Transcription factor Nrf2 mediates an adaptive response to sulforaphane that protects fibroblasts in vitro against the cytotoxic effects of electrophiles, peroxides and redox-cycling agents
Abstract
Sulforaphane can stimulate cellular adaptation to redox stressors through transcription factor Nrf2. Using mouse embryonic fibroblasts (MEFs) as a model, we show herein that the normal homeostatic level of glutathione in Nrf2{sup -/-} MEFs was only 20% of that in their wild-type counterparts. Furthermore, the rate of glutathione synthesis following its acute depletion upon treatment with 3 {mu}mol/l sulforaphane was very substantially lower in Nrf2{sup -/-} MEFs than in wild-type cells, and the rebound leading to a {approx} 1.9-fold increase in glutathione that occurred 12-24 h after Nrf2{sup +/+} MEFs were treated with sulforaphane was not observed in Nrf2{sup -/-} fibroblasts. Wild-type MEFs that had been pre-treated for 24 h with 3 {mu}mol/l sulforaphane exhibited between 1.4- and 3.2-fold resistance against thiol-reactive electrophiles, including isothiocyanates, {alpha},{beta}-unsaturated carbonyl compounds (e.g. acrolein), aryl halides and alkene epoxides. Pre-treatment of Nrf2{sup +/+} MEFs with sulforaphane also protected against hydroperoxides (e.g. cumene hydroperoxide, CuOOH), free radical-generating compounds (e.g. menadione), and genotoxic electrophiles (e.g. chlorambucil). By contrast, Nrf2{sup -/-} MEFs were typically {approx} 50% less tolerant of these agents than wild-type fibroblasts, and sulforaphane pre-treatment did not protect the mutant cells against xenobiotics. To test whether Nrf2-mediated up-regulation of glutathione represents the major cytoprotective mechanismmore »
- Authors:
-
- Biomedical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland (United Kingdom)
- Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY (United Kingdom)
- Center for Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba 305-8577 (Japan)
- Publication Date:
- OSTI Identifier:
- 21272577
- Resource Type:
- Journal Article
- Journal Name:
- Toxicology and Applied Pharmacology
- Additional Journal Information:
- Journal Volume: 237; Journal Issue: 3; Other Information: DOI: 10.1016/j.taap.2009.03.005; PII: S0041-008X(09)00115-X; Copyright (c) 2009 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 60 APPLIED LIFE SCIENCES; ACROLEIN; BENZOQUINONES; CHLORAMBUCIL; CUMENE; CYSTEINE; EPOXIDES; FIBROBLASTS; GLUTATHIONE; ISOTHIOCYANATES; LIGASES; NEOPLASMS; PEROXIDES; TRANSCRIPTION FACTORS; TRANSFERASES
Citation Formats
Higgins, Larry G, Kelleher, Michael O, Eggleston, Ian M, Itoh, Ken, Yamamoto, Masayuki, Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8577, ERATO Environmental Response Project, Japan Science and Technology Corporation, Tsukuba 305-8577, and Hayes, John D. Transcription factor Nrf2 mediates an adaptive response to sulforaphane that protects fibroblasts in vitro against the cytotoxic effects of electrophiles, peroxides and redox-cycling agents. United States: N. p., 2009.
Web. doi:10.1016/j.taap.2009.03.005.
Higgins, Larry G, Kelleher, Michael O, Eggleston, Ian M, Itoh, Ken, Yamamoto, Masayuki, Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8577, ERATO Environmental Response Project, Japan Science and Technology Corporation, Tsukuba 305-8577, & Hayes, John D. Transcription factor Nrf2 mediates an adaptive response to sulforaphane that protects fibroblasts in vitro against the cytotoxic effects of electrophiles, peroxides and redox-cycling agents. United States. https://doi.org/10.1016/j.taap.2009.03.005
Higgins, Larry G, Kelleher, Michael O, Eggleston, Ian M, Itoh, Ken, Yamamoto, Masayuki, Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8577, ERATO Environmental Response Project, Japan Science and Technology Corporation, Tsukuba 305-8577, and Hayes, John D. 2009.
"Transcription factor Nrf2 mediates an adaptive response to sulforaphane that protects fibroblasts in vitro against the cytotoxic effects of electrophiles, peroxides and redox-cycling agents". United States. https://doi.org/10.1016/j.taap.2009.03.005.
@article{osti_21272577,
title = {Transcription factor Nrf2 mediates an adaptive response to sulforaphane that protects fibroblasts in vitro against the cytotoxic effects of electrophiles, peroxides and redox-cycling agents},
author = {Higgins, Larry G and Kelleher, Michael O and Eggleston, Ian M and Itoh, Ken and Yamamoto, Masayuki and Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8577 and ERATO Environmental Response Project, Japan Science and Technology Corporation, Tsukuba 305-8577 and Hayes, John D.},
abstractNote = {Sulforaphane can stimulate cellular adaptation to redox stressors through transcription factor Nrf2. Using mouse embryonic fibroblasts (MEFs) as a model, we show herein that the normal homeostatic level of glutathione in Nrf2{sup -/-} MEFs was only 20% of that in their wild-type counterparts. Furthermore, the rate of glutathione synthesis following its acute depletion upon treatment with 3 {mu}mol/l sulforaphane was very substantially lower in Nrf2{sup -/-} MEFs than in wild-type cells, and the rebound leading to a {approx} 1.9-fold increase in glutathione that occurred 12-24 h after Nrf2{sup +/+} MEFs were treated with sulforaphane was not observed in Nrf2{sup -/-} fibroblasts. Wild-type MEFs that had been pre-treated for 24 h with 3 {mu}mol/l sulforaphane exhibited between 1.4- and 3.2-fold resistance against thiol-reactive electrophiles, including isothiocyanates, {alpha},{beta}-unsaturated carbonyl compounds (e.g. acrolein), aryl halides and alkene epoxides. Pre-treatment of Nrf2{sup +/+} MEFs with sulforaphane also protected against hydroperoxides (e.g. cumene hydroperoxide, CuOOH), free radical-generating compounds (e.g. menadione), and genotoxic electrophiles (e.g. chlorambucil). By contrast, Nrf2{sup -/-} MEFs were typically {approx} 50% less tolerant of these agents than wild-type fibroblasts, and sulforaphane pre-treatment did not protect the mutant cells against xenobiotics. To test whether Nrf2-mediated up-regulation of glutathione represents the major cytoprotective mechanism stimulated by sulforaphane, 5 {mu}mol/l buthionine sulfoximine (BSO) was used to inhibit glutathione synthesis. In Nrf2{sup +/+} MEFs pre-treated with sulforaphane, BSO diminished intrinsic resistance and abolished inducible resistance to acrolein, CuOOH and chlorambucil, but not menadione. Thus Nrf2-dependent up-regulation of GSH is the principal mechanism by which sulforaphane pre-treatment induced resistance to acrolein, CuOOH and chlorambucil, but not menadione.},
doi = {10.1016/j.taap.2009.03.005},
url = {https://www.osti.gov/biblio/21272577},
journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 3,
volume = 237,
place = {United States},
year = {Mon Jun 15 00:00:00 EDT 2009},
month = {Mon Jun 15 00:00:00 EDT 2009}
}