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. Toxicology and applied pharmacology [Toxicol Appl Pharmacol] Journal article | | 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(s) | Higgins LG, Kelleher MO, Eggleston IM, Itoh K, Yamamoto M, Hayes JD | | Institution | Biomedical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, United Kingdom. | | Source | Toxicol Appl Pharmacol 2009 Mar 19. | | 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(-/-)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 proportional, variantmol/l sulforaphane was very substantially lower in Nrf2(-/-)MEFs than in wild-type cells, and the rebound leading to a !1.9-fold increase in glutathione that occurred 12-24 h after Nrf2(+/+)MEFs were treated with sulforaphane was not observed in Nrf2(-/-)fibroblasts. Wild-type MEFs that had been pre-treated for 24 h with 3 proportional, variantmol/l sulforaphane exhibited between 1.4- and 3.2-fold resistance against thiol-active electrophiles, including isothiocyanates, alpha,beta-unsaturated carbonyl compounds (e.g. acrolein), aryl halides and alkene epoxides. Pre-treatment of Nrf2(+/+)MEFs with sulforaphane also protected against hydroperoxides (e.g. CuOOH), free radical-generating compounds (e.g. menadione), and genotoxic electrophiles (e.g. chlorambucil). By contrast, Nrf2(-/-)MEFs were typically approximately 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 proportional, variantmol/l buthionine sulfoximine (BSO) was used to inhibit glutathione synthesis. In Nrf2(+/+) 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. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19303893 |
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