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.

Anti-inflammatory and Anti-oxidant Activity of Hidrox® in Rotenone-Induced Parkinson’s Disease in Mice

“…Nrf2, one of the most important transcription factors that activates several genes with cytoprotective function, participates in antioxidant and anti-inflammatory reactions [ 72 , 73 , 74 , 75 , 76 , 77 ]. These cytoprotective genes encode a wide variety of phase II detoxification enzymes, such as NAD (P) H: quinone oxidoreductase 1 (NQO1), HO-1, γ-GCS, glutathione S-transferase (GST) and glutamate-cysteine ligase, thioredoxin, thioredoxin reductase, thermal shock proteins and many others [ 31 , 78 , 79 , 80 , 81 ]. Cell culture studies have shown that HT was the only olive oil phenol capable of increasing the transactivation of Nrf2, which suggests that this polyphenol could be responsible for the induction of Nrf2-dependent gene expression [ 82 ].…”

Real-time in vivo imaging reveals localised Nrf2 stress responses associated with direct and metabolism-dependent drug toxicity

“…The Nrf2-driven response to chemical and oxidative stress has been associated with several forms of drug toxicity in pre-clinical studies 9 . Amongst ongoing efforts to reduce attrition and improve the benefit:risk balance of new drugs, there is an increasing interest in using the perturbation of Nrf2 and other stress response pathways as mechanism-based markers of toxicity 2 .…”

“…Activation of Nrf2 signalling has been demonstrated in animals exposed to many drugs and chemical entities 9 , yet such in vivo studies have almost exclusively relied on the analysis of a single tissue relevant to the toxicological insult (e.g. our previous work showing activation of Nrf2 in the livers of mice exposed to the hepatotoxin acetaminophen 10 ).…”

The Keap1/Nrf2 pathway in health and disease: from the bench to the clinic

“…However, it also appears to have contrasting effects in response to viral infection as viruses activate Nrf2, which promotes their proliferation in the host [10]. Nrf2 also plays an important role in protecting against chemical toxicity and may be useful in pre-clinical testing of chemicals and drugs that may induce toxicity or adverse drug reactions [11].…”