Inositol-requiring enzyme 1 alpha (IRE1α) is an endoplasmic reticulum (ER)-transmembrane endonuclease that is activated in response to ER stress as part of the unfolded protein response (UPR). Chronic activation of the UPR has been implicated in the pathogenesis of many common diseases including diabetes, cancer, and neurological pathologies such as Huntington's and Alzheimer's disease. 7-Hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde (4µ8C) is widely used as a specific inhibitor of IRE1α ribonuclease activity (IC50 of 6.89 µM in cultured cells). However, in this paper, we demonstrate that 4µ8C acts as a potent reactive oxygen species (ROS) scavenger, both in a cell-free assay and in cultured cells, at concentrations lower than that widely used to inhibit IRE1α activity. In vitro we show that, 4µ8C effectively decreases xanthine/xanthine oxidase catalysed superoxide production with an IC50 of 0.2 µM whereas in cultured endothelial and clonal pancreatic β-cells, 4µ8C inhibits angiotensin II-induced ROS production with IC50 values of 1.92 and 0.29 µM, respectively. In light of this discovery, conclusions reached using 4µ8C as an inhibitor of IRE1α should be carefully evaluated. However, this unexpected off-target effect of 4µ8C may prove therapeutically advantageous for the treatment of pathologies that are thought to be caused by, or exacerbated by, both oxidative and ER stress such as endothelial dysfunction and/or diabetes.
Skip Nav Destination
Follow us on Twitter @Biochem_Journal
Article navigation
March 2018
-
Cover Image
Cover Image
The human immunodeficiency virus. In this issue of the Biochemical Journal, Parajuli et al. report that restricted the HIV Env (envelope glycoprotein) glycan engagement by a lectin reengineered DAVEI protein chimera is sufficient for virolysis. For details, see pages 931–957.
Research Article|
March 09 2018
The inositol-requiring enzyme 1 (IRE1α) RNAse inhibitor, 4µ8C, is also a potent cellular antioxidant
Stanley M.H. Chan;
Stanley M.H. Chan
1School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3083, Australia
Search for other works by this author on:
Mark P. Lowe;
Mark P. Lowe
2Department of Chemistry (Chemical Biology Group), University of Leicester, Leicester LE1 7RH, U.K.
Search for other works by this author on:
Ashton Bernard;
Ashton Bernard
1School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3083, Australia
3Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow G12 8TA, U.K.
Search for other works by this author on:
Alyson A. Miller;
Alyson A. Miller
1School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3083, Australia
3Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow G12 8TA, U.K.
Search for other works by this author on:
Terence P. Herbert
1School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3083, Australia
4School of Pharmacy, College of Science, University of Lincoln, Brayford Pool, Lincoln, Lincolnshire LN6 7TS, U.K.
Correspondence: Terence P. Herbert ([email protected])
Search for other works by this author on:
Publisher: Portland Press Ltd
Received:
September 04 2017
Revision Received:
February 19 2018
Accepted:
February 20 2018
Accepted Manuscript online:
February 20 2018
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2018
Biochem J (2018) 475 (5): 923–929.
Article history
Received:
September 04 2017
Revision Received:
February 19 2018
Accepted:
February 20 2018
Accepted Manuscript online:
February 20 2018
Citation
Stanley M.H. Chan, Mark P. Lowe, Ashton Bernard, Alyson A. Miller, Terence P. Herbert; The inositol-requiring enzyme 1 (IRE1α) RNAse inhibitor, 4µ8C, is also a potent cellular antioxidant. Biochem J 15 March 2018; 475 (5): 923–929. doi: https://doi.org/10.1042/BCJ20170678
Download citation file:
Sign in
Don't already have an account? Register
Sign in to your personal account
You could not be signed in. Please check your email address / username and password and try again.
Could not validate captcha. Please try again.
Biochemical Society Member Sign in
Sign InSign in via your Institution
Sign in via your InstitutionGet Access To This Article
Follow us on Twitter @Biochem_Journal
Open Access for all
We offer compliant routes for all authors from 2025. With library support, there will be no author nor reader charges in 5 journals. Check here |
![]() View past webinars > |