![[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}
|
|
|
|
|
||
AB Okey, LM Vella and PA Harper
Department of Pediatrics, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
Ah "nonresponsive" mice (prototype, DBA/2) show no significant increase in hepatic P1-450 (P450IA1) when treated with 3-methylcholanthrene or other nonhalogenated polycyclic aromatic hydrocarbons. Potent halogenated aromatics such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induce P1-450 in liver of nonresponsive mice, but the dose required is approximately 15-fold higher than in "responsive" mice (prototype, C57BL/6). It was postulated several years ago that the genetic basis of nonresponsiveness was a "defect" in the Ah receptor, which normally binds TCDD and other inducers and mediates the induction process. Cytosolic Ah receptor hitherto had not been detectable in hepatic cytosol from nonresponsive mice. Using a modified sucrose gradient assay that we developed in studies on human tissue [Cancer Res. 47:4861-4868 (1987)], we now have detected cytosolic Ah receptor in nonresponsive mice. By saturation analysis, the concentration of specific binding sites for [3H]TCDD in hepatic cytosol from DBA/2J mice was (mean +/- SE) 55 +/- 6.6 fmol/mg of cytosolic protein (n = 21) compared with 133 +/- 7.1 fmol/mg (n = 21) in responsive C57BL/6J mice. Ah receptor also was detected in significant concentrations in other nonresponsive strains; SWR/J, AKR/J, RF/J, and DBA/2N. The sedimentation coefficient on sucrose gradients was the same (approximately 9 S) in nonresponsive as in responsive strains. The major difference in nonresponsive mice is that hepatic cytosolic Ah receptor has an apparent affinity for [3H]TCDD that is about 10-fold lower than in responsive strains; Kd in DBA/2J mice = 16 +/- 2.5 nM (n = 21) and Kd in C57BL/6J mice = 1.8 +/- 0.2 nM (n = 21). Thus, nonresponsive mice do possess the cytosolic Ah receptor in liver. However, the receptor is present in reduced concentration and appears to be a low affinity form, possibly as the result of a mutation in the gene(s) coding for the receptor protein(s).
This article has been cited by other articles:
|
|
 |
|
  A. K. Kopec, D. R. Boverhof, L. D. Burgoon, D. Ibrahim-Aibo, J. R. Harkema, C. Tashiro, B. Chittim, and T. R. Zacharewski Comparative Toxicogenomic Examination of the Hepatic Effects of PCB126 and TCDD in Immature, Ovariectomized C57BL/6 Mice Toxicol. Sci., March 1, 2008; 102(1): 61 - 75. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Yasui, E.-Y. Kim, H. Iwata, D. G. Franks, S. I. Karchner, M. E. Hahn, and S. Tanabe Functional Characterization and Evolutionary History of Two Aryl Hydrocarbon Receptor Isoforms (AhR1 and AhR2) from Avian Species Toxicol. Sci., September 1, 2007; 99(1): 101 - 117. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. B. Okey An Aryl Hydrocarbon Receptor Odyssey to the Shores of Toxicology: The Deichmann Lecture, International Congress of Toxicology-XI Toxicol. Sci., July 1, 2007; 98(1): 5 - 38. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Ma and A. Y. H. Lu CYP1A Induction and Human Risk Assessment: An Evolving Tale of in Vitro and in Vivo Studies Drug Metab. Dispos., July 1, 2007; 35(7): 1009 - 1016. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. R. Boverhof, L. D. Burgoon, C. Tashiro, B. Sharratt, B. Chittim, J. R. Harkema, D. L. Mendrick, and T. R. Zacharewski Comparative Toxicogenomic Analysis of the Hepatotoxic Effects of TCDD in Sprague Dawley Rats and C57BL/6 Mice Toxicol. Sci., December 1, 2006; 94(2): 398 - 416. