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Review
. 2010 Oct 20;15(10):7266-91.
doi: 10.3390/molecules15107266.

The Nrf2 system as a potential target for the development of indirect antioxidants

Kyeong-Ah Jung  1 , Mi-Kyoung Kwak
Affiliations
Review

The Nrf2 system as a potential target for the development of indirect antioxidants

Kyeong-Ah Jung et al. Molecules. .

Abstract

Oxidative stress causes damage to multiple cellular components such as DNA, proteins, and lipids, and is implicated in various human diseases including cancer, neurodegeneration, inflammatory diseases, and aging. In response to oxidative attack, cells have developed an antioxidant defense system to maintain cellular redox homeostasis and to protect cells from damage. The thiol-containing small molecules (e.g. glutathione), reactive oxygen species-inactivating enzymes (e.g. glutathione peroxidase), and phase 2 detoxifying enzymes (e.g. NAD(P)H: quinine oxidoreductase 1 and glutathione-S-transferases) are members of this antioxidant system. NF-E2-related factor 2 (Nrf2) is a CNC-bZIP transcription factor which regulates the basal and inducible expression of a wide array of antioxidant genes. Following dissociation from the cytosolic protein Keap1, a scaffolding protein which binds Nrf2 and Cul3 ubiquitin ligase for proteasome degradation, Nrf2 rapidly accumulates in the nucleus and transactivates the antioxidant response element in the promoter region of many antioxidant genes. The critical role of Nrf2 has been demonstrated by various animal studies showing that mice with a targeted disruption of the nrf2 gene are prone to develop lesions in response to environmental toxicants/carcinogens, drugs, and inflammatory insults. In this review, we discuss the role of the Nrf2 system, with particular focus on Nrf2-controlled target genes and the potential pleiotropic effects of Nrf2 activation of indirect antioxidants.

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Figures

Figure 1
Figure 1
Nrf2 and its regulation by Keap1. (A) Under normal conditions, Nrf2 is degraded by Keap1-Cul3-dependent pathway; (B) In the presence of indirect antioxidants, Keap1-Nrf2 binding is disturbed and Nrf2 transactivates ARE-driven genes in the nucleus; (C) Protein structure of Keap1 and reactive cysteine residues for the action of Nrf2.
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