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
Y1 - 2009
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 -