There is a wide variety of compounds with different chemical properties, structure, and binding affinities, which have been recognized as AHR ligands.Īmong the exogenous compounds, it may be referred environmental contaminants including the halogenated aromatic hydrocarbons (HAH), such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,7,8-tetrachlorodibenzofuran (TCDF), and 3,4,3′,4,′5-pentachlorobiphenyl (PCB), and the polycyclic aromatic hydrocarbons (PAH), such as benzopyrene (BP) and 3-methylcholanthrene (3-MC). This chaperone complex maintains the proper folding and assures the ligand-binding competency and, overall, the transcriptional effectiveness of AHR (reviewed by ).ĪHR ligands come from the environment and from the microbiota and cellular metabolism. In the present review, a brief introduction will be given to the AHR-CYP1A1 axis, but we would like to invite the reader to find more information about these druggable targets in the excellent reviews suggested throughout this introductory note.Īs a cytosolic protein, the AHR exists in an inactive state bound to the chaperones heat shock protein 90 (HSP90), HSP90-associated co-chaperone p23, AHR-interacting protein (AIP), also called hepatitis B virus X-associated protein 2 (XAP2), and tyrosine kinase c-Src. Other members of this family are the CLOCK-BMAL1 (key components of the circadian clock), the hypoxia-inducible factors (HIFs), and the aryl hydrocarbon receptor translocator (ARNT, also named HIF-1β), and interesting evidence on the cross-play among them have been reported (reviewed by ). The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that belongs to the basic helix-loop-helix/Per-Arnt-Sim (bHLH/PAS) family with important functions in sensing and incorporating environmental and outer stimuli (light–dark, O 2 alterations, xenobiotic exposure, and microbiota metabolites) into cellular adaptive responses (reviewed by ). Moreover, it is a timely opportunity as the first AHR antagonists have recently entered the clinical stage of drug development. This review will serve as a road map for those researchers embracing this emerging therapeutic area targeting the AHR. In this review, we cover the state-of-the-art of the pharmacodynamic and pharmacokinetic properties of AHR antagonists and CYP1A1 inhibitors in different in vivo rodent (mouse or rat) models of disease. However, most of the evidence on the pharmacological abrogation of the AHR-CYP1A1 axis has been reported in vitro, and therefore, guidance for in vivo studies is needed. Expanding evidence has been shown that the modulation of the canonical pathway of AHR occurs during several chronic diseases and that its abrogation might be of clinical interest for metabolic and inflammatory pathological processes. These results clearly suggest that rutaecarpine increases the metabolism of caffeine, theophylline, theobromine, and paraxanthine by inducing CYP1A2 and CYP2E1 in rats.The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that can be activated by structurally diverse compounds arising from the environment and the microbiota and host metabolism. The significant induction of ethoxyresorufin O-deethylase, pentoxyresorufin O-depentylase, and p-nitrophenol hydroxylase strongly supported the decrease in caffeine and its major metabolites in plasma, as well as in urine. The areas under the curve of both caffeine and its three major metabolites (paraxanthine, theophylline, and theobromine) were significantly reduced by rutaecarpine, indicating that caffeine was rapidly converted into the desmethylated metabolites, and that those were also quickly transformed into further metabolites via the hydroxyl metabolites due to the remarkable induction of CYP1A2 and 2E1. Plasma and urine were collected serially for up to 24 h and the plasma and urine concentrations of caffeine and its metabolites were measured, and compared with those in control rats. Following oral administration of 80 mg/kg rutaecarpine for three consecutive days, caffeine (20 mg/kg) was given orally. We investigated the microsomal enzyme activity using hepatic S-9 fraction and the plasma concentration-time profiles and urinary excretion of caffeine and its major metabolites after an oral administration of caffeine in the presence and absence of rutaecarpine in rats. Although rutaecarpine, an alkaloid originally isolated from the unripe fruit of Evodia rutaecarpa, has been reported to reduce the systemic exposure of caffeine, the mechanism of this phenomenon is unclear.
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