Detection and characterization of the Ah receptor for 2,3,7,8-tetrachlorodibenzo-p-dioxin in the human colon adenocarcinoma cell line LS180

Harper, Patricia A.; Prokipcak, Rebecca D.; Bush, Leslie E.; Golas, Cheryl L.; Okey, Allan B.

doi:10.1016/0003-9861(91)90587-9

Cited by 83 publications

(60 citation statements)

References 28 publications

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“…3), suggesting participation of AhR in the induction of CYP1A1. Once ligands bind to AhR, the transcriptional factor translocates into the nucleus and interacts with ARNT to bind XRE (Henry and Gasiewicz, 2003;Harper et al, 1991;Fujisawa-Sehara et al, 1987;Soshilov and Denison, 2008). As expected, treatments with TBQ, 1,4-BQ, 1,4-NQ and 1,2-NQ caused translocation of AhR into the nucleus in HepG2 cells as detected by immunostaining (Fig.…”

Section: Resultssupporting

confidence: 76%

Quinone-mediated induction of cytochrome P450 1A1 in HepG2 cells through increased interaction of aryl hydrocarbon receptor with aryl hydrocarbon receptor nuclear translocator

Abiko

Lin²,

Lee

et al. 2016

J. Toxicol. Sci.

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-While it has long been believed that benzenes and naphthalenes are unable to activate the aryl hydrocarbon receptor (AhR) because they are poor ligands, we recently reported that these quinoid metabolites upregulated cytochrome P450 1A1 (CYP1A1) in Hepa1c1c7 cells (Abiko et al., 2015). In the current study, AhR activation, measured with a bioluminescence-based cell free assay, was induced by 1,2-naphthoquinone (1,2-NQ), a metabolite of naphthalene. Consistent with this, 1,4-benzoquinone (1,4-BQ), tert-butyl-1,4-BQ, and 1,4-NQ, as well as 1,2-NQ, all electrophilic mono-and bi-cyclic quinones, upregulated CYP1A1 mRNA and protein in HepG2 cells, whereas their parent aromatic hydrocarbons had little effect. Furthermore, immunofluorescence analysis confirmed that these quinones enhanced translocation of AhR to the nucleus.

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Section: Resultssupporting

confidence: 76%

Quinone-mediated induction of cytochrome P450 1A1 in HepG2 cells through increased interaction of aryl hydrocarbon receptor with aryl hydrocarbon receptor nuclear translocator

Abiko

Lin²,

Lee

et al. 2016

J. Toxicol. Sci.

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“…Collectively, these findings suggest that quinone-mediated induction of Cyp1a1 is not cell-specific. It is generally considered that efficient AhR ligands, such as TCDD, MC, and benzo[a]pyrene exhibit a high affinity for this transcription factor and thus cause a conformational change in AhR, leading to facilitation of its translocation into the nucleus in cells (Henry and Gasiewicz, 2003;Harper et al, 1991). In the present study, 1,4-BQ, TBQ, 1,2-NQ, and 1,4-NQ also translocated AhR into the nucleus and induced Cyp1a1 in Hepa1c1c7 cells, whereas benzene and naphthalene without electrophilic properties did not translocate AhR in the cells because of their poor ligand characteristics (Badham and Winn, 2007;Genter et al, 2006).…”

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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“…These assays were performed at a concentration of YH439 (10 M) in which the highest induction of target gene CYP1A1 has been identified (Lee et al, 1996), and the PAH/ HAH ligands were used at concentrations that are saturating for wt AhR (Harper et al, 1991;Okey et al, 1994). Therefore, we considered the possibility that H285Y was a weakly activatible mutant mAhR and that the activation we observed was simply due to a vast excess of YH439.…”

Section: Novel Mode Of Interaction For Ah Receptor Activator Yh439mentioning

confidence: 99%

Amino Acid Substitutions in the Aryl Hydrocarbon Receptor Ligand Binding Domain Reveal YH439 As an Atypical AhR Activator

Whelan¹,

Hao²,

Furness³

et al. 2010

Mol Pharmacol

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The aryl hydrocarbon receptor (AhR) is traditionally defined as a transcription factor activated by exogenous polyaromatic and halogenated aromatic hydrocarbon (PAH/HAH) ligands. Active AhR induces genes involved in xenobiotic metabolism, including cytochrome P4501A1, which function to metabolize activating ligands. However, recent studies implicate AhR in biological events that are apparently unrelated to the xenobiotic response, implying that endogenous activation mechanisms exist. Three AhR genes in zebrafish (Danio rerio) encode proteins that demonstrate differential activation in response to PAH/HAHs, with the nonresponsive drAhR1a having some sequence divergence from the PAH/HAH-responsive AhRs in the ligand binding domain (LBD). We used these differences to guide the mutagenesis of mouse AhR (mAhR), aiming to generate variants that functionally discriminate between activation mechanisms. We found substitution of histidine 285 in the LBD with tyrosine gave a receptor that could be activated by iso-, a potential AhR ligand chemically distinct from classic PAH/HAH-type ligands, but prevented activation by both exogenous PAH/HAH ligands and the endogenous activation mimics of suspension culture and application of shear-stressed serum. The differential response of H285Y mAhR to YH439 suggests that this activator has a novel mode of interaction that tolerates tyrosine at position 285 in the LBD and is distinct from the binding mode of the well characterized PAH/HAH ligands. In support of this, the PAHtype antagonist 3Ј,4Ј-dimethoxyflavone blocked mAhR activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin but not YH439. Furthermore, the strict correlation between response to exogenous PAH/HAH ligands and mimics of endogenous activation suggests that a PAH-type ligand may underpin endogenous mechanisms of activation.The aryl hydrocarbon receptor (AhR), also known as the dioxin receptor, is a basic helix-loop-helix-Per-aryl hydrocarbon receptor nuclear translocator (ARNT)-Sim transcription factor best characterized by activation in response to exogenous polyaromatic and halogenated aromatic hydrocarbon (PAH/HAH) type ligands. Latent AhR is bound by chaperones, which serve to present a ligand-accessible conformation of the ligand binding domain (LBD) and maintain cytoplasmic localization (Mitchell and Elferink, 2009). Xenobiotic PAH ligands such as 3-methylcholanthrene (3MC) and benzo[a]pyrene (B[a]P), and the prototypical HAH, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) bind to the AhR within the LBD, causing a conformational change that allows nuclear import and exchange of chaperones for the AhR partner ARNT. The AhR/ARNT heterodimer binds xenobiotic-response elements (XREs) in regulatory regions of target genes and associates with coactivators to initiate transcription (Kobayashi et al., 1997;Kumar et al., 1999). PAH activation

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Detection and characterization of the Ah receptor for 2,3,7,8-tetrachlorodibenzo-p-dioxin in the human colon adenocarcinoma cell line LS180

Cited by 83 publications

References 28 publications

Quinone-mediated induction of cytochrome P450 1A1 in HepG2 cells through increased interaction of aryl hydrocarbon receptor with aryl hydrocarbon receptor nuclear translocator

Quinone-mediated induction of cytochrome P450 1A1 in HepG2 cells through increased interaction of aryl hydrocarbon receptor with aryl hydrocarbon receptor nuclear translocator

Covalent binding of quinones activates the Ah receptor in Hepa1c1c7 cells

Amino Acid Substitutions in the Aryl Hydrocarbon Receptor Ligand Binding Domain Reveal YH439 As an Atypical AhR Activator

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