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Effect of combined exposure to environmental aliphatic electrophiles from plants on Keap1/Nrf2 activation and cytotoxicity in HepG2 cells: A model of an electrophile exposome.

Abstract：

:Electrophiles, ubiquitously found in the environment, modify thiol groups of sensor proteins, leading to activation of redox signaling pathways such as the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor E2 related factor 2 (Nrf2) pathway. Nrf2 activation by exposure to single electrophiles has been established. However, the effect of exposure to a combination of electrophiles on Nrf2 activation has not been well evaluated. The current study examined whether combined exposure to electrophiles enhances the modification of thiol groups and Keap1/Nrf2 activation in HepG2 cells. Six electrophiles [1,2-naphthoquinone (1,2-NQ), 1,4-NQ, 1,4-benzoquinone, (E)-2-hexenal (hexenal), (E)-2-decenal, and (E)-2-butenal] were tested for S-modification of albumin in vitro and for cytotoxicity to HepG2 cells. Interestingly, a mixture of the electrophiles enhanced S-modification of albumin and cytotoxicity compared with exposure to each electrophile separately. Herein, we focused on 1,2-NQ, 1,4-NQ, and hexenal to clarify the combined effect of electrophiles on Keap1/Nrf2 activation in HepG2 cells. A concentration addition model revealed that 1,2-NQ and/or 1,4-NQ additively enhanced hexenal-mediated S-modification of GSH in vitro, whereas the cytotoxicity of hexenal was synergistically increased by simultaneous exposure of HepG2 cells to the NQs. Furthermore, an NQ cocktail (2.5 μM each) that does not activate Nrf2 enhanced hexenal-mediated Nrf2 activation. These results suggest that combined exposure to electrophiles at low concentrations induces stronger activation of redox signaling compared with exposure to each electrophile alone and worsens their cytotoxicity.

journal_name

Toxicol Appl Pharmacol

journal_title

Toxicology and applied pharmacology

authors

Abiko Y,Aoki H,Kumagai Y

doi

10.1016/j.taap.2020.115392

subject

Has Abstract

pub_date

2021-01-09 00:00:00

pages

115392

eissn

0041-008X

issn

1096-0333

pii

S0041-008X(20)30514-7

journal_volume

413

pub_type

杂志文章

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Effect of combined exposure to environmental aliphatic electrophiles from plants on Keap1/Nrf2 activation and cytotoxicity in HepG2 cells: A model of an electrophile exposome.