The Nrf2–Keap1 defence pathway: Role in protection against drug-induced toxicity

Copple, Ian M.; Goldring, Christopher E.; Kitteringham, Neil R.; Park, B. Kevin

doi:10.1016/j.tox.2007.10.029

Cited by 302 publications

(219 citation statements)

References 150 publications

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“…This process depends on either phosphorylation of Nrf2 and/or oxidative or covalent modification of thiols in cysteine residue of Keap1. 30,31 By means of phosphorylation of Nrf2, several upstream kinases including PERK can activate Nrf2 to induce production of antioxidant and cytoprotective molecules. 32 This phenomenon represents an important component of adaptive/cytoprotective responses of ER stress to maintain the cellular redox homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Participation of endoplasmic reticulum stress in the pathogenesis of spontaneous glomerulosclerosis–Role of intra-renal angiotensin system

Aminzadeh

Satô

Vaziri

2012

Translational Research

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Section: Discussionmentioning

confidence: 99%

Participation of endoplasmic reticulum stress in the pathogenesis of spontaneous glomerulosclerosis–Role of intra-renal angiotensin system

Aminzadeh

Satô

Vaziri

2012

Translational Research

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“…To avoid cellular damage by reactive compounds, various cytoprotective genes, including those under the control of the transcription factor nuclear factor (erythroid 2)-like 2 (Nrf2, NFE2L2 gene), are involved in conjugation reactions, export functions, defense against oxidative stress and repair mechanisms. Nrf2 is a key regulator of the anti-oxidant cell defense system that controls both basal and ligand-induced expression of important cytoprotective enzymes [18,19]. Nrf2 target genes include essential phase II detoxification enzymes such as NAD(P)H:Quinone Oxidoreductases (NQO), Hemeoxygenase-1 (HO-1, HMOX1 gene) and Glutathione S-Transferases (GST) that are induced, among other factors, by oxidative stress caused by xenobiotics [18,[20][21][22][23].…”

Section: Introductionmentioning

confidence: 99%

“…Nrf2 is a key regulator of the anti-oxidant cell defense system that controls both basal and ligand-induced expression of important cytoprotective enzymes [18,19]. Nrf2 target genes include essential phase II detoxification enzymes such as NAD(P)H:Quinone Oxidoreductases (NQO), Hemeoxygenase-1 (HO-1, HMOX1 gene) and Glutathione S-Transferases (GST) that are induced, among other factors, by oxidative stress caused by xenobiotics [18,[20][21][22][23]. The importance of Nrf2 is demonstrated in knockout mice, exhibiting an enhanced susceptibility towards oxidative stress caused by xenobiotics as a result of diminished expression of cytoprotective genes [24][25][26].…”

Section: Introductionmentioning

confidence: 99%

Characterization of a Rat Multi-Cell Type 3D-Liver Microtissue System

Odermatt¹

2013

J Tissue Sci Eng

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Background: Primary hepatocytes rapidly lose their polarized morphology and the expression of important liverspecific metabolic enzymes, receptors and transport proteins under normal two-dimensional (2D) culture conditions. Thus, their use as a reliable predictive in vitro model for drug-induced liver injury is limited. Three-dimensional (3D) liver micro tissue culture systems have become an increasingly attractive alternative for the evaluation of druginduced liver toxicity. However, several liver-specific pathways remain to be characterized in such models. Methods and principal findings:In the present work, we compared the expression of several genes with a role in the anti-oxidant cell defense and glucocorticoid pathways in rat H4IIE hepatoma cells, primary rat hepatocytes, 2D-hepatocyte sandwich culture, and a multi-cell type micro tissue model comprising primary rat hepatocytes in coculture with liver-derived nonparenchymal cells and macrophage (Kupffer cells). Gene expression was studied for up to 25 days in culture. High expression levels of the Nrf2-dependent genes NQO1, ABCC3 and GST2A were detected in H4IIE cells and in 3D-liver microtissues, in contrast to 2D-hepatocytes where a rapid decline of these genes was observed. The glucocorticoid-dependent genes ORM1, G6PC, PCK1 and HSD11B1 were highly expressed up to 25 days of cultivation in 3D-liver microtissues, but they showed very low or background expression in H4IIE and 2D-hepatocyte models. Conclusions:The tested 3D-multi-cell type liver micro tissue represents a stable and functionally active model system, with sustained expression for more than three weeks of cultivation of important metabolic proteins regulated by the glucocorticoid and anti-oxidant cell defense pathway.

