A schematic diagram of some AHR signaling pathways. The canonical pathway is depicted with solid black arrows, alternative pathways with dashed arrows, and an intersection of these two with a solid red arrow. The green bars represent the AHR, red bars ARNT, yellow bars ARA9 (AIP, Xap2), blue bars HSP90 and the blue ovals p23.<unk>  binding to the AHR (1.) leads to its translocation into the nucleus by importin-β, (2.) heterodimerization with ARNT and binding to the DNA at DREs, (3.) modulating expression levels of target genes (green arrows). One of the gene products elevated by this mechanism is AHRR, a repressor protein which forms a feedback loop that inhibits AHR action. The AHR is finally degraded by the ubiquitin–proteasome system (4.). AHR activation can also rapidly increase intracellular Ca2+ concentration (5.) which in turn may ultimately result in augmented Cox2 gene expression. Elevation of Ca2+ activates CaMKs, which appear to have a critical role in the translocation of the AHR. Another example of effects mediated by the AHR via non-canonical pathways is suppression of acute-phase proteins (6.) which does not involve DNA binding. (simplified and modified from Lindén et al.) The AH receptor is an ancient receptor, and its many functions have been revealed only recently. It is an over 600 million year old protein occurring in all vertebrates, and its homologs have been discovered in invertebrates and insects. It belongs to basic Helix–Loop–Helix-PAS proteins and acts as a transcription factor modifying transcription of a number of genes (see figure). AH receptor activity is necessary for normal development and many physiological functions. Mice lacking the AH receptor (knockouts) are sick with cardiac hypertrophy, liver fibrosis, reproductive problems, and impaired immunology. The AH receptor is relevant in toxicology for two very different reasons. First, it induces several enzymes important in the metabolism of foreign substances, so called xenobiotics. These include both oxidative phase I enzymes and conjugative phase II enzymes, e.g. CYP1A2, CYP1B1, CYP2S1, CYP2A5, ALDH3, GSTA1, UGT1A1, UGT1A6, UGT1A7 and NQO1. This is in essence a protective function preventing toxic or carcinogenic effects of xenobiotics, but in some conditions it may also result in the production of reactive metabolites that are mutagenic and carcinogenic. This enzyme induction can be initiated by many natural or synthetic<unk> , e.g., carcinogenic polycyclic hydrocarbons such as benzo(a)pyrene, several natural<unk> , and<unk> s. Secondly, AH receptors are involved in the activation or silencing of genes that lead to the toxic effects of high doses of<unk> s. Because TCDD at high doses can influence the transcription of perhaps hundreds of genes, the genes crucial for the multitude of toxic effects of<unk> s are still not known very well. Binding of<unk> -like<unk>  to the AH receptor has made it possible to measure total<unk> -like activity of a sample using CALUX (Chemical Activated LUciferase gene eXpression) bioassay. The results have been comparable to TEQ levels measured by much more expensive gas chromatography-high resolution mass spectrometry in environmental samples.
Dioxins and dioxin-like compounds
Polychlorinated naphthalene
Polychlorinated dibenzodioxins
Organobromine compound
Organochlorine compound
Polycyclic aromatic hydrocarbon
Loline alkaloid
Polychlorinated dibenzofurans