The human aryl hydrocarbon receptor (AHR) was cloned in 1993 [Article:8246913]. AHR was found to be 848 amino acids long [Article:8246913], and to show some regional conservation to the murine AHR [Article:8408082]. The AHR protein contains several structurally-recognized motifs including: a basic helix-loop-helix (bHLH) sequence, a nuclear localization sequence, a Per-ARNT-Sim (PAS) domain, a nuclear export signal (NES), and a transactivation domain (TAD) [Articles:15581594, 16153594, 17481570]. AHR was originally of interest due to its role in inducing the transcription of genes involved in xenobiotic metabolism, although recent work, particularly in model organisms, has suggested that AHR may have endogenous roles as well [Article:17535977].
The inactive form of AHR is associated with a protein complex in the cytoplasm [Articles:16780804, 17266942, 17535977]. The protein complex consists of inactive AHR, two Hsp90 subunits, p23, and ARA9 [Article:16780804]. This complex is activated by the binding of a xenobiotic ligand to AHR. The activated complex then migrates out of the cytoplasm and into the nucleus [Articles:16780804, 17266942, 17535977]. Once the complex has relocated to the nucleus, AHR dissociates from the complex and forms a heterodimer with ARNT [Articles:16780804, 17266942, 17535977]. Together, these two proteins form a complex that recognizes a Xenobiotic Response Element (XRE), also called a Dioxin Response Element (DRE) [Articles:16780804, 17266942, 17535977]. The consensus sequence of this response element is TNGCGTG [Article:16780804]. The complex binds the response element and drives the transcription of its target genes. Genes that are under transcriptional regulation from the AHR/ARNT heterodimer include: CYP1A1, CYP1A2, CYP1B1, NQO1, GSTA2, UGT1A1, UGT1A6, and Nrf2 (NFE2L2) [Articles:16780804, 17481570].
AHR recognizes the presence of xenobiotics in the cytoplasm, and then acts to induce metabolic genes to facilitate the elimination of the foreign compounds [Article:17481570]. AHR recognizes planar aromatic hydrocarbons as its substrates [Article:12213382]. Frequently used model compounds include 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 3-methylcholanthrene (MC) [Article:17481570]. Chemicals that activate AHR can be found in various consumable vegetables such as cabbage, broccoli, and cauliflower [Article:16780804].
The role of AHR in regulating genes for xenobiotic metabolism is considered to be an adaptive function. Studies in model organisms suggest that orthologs of AHR are involved in growth and development [Articles:950178, 9573046, 8589437, 17535977]. Several different laboratories have generated AHR knockout mice [Articles:7732381, 9427285, 8692887]. Although these mice are viable, they do have some abnormalities including a decreased liver size, lower fecundity, and portal fibrosis; this further supports a role for AHR beyond xenobiotic metabolism [Articles:7732381, 9427285, 8692887, 17353977]. Additionally, AHR knockout mice are resistant to TCDD toxicities [Articles:7732381, 9427285, 8692887, 17353977]. The physiological role of AHR in humans has not been well studied, and is to this point poorly understood.
M. Whirl-Carrillo, E.M. McDonagh, J. M. Hebert, L. Gong, K. Sangkuhl, C.F. Thorn, R.B. Altman and T.E. Klein. "Pharmacogenomics Knowledge for Personalized Medicine" Clinical Pharmacology & Therapeutics (2012) 92(4): 414-417. Full text
Submitted by Ryan Owen