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. I. Karchner, D. G. Franks, S. W. Kennedy, and M. E. Hahn The molecular basis for differential dioxin sensitivity in birds: Role of the aryl hydrocarbon receptor PNAS, April 18, 2006; 103(16): 6252 - 6257. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. R. Boverhof, L. D. Burgoon, C. Tashiro, B. Chittim, J. R. Harkema, D. B. Jump, and T. R. Zacharewski Temporal and Dose-Dependent Hepatic Gene Expression Patterns in Mice Provide New Insights into TCDD-Mediated Hepatotoxicity Toxicol. Sci., June 1, 2005; 85(2): 1048 - 1063. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Tang, J. H. Lin, and A. Y. H. Lu METABOLISM-BASED DRUG-DRUG INTERACTIONS: WHAT DETERMINES INDIVIDUAL VARIABILITY IN CYTOCHROME P450 INDUCTION? Drug Metab. Dispos., May 1, 2005; 33(5): 603 - 613. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Zhang, B. Moorthy, M. Chen, K. Muthiah, R. Coffee, A. F. Purchio, and D. B. West A Cyp1a2-Luciferase Transgenic CD-1 Mouse Model: Responses to Aryl Hydrocarbons Similar to the Humanized AhR Mice Toxicol. Sci., November 1, 2004; 82(1): 297 - 307. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. V. Sun, D. R. Boverhof, L. D. Burgoon, M. R. Fielden, and T. R. Zacharewski Comparative analysis of dioxin response elements in human, mouse and rat genomic sequences Nucleic Acids Res., August 24, 2004; 32(15): 4512 - 4523. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Moriguchi, H. Motohashi, T. Hosoya, O. Nakajima, S. Takahashi, S. Ohsako, Y. Aoki, N. Nishimura, C. Tohyama, Y. Fujii-Kuriyama, et al. Distinct response to dioxin in an arylhydrocarbon receptor (AHR)-humanized mouse PNAS, May 13, 2003; 100(10): 5652 - 5657. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. K. Bunger, S. M. Moran, E. Glover, T. L. Thomae, G. P. Lahvis, B. C. Lin, and C. A. Bradfield Resistance to 2,3,7,8-Tetrachlorodibenzo-p-dioxin Toxicity and Abnormal Liver Development in Mice Carrying a Mutation in the Nuclear Localization Sequence of the Aryl Hydrocarbon Receptor J. Biol. Chem., May 9, 2003; 278(20): 17767 - 17774. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. A. Jensen and M. E. Hahn cDNA Cloning and Characterization of a High Affinity Aryl Hydrocarbon Receptor in a Cetacean, the Beluga, Delphinapterus leucas Toxicol. Sci., November 1, 2001; 64(1): 41 - 56. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Fletcher, A. Hanberg, and H. Hakansson Hepatic Vitamin A Depletion Is a Sensitive Marker of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Exposure in Four Rodent Species Toxicol. Sci., July 1, 2001; 62(1): 166 - 175. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Bello, D. G. Franks, J. J. Stegeman, and M. E. Hahn Acquired Resistance to Ah Receptor Agonists in a Population of Atlantic Killifish (Fundulus heteroclitus) Inhabiting a Marine Superfund Site: In Vivo and in Vitro Studies on the Inducibility of Xenobiotic Metabolizing Enzymes Toxicol. Sci., March 1, 2001; 60(1): 77 - 91. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Regulations and Advisories Toxicology and Industrial Health, April 1, 2000; 16(3-5): 173 - 201. [PDF]
|
|
|
|
 |
|
 R. Pohjanvirta, J. M. Y. Wong, W. Li, P. A. Harper, J. Tuomisto, and A. B. Okey Point Mutation in Intron Sequence Causes Altered Carboxyl-Terminal Structure in the Aryl Hydrocarbon Receptor of the Most 2,3,7,8-Tetrachlorodibenzo-p-dioxin-Resistant Rat Strain Mol. Pharmacol., July 1, 1998; 54(1): 86 - 93. [Abstract] [Full Text]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 T. E. Gram Chemically Reactive Intermediates and Pulmonary Xenobiotic Toxicity Pharmacol. Rev., December 1, 1997; 49(4): 297 - 342. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
