Substituted flavones as aryl hydrocarbon (Ah) receptor agonists and antagonists

Lü, Yi; Santostefano, Michael J.; Cunningham, Bernadette; Threadgill, Michael D.; Safe, Stephen

doi:10.1016/0006-2952(96)00063-9

Cited by 73 publications

(54 citation statements)

References 39 publications

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“…To test this hypothesis, COS-1 cells were transfected with either pcDNA3/␤mAhR or pcDNA3/␤mAhR plus pCI/XAP2 at two different levels, followed by treatment with various concentrations of iodoflavone. Iodoflavone was chosen because it has intermediate affinity for the AhR (25). AhR transcriptional activity was assessed using a DRE-driven luciferase reporter.…”

Section: Xap2 Represses Mahr Transactivation Potential At Lowmentioning

confidence: 99%

The hsp90 Co-chaperone XAP2 Alters Importin β Recognition of the Bipartite Nuclear Localization Signal of the Ah Receptor and Represses Transcriptional Activity

Petrulis

Kusnadi

Ramadoss

et al. 2003

Journal of Biological Chemistry

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The mouse aryl hydrocarbon receptor (mAhR) is a ligand-activated transcription factor that exists in a tetrameric, core complex with a dimer of the 90-kDa heat shock protein, and the hepatitis B virus X-associated protein 2 (XAP2). Transiently expressed mAhR-YFP (yellow fluorescent protein fused with the mAhR) localizes throughout cells, with a majority occupying nuclei. Coexpression of XAP2 with mAhR-YFP results in a distinct redistribution to the cytoplasm. We have utilized several approaches to attempt to identify the mechanism by which XAP2 modulates the sub-cellular localization of the mAhR. The nuclear export inhibitor, leptomycin B, was used to demonstrate that XAP2 inhibits ligand-independent nucleocytoplasmic shuttling of the receptor. Results from cytoskeletal disruption and the addition of an alternate nuclear localization sequence (NLS) to mAhR-YFP suggest that XAP2 does not physically tether the complex in the cytoplasm. The use of a rabbit polyclonal antibody raised against a portion of the bipartite NLS of the mAhR revealed that XAP2 does not appear to block access to the NLS. However, XAP2 hinders importin ␤ binding to the mAhR complex, suggesting that XAP2 alters the conformation of the bipartite NLS of mAhR. XAP2 also represses the transactivation potential of the AhR, in contrast to previously published reports, perhaps by stabilizing the receptor complex and/or blocking nucleocytoplasmic shuttling of the AhR complex.

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Section: Xap2 Represses Mahr Transactivation Potential At Lowmentioning

confidence: 99%

The hsp90 Co-chaperone XAP2 Alters Importin β Recognition of the Bipartite Nuclear Localization Signal of the Ah Receptor and Represses Transcriptional Activity

Petrulis

Kusnadi

Ramadoss

et al. 2003

Journal of Biological Chemistry

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“…CYP1A1 and CYP1A2 protein expression and catalytic activities are induced in the liver and other tissues by some of those same substrates (Eaton et al, 1995). In particular, flavonoids have been reported to bind to the Ah receptor involved in CYP1A isoform induction, leading to increased synthesis of CYP1A1 and CYP1A2 (Huang et al, 1981;Lu et al, 1995Lu et al, , 1996. In addition, P450s are involved in enzymatic activation of a number of antitumor agents in the liver (e.g., cyclophosphamide, dacarbazine, and trans-retinoic acid), lending plausibility to the idea that a cytotoxic flavonoid might induce the P450s that metabolize it to active species.…”

