Leukotriene A4 Metabolites Are Endogenous Ligands for the Ah Receptor

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 A 4 (5,6-LTA 4) metabolites were identified in DRE-driven luciferase reporter assays as activators of AHR signaling. Various LTA 4 metabolites, including several 5,6- and 5,12-DiHETE products, were screened for AHR activity with 6- trans-LTB 4, 6- trans-12- epi-LTB 4, 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.