Fifty Years of Aryl Hydrocarbon Receptor Research as Reflected in the Pages ofDrug Metabolism and Disposition

Abstract

The induction of multiple drug-metabolizing enzymes by halogenated and polycyclic aromatic hydrocarbon toxicants is mediated by the aryl hydrocarbons receptor (AHR). This fascinating receptor also has natural dietary and endogenous ligands, and much is now appreciated about the AHR's developmental and physiological roles, as well as its importance in cancer and other diseases. The past several years has witnessed increasing emphasis on understanding the multifaceted roles of the AHR in the immune system. Most would agree that the "discovery" of the AHR occurred in 1976, with the report of specific binding of a high affinity radioligand in mouse liver, just three years after the launch of the journal Drug Metabolism and Disposition (DMD) in 1973. Over the ensuing fifty years, the AHR and DMD have led parallel and often intersecting lives. The overall goal of this minireview is to provide a decade-by-decade overview of major historical landmark discoveries in the AHR field and to highlight the numerous contributions made by publications appearing in the pages of DMD. It is hoped that this historical tour might inspire current and future research in the AHR field. Significance Statement With the launch of Drug Metabolism and Disposition (DMD) in 1973 and the discovery of the aryl hydrocarbon receptor (AHR) in 1976, the journal and the receptor have led parallel and often intersecting lives over the past fifty years. Tracing the history of the AHR can reveal how knowledge in the field has evolved to the present and highlight the important contributions made by discoveries reported in DMD. This may inspire additional DMD papers reporting future AHR landmark discoveries.

A Review of CYP-Mediated Drug Interactions: Mechanisms and In Vitro Drug-Drug Interaction Assessment

“…Extensive studies in the past two decades have identified many natural dietary and endogenous ligands of AhR and unmasked various physiological functions in normal development and homeostasis [144][145][146]. However, most AhR ligands are toxic xenobiotics, including halogenated aromatic hydrocarbons and polycyclic aromatic hydrocarbons [134,145]. In addition, AhR binds with several pharmaceuticals that are used clinically for multiple disorders [147].…”

Investigating the Aryl Hydrocarbon Receptor Agonist/Antagonist Conformational Switch Using Well-Tempered Metadynamics Simulations

“…Members of the animal kingdom have grown distinctive protein sensors that enable them to acclimatize to the surrounding environment, such as the aryl hydrocarbon receptor (AhR). 1,2 AhR belongs to the basic helix−loop− helix(bHLH) PER-ARNT-SIM(PAS) family, which is composed of bHLH, PAS-A, PAS-B, and transactivation domains. 3−5 It is a ligand-activated transcription factor that integrates biological and metabolic inputs to control sophisticated cellular reactions, cell cycle regulations, and the immune system.…”

“…Members of the animal kingdom have grown distinctive protein sensors that enable them to acclimatize to the surrounding environment, such as the aryl hydrocarbon receptor (AhR). , AhR belongs to the basic helix–loop–helix­(bHLH) PER-ARNT-SIM­(PAS) family, which is composed of bHLH, PAS-A, PAS-B, and transactivation domains. − It is a ligand-activated transcription factor that integrates biological and metabolic inputs to control sophisticated cellular reactions, cell cycle regulations, and the immune system. Upon activation, AhR regulates the expression of several genes, such as cytochrome P450 (CYP) family genes, including CYP1A1, CYP1A2, and CYP1B1, that contribute to xenobiotic metabolism-related functions. − This ongoing stimulation of AhR by xenobiotics and environmental pollutants can lead to toxic consequences .…”

“…Subsequently, accumulating experimental evidence has proved that AhR is involved in pathophysiological functions in various diseases, including tumor growth, cardiovascular disease, diabetes, obesity, and viral infection. − Several chemical structures, including polycyclic aromatic hydrocarbon (PAHs) compounds from endogenous substances like indole derivatives and exogenous dioxin (2,3,7,8-tetrachlorodibenzo- p -dioxin known as TCDD), bind with a strong affinity to the AhR PAS-B domain. These binding reactions trigger AhR signaling pathways to function as AhR ligands. , In the cytoplasm, AhR is present in an inactive complex with its protein partners, including heat shock protein 90 (HSP90), cochaperone-like X-associated protein (XAP2), and p23. As soon as an AhR ligand binds to the AhR PAS-B domain, AhR undergoes structural changes in various regions that enhance ligand access to the binding pocket in the PAS-B domain.…”

“…These binding reactions trigger AhR signaling pathways to function as AhR ligands. 2,16 In the cytoplasm, AhR is present in an inactive complex with its protein partners, including heat shock protein 90 (HSP90), cochaperone-like Xassociated protein (XAP2), and p23. As soon as an AhR ligand binds to the AhR PAS-B domain, AhR undergoes structural changes in various regions that enhance ligand access to the binding pocket in the PAS-B domain.…”