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

Colin A. Flaveny, Gary H. Perdew

Research output: Contribution to journalComment/debatepeer-review

29 Scopus citations

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 - 2009

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Pharmaceutical Science

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