Leukotriene A4 metabolites are endogenous ligands for the Ah receptor

Christopher R. Chiaro, J. Luis Morales, Kumble Sandeep Prabhu, Gary H. Perdew

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

In addition to orchestrating an adaptive metabolic response to xenobiotic compounds, the aryl hydrocarbon receptor (AHR) also plays a necessary role in the normal physiology of mice. The AHR is activated by a structurally diverse group of chemicals ranging from carcinogenic environmental pollutants to dietary metabolites and a number of endogenous molecules. Leukotriene A4 (5,6-LTA4) metabolites were identified in DRE-driven luciferase reporter assays as activators of AHR signaling. Various LTA4 metabolites, including several 5,6- and 5,12-DiHETE products, were screened for AHR activity with 6-trans-LTB4, 6-trans-12-epi-LTB4, 5(S),6(S)-DiHETE, and 5(S),6(R)-DiHETE eliciting a significant level of AHR transcriptional activity. However, electrophoretic mobility shift assays (EMSAs) revealed that only 5,6-DiHETE isomers were capable of directly binding and activating the AHR to a DNA-binding species in vitro. Furthermore, ligand competition binding experiments confirm the ability of these compounds to directly bind to the AHR. Interestingly, "aged" preparations of 5,6-DiHETE isomers produced an enhanced level of AHR activation while demonstrating an increase in binding affinity for the receptor. Although the reason for this has not been fully determined, the formation of geometric isomers in the conjugated triene region of these molecules may play a role in the observed increase in AHR-mediated transcriptional activity. This work suggests a connection between AHR activation and inflammatory signaling molecules produced by the 5-lipoxygenase pathway.

Original languageEnglish (US)
Pages (from-to)8445-8455
Number of pages11
JournalBiochemistry
Volume47
Issue number32
DOIs
StatePublished - Aug 12 2008

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Leukotriene A4
Aryl Hydrocarbon Receptors
Metabolites
Ligands
Isomers
Leukotriene B4
Molecules
Assays
Chemical activation
Arachidonate 5-Lipoxygenase
Environmental Pollutants
Electrophoretic mobility
Physiology
Electrophoretic Mobility Shift Assay
Xenobiotics
Luciferases

All Science Journal Classification (ASJC) codes

  • Biochemistry

Cite this

Chiaro, Christopher R. ; Morales, J. Luis ; Prabhu, Kumble Sandeep ; Perdew, Gary H. / Leukotriene A4 metabolites are endogenous ligands for the Ah receptor. In: Biochemistry. 2008 ; Vol. 47, No. 32. pp. 8445-8455.
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Leukotriene A4 metabolites are endogenous ligands for the Ah receptor. / Chiaro, Christopher R.; Morales, J. Luis; Prabhu, Kumble Sandeep; Perdew, Gary H.

In: Biochemistry, Vol. 47, No. 32, 12.08.2008, p. 8445-8455.

Research output: Contribution to journalArticle

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