4-NQ-S-1,4-NQ, 1,4-NQ-S-1,4-NQ-OH, NAPQIH 2 -SSSCys, NAPQIH 2 -SSCys and NAPQIH 2 -SSG [5,12,[75][76][77][78]. Additionally, (MeHg) 2 S and NAPQIH 2 -SSSCys were identified as novel metabolites of MeHg and acetaminophen from the liver and urine of mice treated with these compounds [78,79].…”

“…Nucleophilic biomacromolecules, such as the side chains on protein amino acids (e.g., Cys, His, Arg and Lys) and aromatic nitrogen sites on DNA bases, are targeted by electrophiles to form stable adducts [4]; thus, these electrophile-nucleophile interactions are involved in deleterious effects [5][6][7][8][9]. However, the chemical modification of sensor proteins with reactive thiols by xenobiotic electrophiles at low doses results in the activation of cellular signal transduction pathways to maintain cellular homeostasis [5,6,8,[10][11][12]. This adaptive cellular response to electrophiles is termed electrophilic signaling and involves both basal metabolism and oxidative/inflammatory responses [13][14][15][16].…”