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“…Therefore, it is obvious that cells must constantly labor to control levels of ROS, preventing them from accumulating. Cells have mechanisms to activate over two hundred defensive genes that protect against ROS and the diseases they contribute to (1,(5)(6)(7).…”

mentioning

confidence: 99%

“…Cellular exposure to oxidative stress leads to dissociation of Nrf2 from the INrf2/Cul3-Rbx1 complex (1,(5)(6)(7). Nrf2 escapes proteolysis and stabilizes, translocates into the nucleus, and causes activation of ARE-mediated genes leading to cytoprotection.…”

mentioning

confidence: 99%

An Autoregulatory Loop between Nrf2 and Cul3-Rbx1 Controls Their Cellular Abundance

Kaspar

Jaiswal

2010

Journal of Biological Chemistry

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The cellular defense system protects against oxidative stress caused by a vast range of xenobiotics, inflammation, and ionizing radiation (1-3). Disruption of these protective systems causes the accumulation of reactive oxygen species (ROS) 2 and electrophiles that can contribute to diseases such as cancer, cardiovascular complications, acute and chronic inflammation, and neurodegenerative diseases (4). Therefore, it is obvious that cells must constantly labor to control levels of ROS, preventing them from accumulating. Cells have mechanisms to activate over two hundred defensive genes that protect against ROS and the diseases they contribute to (1, 5-7).The antioxidant response element (ARE) was first identified as cis-element in the upstream regulatory region of the GSTA2 gene (8) and was found in the promoters of detoxifying enzyme genes such as glutathione S-transferases, NAD(P)H:quinone oxidoreductases, gastrointestinal glutathione peroxidase, and peroxiredoxin1 (9 -13). The ARE is recognized by the family of Cap'n'Collar containing basic leucine zipper proteins including Nrf2. Among the family, Nrf2 is the most potent transcription factor in regulating the basal and inducible expression of antioxidant enzyme genes (14). Gene deletion studies also supported the important function of Nrf2 in cellular protection against oxidative stress and neoplasia (15).At basal levels, Nrf2 resides within the cytoplasm of the cells by an interaction with an actin-bound cytosolic protein, INrf2 (inhibitor of Nrf2) or Keap1 (Kelch-like ECH-associated protein 1) (16 -18). INrf2 functions as a substrate adaptor protein for a Cullin 3 (Cul3)-dependent ubiquitin-protein ligase complex to maintain the steady-state levels of Nrf2 (19). Covalent conjugation of proteins by ubiquitin usually involve three enzymatic activities for activating (E1), conjugating (E2), and ligating (E3) ubiquitin to a substrate (20). In this case, Nrf2 serves as the substrate, while Cul3 serves as a scaffold protein that forms the E3 ligase complex with Ring Box1 (Rbx1) that recruits a cognate E2 enzyme (6). INrf2, via its N-terminal BTB/POZ domain, binds to Cul3 (20, 22) and via its C-terminal Kelch domain binds to the substrate Nrf2, leading to the ubiquitination and subsequent degradation of Nrf2 through the 26 S proteasome (23-27).Cellular exposure to oxidative stress leads to dissociation of Nrf2 from the INrf2/Cul3-Rbx1 complex (1, 5-7). Nrf2 escapes proteolysis and stabilizes, translocates into the nucleus, and causes activation of ARE-mediated genes leading to cytoprotection. Several reports suggest that persistent accumulation of Nrf2 in the nucleus is harmful. Nrf2 regulates the expression of several multidrug resistance-associated protein (MRP) efflux transporters in responses to oxidative stress (28) which could lead to chemotherapeutic drug resistance. INrf2-null mice demonstrated persistent accumulation of Nrf2 in the nucleus that led to postnatal death from malnutrition resulting from hyperkeratosis in the esophagus and forestomach (29

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The Nrf2–Keap1 defence pathway: Role in protection against drug-induced toxicity

Cited by 302 publications

References 150 publications

Participation of endoplasmic reticulum stress in the pathogenesis of spontaneous glomerulosclerosis–Role of intra-renal angiotensin system

Participation of endoplasmic reticulum stress in the pathogenesis of spontaneous glomerulosclerosis–Role of intra-renal angiotensin system

Characterization of a Rat Multi-Cell Type 3D-Liver Microtissue System

An Autoregulatory Loop between Nrf2 and Cul3-Rbx1 Controls Their Cellular Abundance

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