An evolutionary perspective on the conservation of endogenous Ah receptor activation

The aryl hydrocarbon receptor (AHR) senses environmental and physiological cues by responding to a wide range of chemicals, thereby mediating diverse physiological functions. There are four sources of AHR agonists: anthropogenic, microbial, dietary, and host origin. The structural diversity and potency of the chemicals that activate the AHR makes it difficult to discern key ligands that facilitate various activities. However, it is becoming increasingly clear that the primary source of microbial and host-mediated production of AHR agonists is through tryptophan metabolism. This review draws on evolutionary insights into the conservation of endogenous ligand potency to identify the primary drivers of physiological activation of the AHR. In various mouse strains, high- and low-affinity variants of AHR for polycyclic aromatic hydrocarbons (PAHs) exist due to a V375A substitution in the ligand-binding pocket. Phenotypically, there appears to be no known physiological consequence to this change. A comparison of the AHR sequence between hominids reveals that only homo sapiens harbors a valine residue at position 381 instead of an alanine (same residue as A375 in mouse), leading to lower affinity for PAHs, which is consistent with the concept of decreased toxicity mediated by smoke exposure. Endogenous polycyclic tryptophan metabolites such as 6-formylindolo[3,2-b]carbazole, although potent, exhibit ~10-fold lower activation potential for the human AHR compared to the mouse AHR. In contrast, enzymatic sources of tryptophan metabolism can produce kynurenine and certain bicyclic tryptophan metabolites which, although relatively weak activators, are systemically abundant and exhibit conservation of AHR activation potential across mammals, supporting the importance of these ligands to AHR function through mammalian evolution.