Transgenic humanized AHR mouse reveals differences between human and mouse AHR ligand selectivity

Colin A. Flaveny, Gary H. Perdew

Research output: Contribution to journalComment/debate

27 Citations (Scopus)

Abstract

The Aryl-hydrocarbon receptor (AHR) is a ligand activated transcription factor involved in xenobiotic metabolism. Most of the toxic effects of halogenated and non-halogenated polycyclic aromatic hydrocarbons (HAHs and PAHs respectively) are mediated by the AHR. For the AHR, a number of intra and interspecies differences exist in terms of responsiveness to the prototypical AHR ligand 2,3,7,8-tetrachlorodibenzop-dioxin (TCDD). Interspecies differences in AHR ligand binding affinity has been shown to be linked to contrasting TCDD tolerance between species and among inbred strains of mice expressing different AHR alleles. Compared to the human AHR (hAHR), the mouse AHRb (mAHRb) has a ∼10 fold higher affinity for typical AHR ligands. Using a transgenic humanized mouse model that expresses hAHR protein specifically in the liver, we have discovered that for certain ligands, such as indirubin, the hAHR exhibits higher relative ligand binding affinity and responsiveness compared to the mAHRb. These findings may potentially influence the ongoing search for endogenous hAHR ligands and expand our understanding of the unique physiological role of the hAHR.

Original languageEnglish (US)
Pages (from-to)119-123
Number of pages5
JournalMolecular and Cellular Pharmacology
Volume1
Issue number3
DOIs
StatePublished - Dec 1 2009

Fingerprint

Aryl Hydrocarbon Receptors
Ligands
Dioxins
Inbred Strains Mice
Poisons
Polycyclic Aromatic Hydrocarbons
Xenobiotics
human AHR protein
Mouse Ahr protein
Transgenic Mice
Transcription Factors
Alleles
Liver

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Pharmaceutical Science

Cite this

@article{09a50fad22934bd183a9ca0a1f2fd234,
title = "Transgenic humanized AHR mouse reveals differences between human and mouse AHR ligand selectivity",
abstract = "The Aryl-hydrocarbon receptor (AHR) is a ligand activated transcription factor involved in xenobiotic metabolism. Most of the toxic effects of halogenated and non-halogenated polycyclic aromatic hydrocarbons (HAHs and PAHs respectively) are mediated by the AHR. For the AHR, a number of intra and interspecies differences exist in terms of responsiveness to the prototypical AHR ligand 2,3,7,8-tetrachlorodibenzop-dioxin (TCDD). Interspecies differences in AHR ligand binding affinity has been shown to be linked to contrasting TCDD tolerance between species and among inbred strains of mice expressing different AHR alleles. Compared to the human AHR (hAHR), the mouse AHRb (mAHRb) has a ∼10 fold higher affinity for typical AHR ligands. Using a transgenic humanized mouse model that expresses hAHR protein specifically in the liver, we have discovered that for certain ligands, such as indirubin, the hAHR exhibits higher relative ligand binding affinity and responsiveness compared to the mAHRb. These findings may potentially influence the ongoing search for endogenous hAHR ligands and expand our understanding of the unique physiological role of the hAHR.",
author = "Flaveny, {Colin A.} and Perdew, {Gary H.}",
year = "2009",
month = "12",
day = "1",
doi = "10.4255/mcpharmacol.09.15",
language = "English (US)",
volume = "1",
pages = "119--123",
journal = "Molecular and Cellular Pharmacology",
issn = "1938-1247",
publisher = "Lumitext Publishing",
number = "3",

}

Transgenic humanized AHR mouse reveals differences between human and mouse AHR ligand selectivity. / Flaveny, Colin A.; Perdew, Gary H.

In: Molecular and Cellular Pharmacology, Vol. 1, No. 3, 01.12.2009, p. 119-123.

Research output: Contribution to journalComment/debate

TY - JOUR

T1 - Transgenic humanized AHR mouse reveals differences between human and mouse AHR ligand selectivity

AU - Flaveny, Colin A.

AU - Perdew, Gary H.

PY - 2009/12/1

Y1 - 2009/12/1

N2 - The Aryl-hydrocarbon receptor (AHR) is a ligand activated transcription factor involved in xenobiotic metabolism. Most of the toxic effects of halogenated and non-halogenated polycyclic aromatic hydrocarbons (HAHs and PAHs respectively) are mediated by the AHR. For the AHR, a number of intra and interspecies differences exist in terms of responsiveness to the prototypical AHR ligand 2,3,7,8-tetrachlorodibenzop-dioxin (TCDD). Interspecies differences in AHR ligand binding affinity has been shown to be linked to contrasting TCDD tolerance between species and among inbred strains of mice expressing different AHR alleles. Compared to the human AHR (hAHR), the mouse AHRb (mAHRb) has a ∼10 fold higher affinity for typical AHR ligands. Using a transgenic humanized mouse model that expresses hAHR protein specifically in the liver, we have discovered that for certain ligands, such as indirubin, the hAHR exhibits higher relative ligand binding affinity and responsiveness compared to the mAHRb. These findings may potentially influence the ongoing search for endogenous hAHR ligands and expand our understanding of the unique physiological role of the hAHR.

AB - The Aryl-hydrocarbon receptor (AHR) is a ligand activated transcription factor involved in xenobiotic metabolism. Most of the toxic effects of halogenated and non-halogenated polycyclic aromatic hydrocarbons (HAHs and PAHs respectively) are mediated by the AHR. For the AHR, a number of intra and interspecies differences exist in terms of responsiveness to the prototypical AHR ligand 2,3,7,8-tetrachlorodibenzop-dioxin (TCDD). Interspecies differences in AHR ligand binding affinity has been shown to be linked to contrasting TCDD tolerance between species and among inbred strains of mice expressing different AHR alleles. Compared to the human AHR (hAHR), the mouse AHRb (mAHRb) has a ∼10 fold higher affinity for typical AHR ligands. Using a transgenic humanized mouse model that expresses hAHR protein specifically in the liver, we have discovered that for certain ligands, such as indirubin, the hAHR exhibits higher relative ligand binding affinity and responsiveness compared to the mAHRb. These findings may potentially influence the ongoing search for endogenous hAHR ligands and expand our understanding of the unique physiological role of the hAHR.

UR - http://www.scopus.com/inward/record.url?scp=77953376096&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77953376096&partnerID=8YFLogxK

U2 - 10.4255/mcpharmacol.09.15

DO - 10.4255/mcpharmacol.09.15

M3 - Comment/debate

AN - SCOPUS:77953376096

VL - 1

SP - 119

EP - 123

JO - Molecular and Cellular Pharmacology

JF - Molecular and Cellular Pharmacology

SN - 1938-1247

IS - 3

ER -