title: Value of monitoring Nrf2 activity for the detection of chemical and oxidative stress.
abstract: Beyond specific limits of exposure, chemical entities can provoke deleterious effects in mammalian cells via direct interaction with critical macromolecules or by stimulating the accumulation of reactive oxygen species (ROS). In particular, these chemical and oxidative stresses can underpin adverse reactions to therapeutic drugs, which pose an unnecessary burden in the clinic and pharmaceutical industry. Novel pre-clinical testing strategies are required to identify, at an earlier stage in the development pathway, chemicals and drugs that are likely to provoke toxicity in humans. Mammalian cells can adapt to chemical and oxidative stress via the action of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which up-regulates the expression of numerous cell defence genes and has been shown to protect against a variety of chemical toxicities. Here, we provide a brief overview of the Nrf2 pathway and summarize novel experimental models that can be used to monitor changes in Nrf2 pathway activity and thus understand the functional consequences of such perturbations in the context of chemical and drug toxicity. We also provide an outlook on the potential value of monitoring Nrf2 activity for improving the pre-clinical identification of chemicals and drugs with toxic liability in humans.
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular & Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, U.K.
authors.forename: Fiona E
authors.initials: FE
authors.lastname: Mutter
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular & Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, U.K.
authors.forename: B Kevin
authors.initials: BK
authors.lastname: Park
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular & Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, U.K. ian.copple@liv.ac.uk.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Copple
mesh_terms: D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D046911:Macromolecular Substances / Q000633:toxicity*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D046911:Macromolecular Substances; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D017382:Reactive Oxygen Species
keywords: Kelch-like ECH-associated protein 1 (Keap1); antioxidant response element; hazard assessment; nuclear factor erythroid 2-related factor 2 (Nrf2); stress response; toxicity