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Review
, 35 (4), 303-310

Adaptive Responses to Electrophilic Stress and Reactive Sulfur Species as Their Regulator Molecules

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Review

Adaptive Responses to Electrophilic Stress and Reactive Sulfur Species as Their Regulator Molecules

Yoshito Kumagai et al. Toxicol Res.

Abstract

We are exposed to numerous xenobiotic electrophiles on a daily basis through the environment, lifestyle, and dietary habits. Although such reactive species have been associated with detrimental effects, recent accumulated evidence indicates that xenobiotic electrophiles appear to act as signaling molecules. In this review, we introduce our findings on 1) activation of various redox signaling pathways involved in cell proliferation, detoxification/excretion of electrophiles, quality control of cellular proteins, and cell survival during exposure to xenobiotic electrophiles at low concentrations through covalent modification of thiol groups in sensor proteins, and 2) negative regulation of reactive sulfur species (RSS) in the modulation of redox signaling and toxicity caused by xenobiotic electrophiles.

Keywords: Covalent modification; Electrophiles; Reactive sulfur species; Redox signaling.

Conflict of interest statement

CONFLICT OF INTEREST The authors declare they have no actual or potential competing financial interests.

Figures

Fig. 1
Fig. 1
Structures of representative xenobiotic and endogenous electrophiles. We are routinely exposed to electrophilic stress by a large number of diverse xenobiotic electrophiles in the environment. However, various endogenous electrophiles have been identified. Recent accumulated evidence indicates that both xenobiotic and endogenous electrophiles appear to act as signaling molecules.
Fig. 2
Fig. 2
Modulation of redox signaling pathways by xenobiotic electrophiles. Two different aspects of xenobiotic electrophiles: xenobiotic electrophile-mediated activation (low dose) and disruption (high dose) of redox signaling by sensor proteins with low pKa thiols and effector molecules that are negatively regulated by RSS through sulfur adduct formation. E, xenobiotic electrophiles; RSS, reactive sulfur species.
Fig. 3
Fig. 3
Two defense systems against xenobiotic electrophiles. Canonical pathway: electrophiles conjugate with GSH to form electrophile-SG adducts that are rapidly excreted into the extracellular space. Nrf2 plays a critical role in the detoxification and excretion of electrophiles via GSH conjugation by initiating the transcription of GCL, GST, and MRP. Noncanonical pathway: reactive sulfur species produced by trans-sulfuration enzymes, such as CSE and CARS2, inactivate electrophiles through the formation of sulfur adducts. CARS2, cysteinyl-tRNA synthetase 2; CSE, cystathionine γ-lyase; GCL, glutamate-cysteine ligase; GST, glutathione S-transferase; MRP, multidrug resistance-associated protein; Nrf2, NF-E2-related factor 2.
Fig. 4
Fig. 4
Sulfur adducts of xenobiotic electrophiles identified in our laboratory. Reactions of electrophiles with reactive sulfur species yield various sulfur adducts of electrophiles in vitro and in vivo.

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