![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
TA Gasiewicz and G Rucci
Department of Biophysics, University of Rochester Medical Center, New York 14642.
alpha-Naphthoflavone (ANF) has previously been shown to compete with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for binding to the Ah receptor under conditions in vitro. However, ANF also prevents TCDD- elicited cytochrome P450lA1 induction, immunosuppression, and down- regulation of the estrogen receptor in vivo and within intact isolated cells. These data suggest that ANF is a TCDD antagonist. This study investigated the ability of ANF to transform the Ah receptor contained in rat hepatic cytosol or mouse hepatoma cells to a form that recognizes the dioxin-responsive enhancer element (DRE) upstream of the cytochrome P450lA1 gene. Gel retardation analysis indicated that TCDD- or beta-naphthoflavone (BNF)-bound receptor was able to bind to the DRE, whereas essentially no receptor-DRE complexes were observed using cytosol incubated with ANF concentrations as high as 1000 nM. Furthermore, an excess of ANF, when added to cytosol just before TCDD, blocked, in a concentration-dependent manner, the ability of TCDD to transform the receptor to a form that bound to the DRE. These studies indicated that ANF binds to the receptor and confers on it a conformation that cannot recognize the DNA recognition sequence contained in the DRE. Although an excess of the agonist 2,3,7,8- tetrachlorodibenzofuran (TCDF) readily reversed the inhibitory actions of ANF, ANF was unable to reverse the effects of TCDD, TCDF, or BNF on the receptor. These studies suggested that TCDD binding, unlike that of ANF, results in a receptor conformation that has higher affinity for the ligand. Treatment of mouse hepatoma Hepa 1c1c7 cells with TCDD or BNF resulted in receptor contained in nuclear extracts that bound to the DRE. Only a very minor ligand-dependent protein-DNA complex was detected when cells were treated with ANF. These data indicated that ANF acts as an antagonist of TCDD by directly binding to the Ah receptor and eliciting a protein conformation that has very low affinity for DNA.
This article has been cited by other articles:
|
|
 |
|
  M. Chang, K.-w. Peng, I. Kastrati, C. R. Overk, Z.-H. Qin, P. Yao, J. L. Bolton, and G. R. J. Thatcher Activation of Estrogen Receptor-Mediated Gene Transcription by the Equine Estrogen Metabolite, 4-Methoxyequilenin, in Human Breast Cancer Cells Endocrinology, October 1, 2007; 148(10): 4793 - 4802. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Billiard, A. R. Timme-Laragy, D. M. Wassenberg, C. Cockman, and R. T. Di Giulio The Role of the Aryl Hydrocarbon Receptor Pathway in Mediating Synergistic Developmental Toxicity of Polycyclic Aromatic Hydrocarbons to Zebrafish Toxicol. Sci., August 1, 2006; 92(2): 526 - 536. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. A. Bussmann, L. E. Bussmann, and J. L. Baranao An Aryl Hydrocarbon Receptor Agonist Amplifies the Mitogenic Actions of Estradiol in Granulosa Cells: Evidence of Involvement of the Cognate Receptors Biol Reprod, February 1, 2006; 74(2): 417 - 426. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Pocar, R. Augustin, and B. Fischer Constitutive Expression of CYP1A1 in Bovine Cumulus Oocyte-Complexes in Vitro: Mechanisms and Biological Implications Endocrinology, April 1, 2004; 145(4): 1594 - 1601. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-g. Zhou, E. C. Henry, C. M. Palermo, S. D. Dertinger, and T. A. Gasiewicz Species-Specific Transcriptional Activity of Synthetic Flavonoids in Guinea Pig and Mouse Cells as a Result of Differential Activation of the Aryl Hydrocarbon Receptor to Interact with Dioxin-Responsive Elements Mol. Pharmacol., April 1, 2003; 63(4): 915 - 924. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Raucy, L. Warfe, M.-F. Yueh, and S. W. Allen A Cell-Based Reporter Gene Assay for Determining Induction of CYP3A4 in a High-Volume System J. Pharmacol. Exp. Ther., October 1, 2002; 303(1): 412 - 423. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Dong, H. Teraoka, K. Yamazaki, S. Tsukiyama, S. Imani, T. Imagawa, J. J. Stegeman, R. E. Peterson, and T. Hiraga 2,3,7,8-Tetrachlorodibenzo-p-dioxin Toxicity in the Zebrafish Embryo: Local Circulation Failure in the Dorsal Midbrain Is Associated with Increased Apoptosis Toxicol. Sci., September 1, 2002; 69(1): 191 - 201. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Nazarenko, S. D. Dertinger, and T. A. Gasiewicz In Vivo Antagonism of AhR-Mediated Gene Induction by 3'-Methoxy-4'-nitroflavone in TCDD-Responsive lacZ Mice Toxicol. Sci., June 1, 2001; 61(2): 256 - 264. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-E. Lee and S. Safe 3',4'-Dimethoxyflavone as an Aryl Hydrocarbon Receptor Antagonist in Human Breast Cancer Cells Toxicol. Sci., December 1, 2000; 58(2): 235 - 242. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. W. Davis II, K. Melendez, V. M. Salas, F. T. Lauer, and S. W. Burchiel 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) inhibits growth factor withdrawal-induced apoptosis in the human mammary epithelial cell line, MCF-10A Carcinogenesis, May 1, 2000; 21(5): 881 - 886. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. D. Seidel, V. Li, G. M. Winter, W. J. Rogers, E. I. Martinez, and M. S. Denison Ah Receptor-Based Chemical Screening Bioassays: Application and Limitations for the Detection of Ah Receptor Agonists Toxicol. Sci., May 1, 2000; 55(1): 107 - 115. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Regulations and Advisories Toxicology and Industrial Health, April 1, 2000; 16(3-5): 173 - 201. [PDF]
|
|
|
|
|
|
M. H. Ziccardi, I. A. Gardner, and M. S. Denison Development and Modification of a Recombinant Cell Bioassay to Directly Detect Halogenated and Polycyclic Aromatic Hydrocarbons in Serum Toxicol. Sci., March 1, 2000; 54(1): 183 - 193. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. F. Casper, M. Quesne, I. M. Rogers, T. Shirota, A. Jolivet, E. Milgrom, and J.-F. Savouret Resveratrol Has Antagonist Activity on the Aryl Hydrocarbon Receptor: Implications for Prevention of Dioxin Toxicity Mol. Pharmacol., October 1, 1999; 56(4): 784 - 790. [Abstract] [Full Text]
|
|
|
|
 |
|
 Y. Tian, S. Ke, Michael. S. Denison, A. B. Rabson, and M. A. Gallo Ah Receptor and NF-kappa B Interactions, a Potential Mechanism for Dioxin Toxicity J. Biol. Chem., January 1, 1999; 274(1): 510 - 515. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-Y. C. a. A. Puga Constitutive Activation of the Aromatic Hydrocarbon Receptor Mol. Cell. Biol., January 1, 1998; 18(1): 525 - 535. [Abstract] [Full Text]
|
|
|
|
 |
|
 M Phillips, E Enan, P. Liu, and F Matsumura Inhibition of 3T3-L1 adipose differentiation by 2,3,7,8-tetrachlorodibenzo-p-dioxin J. Cell Sci., January 1, 1995; 108(1): 395 - 402. [Abstract] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
