Participation of covalent modification of Keap1 in the activation of Nrf2 by tert-butylbenzoquinone, an electrophilic metabolite of butylated hydroxyanisole

Abiko, Yoshihiro; Miura, Takashi; Phuc, Bui Hoang; Shinkai, Yasuhiro; Kumagai, Yoshito

doi:10.1016/j.taap.2011.05.013

Cited by 87 publications

(80 citation statements)

References 30 publications

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“…As shown in Scheme 1B, there is little doubt that activation of both AhR and Nrf2 mediated by NQs derived from naphthalene causes increased levels of phase-I enzymes (e.g., CYP1A1), phase-II enzymes (e.g., aldo-keto reductases and UDPglucuronosyltransferases) and phase-III transporters (e.g., multi-drug resistance associated proteins). We therefore speculate that NQs would be unique metabolites that facilitate eventually the metabolism of its parent compound (i.e., naphthalene) associated with detoxification and excretion into extracellular space (Abiko et al, 2011;Kumagai et al, 2012;Miura et al, 2011) (Scheme 1B).…”

Section: Discussionmentioning

confidence: 99%

Covalent binding of quinones activates the Ah receptor in Hepa1c1c7 cells

2015

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-Highly reactive quinone species produced by photooxidation and/or metabolic activation of mono-or bi-aromatic hydrocarbons modulate cellular homeostasis and electrophilic signal transduction pathways through the covalent modification of proteins. Polycyclic aromatic hydrocarbons, but not mono-or bi-aromatic hydrocarbons, are well recognized as ligands for the aryl hydrocarbon receptor (AhR). However, quinone species produced from mono-and bi-aromatic hydrocarbons could potentially cause AhR activation. To clarify the AhR response to mono-and bi-aromatic hydrocarbon quinones, we studied Cyp1a1 (cytochrome P450 1A1) induction and AhR activation by these quinones. We detected Cyp1a1 induction during treatment with quinones in Hepa1c1c7 cells, but not their parent compounds. Nine of the twelve quinones with covalent binding capability for proteins induced Cyp1a1. Cyp1a1 induction mediated by 1,2-naphthoquinone (1,2-NQ), 1,4-NQ, 1,4-benzoquinone (1,4-BQ) and tert-butyl-1,4-BQ was suppressed by a specific AhR inhibitor and was not observed in c35 cells, which do not have a functional AhR. These quinones stimulated AhR nuclear translocation and interaction with the AhR nuclear translocator. Interestingly, 1,2-NQ covalently modified AhR, which was detected by an immunoprecipitation assay using a specific antibody against 1,2-NQ, resulting in enhancement of xenobiotic responsive element (XRE)-derived luciferase activity and binding of AhR to the Cyp1a1 promoter region. While mono-and bi-aromatic hydrocarbons are generally believed to be poor ligands for AhR and hence unable to induce Cyp1a1, our study suggests that the quinones of these molecules are able to modify AhR and activate the AhR/XRE pathway, thereby inducing Cyp1a1. Since we previously reported that 1,2-NQ and tert-butyl-1,4-BQ also activate NF-E2-related factor 2, it seems likely that some of quinones are bi-functional inducers for phase-I and phase-II reaction of xenobiotics.

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Section: Discussionmentioning

confidence: 99%

Covalent binding of quinones activates the Ah receptor in Hepa1c1c7 cells

2015

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“…Of interest are the findings that members of the Src superfamily (e.g., Fyn, Src, Fgr, Yes) terminate the nuclear transcriptional activity of Nrf2 by mediating Tyr 568 phosphorylation. This phosphorylated form of Nrf2 dissociates from the transcription complex and is exported to the cytoplasm (Abiko et al, 2011;Niture et al, 2011Niture et al, , 2014.…”

Section: Protective Mechanisms Against Oxidative Stressoxidative Condmentioning

confidence: 99%

Hormetic and regulatory effects of lipid peroxidation mediators in pancreatic beta cells

Maulucci

Daniel

Cohen

et al. 2016

Molecular Aspects of Medicine

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“…Paraquat can cause oxidative stress and is thought to activate Nrf2 through the oxidation of cysteine residues on Keap1 (Suntres, 2002). tBHQ can activate Nrf2 by increasing mitochondrial reactive oxygen species and the tBHQ metabolite tert-butylbenzoquinone can directly modify Keap1 (Imhoff and Hansen, 2010;Abiko et al, 2011). The mechanisms by which phenobarbital regulates Keap1-Nrf2 as well as dKeap1-CncC were not known.…”

Section: Selective Regulation Of Dkeap1 and Cncc Binding And Of Gene mentioning

confidence: 99%

Visualization of the Drosophila dKeap1-CncC interaction on chromatin illumines cooperative, xenobiotic-specific gene activation

Huai

Kerppola

2014

Development

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Interactions among transcription factors control their physiological functions by regulating their binding specificities and transcriptional activities. We implement a strategy to visualize directly the genomic loci that are bound by multi-protein complexes in single cells in Drosophila. This method is based on bimolecular fluorescence complementation (BiFC) analysis of protein interactions on polytene chromosomes. Drosophila Keap1 (dKeap1)-CncC complexes localized to the nucleus and bound chromatin loci that were not bound preferentially by dKeap1 or CncC when they were expressed separately. dKeap1 and CncC binding at these loci was enhanced by phenobarbital, but not by tert-butylhydroquinone (tBHQ) or paraquat. Endogenous dKeap1 and CncC activated transcription of the Jheh (Jheh1, Jheh2, Jheh3) and dKeap1 genes at these loci, whereas CncC alone activated other xenobiotic response genes. Ectopic dKeap1 expression increased CncC binding at the Jheh and dKeap1 gene loci and activated their transcription, whereas dKeap1 inhibited CncC binding at other xenobiotic response gene loci and suppressed their transcription. The combinatorial chromatin-binding specificities and transcriptional activities of dKeap1-CncC complexes mediated the selective activation of different sets of genes by different xenobiotic compounds, in part through feed-forward activation of dKeap1 transcription.

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Participation of covalent modification of Keap1 in the activation of Nrf2 by tert-butylbenzoquinone, an electrophilic metabolite of butylated hydroxyanisole

Cited by 87 publications

References 30 publications

Covalent binding of quinones activates the Ah receptor in Hepa1c1c7 cells

Covalent binding of quinones activates the Ah receptor in Hepa1c1c7 cells

Hormetic and regulatory effects of lipid peroxidation mediators in pancreatic beta cells

Visualization of the Drosophila dKeap1-CncC interaction on chromatin illumines cooperative, xenobiotic-specific gene activation

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