Section: Af (mentioning

confidence: 99%

Activation of the Antitumor Agent Aminoflavone (NSC 686288) Is Mediated by Induction of Tumor Cell Cytochrome P450 1A1/1A2

et al. 2002

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The present studies were performed to elucidate the mechanism of cytotoxicity of the aminoflavone analog (5-amino-2,3-fluorophenyl)-6,8-difluoro-7-methyl-4H-1-benzopyran-4-one (AF; NSC 686288), a novel flavone with potent in vitro and in vivo antiproliferative activity against a number of human tumor cell lines and with a unique pattern of antiproliferative activity in the National Cancer Institute tumor cell line screen. AF was extensively metabolized by cytochrome P450 (P450) 1A1 and 1A2 to several metabolites, one of which was identified by mass spectrometry as a potentially reactive hydroxylamine. Radiolabeled AF was converted by rat and human microsomes, by recombinant CYP1A1 and CYP1A2, and by sensitive human tumor cell lines to species that covalently bound macromolecules. Treatment of sensitive human MCF7 cells with AF resulted in increased CYP1A1 mRNA and CYP1A1/1A2 protein followed by covalent binding of an AF metabolite to DNA, phosphorylation and stabilization of p53, and increased expression of the p53 transcriptional target p21. Covalent binding of the AF metabolite was increased by pretreatment with the CYP1A inducer 3-methylcholanthrene and decreased by coincubation with the CYP1A inhibitor ␣-naphthoflavone. In contrast, induction of CYP1A1 and covalent binding of the AF metabolite did not occur in AF-resistant M14-MEL cells. These observations suggest that AF is uniquely able to induce its own metabolic activation via CYP1A1/1A2 in duction to cytotoxic DNA-damaging species directly in tumor cells. AF, and possibly other agents, may offer a treatment strategy for tumors responsive to CYP1A1/1A2 induction, such as breast, ovarian, and renal cancers. AF (Fig.

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“…The cell context-and gene-specific AhR agonist and antagonist activities of the tryptophan metabolites are not unique and have been observed for other AhR ligands including 6-methyl-1,3,8-trichlorobenzofuran, flavonoids, and pharmaceuticals (Astroff et al, 1988;Lu et al, 1996;McDougal et al, 2001;Zhou and Gasiewicz, 2003;Jin et al, 2012;Safe et al, 2012). We also observed that the AhR antagonist CH inhibited Cyp1a1 induction by TCDD and the tryptophan metabolites, indicating that CH inhibited induction of Cyp1a1 by a diverse spectrum of AhR ligands, as previously reported elsewhere (Choi et al, 2012).…”

Section: Downloaded Frommentioning

confidence: 99%

Aryl Hydrocarbon Receptor Activity of Tryptophan Metabolites in Young Adult Mouse Colonocytes

et al. 2015

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The tryptophan microbiota metabolites indole-3-acetate, indole-3-aldehyde, indole, and tryptamine are aryl hydrocarbon receptor (AhR) ligands, and in this study we investigated their AhR agonist and antagonist activities in nontransformed young adult mouse colonocyte (YAMC) cells. Using Cyp1a1 mRNA as an Ah-responsive end point, we observed that the tryptophan metabolites were weak AhR agonists and partial antagonists in YAMC cells, and the pattern of activity was different from that previously observed in CaCo2 colon cancer cells. However, expansion of the end points to other Ah-responsive genes including the Cyp1b1, the AhR repressor (Ahrr), and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly(ADP-ribose) polymerase (TiParp) revealed a highly complex pattern of AhR agonist/antagonist activities that were both ligand-and genedependent. For example, the magnitude of induction of Cyp1b1 mRNA was similar for TCDD, tryptamine, and indole-3-acetate, whereas lower induction was observed for indole and indole-3-aldehyde was inactive. These results suggest that the tryptophan metabolites identified in microbiota are selective AhR modulators.

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Substituted flavones as aryl hydrocarbon (Ah) receptor agonists and antagonists

Cited by 73 publications

References 39 publications

The hsp90 Co-chaperone XAP2 Alters Importin β Recognition of the Bipartite Nuclear Localization Signal of the Ah Receptor and Represses Transcriptional Activity

The hsp90 Co-chaperone XAP2 Alters Importin β Recognition of the Bipartite Nuclear Localization Signal of the Ah Receptor and Represses Transcriptional Activity

Activation of the Antitumor Agent Aminoflavone (NSC 686288) Is Mediated by Induction of Tumor Cell Cytochrome P450 1A1/1A2

Aryl Hydrocarbon Receptor Activity of Tryptophan Metabolites in Young Adult Mouse Colonocytes

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