AhR-receptor

Polychlorinated hydrocarbons, such as polychlorinated dibenzodioxins, dibenzofurans, and biphenyls exist as a number of different congeners. Some of these are geometric isomers. Many cause a range of toxic effects that are believed to be mediated by interaction with the aryl hydrocarbon receptor (AhR) (they are known as pleiotropic effects). However, not all the isomers cause these effects because they do not all interact with the AhR receptor. To interact with this receptor, the molecule needs to be flat (planar). It can be seen in the diagram (Fig. 5.2)... 

Figure 5.2 The structures of 2,2, 3,3, 6,6 -hexachlorobiphenyl and the geometric isomer 3,3, 4,4, 5,5 -hexachlorobiphenyl. This shows that only one isomer, which is planar, can interact with the AhR receptor.

Different strains of mice exhibit different susceptibilities to TCDD (dioxin) and other polycyclic hydrocarbons. Thus the C57B1 6 mouse is more responsive to substances such as TCCD and 3-methylcholanthrene, which interact with the AhR receptor and induce enzymes such as CYP1A1, whereas the DBA/2 mouse is less responsive. This has been found to be inherited as an autosomal dominant trait. The nonresponsive allele Ahd expresses a protein with diminished affinity for binding ligands such as TCDD. 

A particularly potent immunosuppressive chemical is TCDD, dioxin. This inhibits the differentiation of T cells by damaging the epithelial cells in the cortex of the thymus. These cells are involved in the maturation of T cells. A receptor is involved with this toxic effect, the AHR receptor, to which TCDD binds very strongly. The receptor is expressed in the thymus. Mice, which to do not express this receptor, do not show this particular toxic effect of TCDD even at 10 times higher doses. 

AhR-mediated activity results Dioxin-like activity is a useful marker of compounds that are able to activate the AhR receptor, which had been shown to be involved in numerous health effects such as impairment of immunity and nervous system or reproduction (Mukeijee 1998). There have been several studies describing AhR-mediated effects of the PMi (Wenger et al. 2009) and PMio (Clemons et al. 1998 Ciganek et al. 2004 Brown et al. 2005) aerosol size fractions. The TEQ calculated from the data of 28 PAHs (25 parent PAHs, retene, biphenyl and triphenylene) represents by average 7.5 and 95% of the dioxin-like activity associated with the particulate and gaseous fractions, respectively. Most of the activity could be produced by dioxins and furans, but also by partly oxygenated PAHs, such as polycyclic aromatic ketones and quinones that were also shown to activate AhR and to be produced by combustion pollution sources (Misaki et al. 2007). The results, furthermore, confirm that a significant portion of the AhR-mediated activity was produced by compounds present in the gas-phase at many polluted localities as it have been shown previously (Klein et al. 2006 Novak et al. 2009). 

Indolo[3,2-fi]carbazole (4) has also been the focus of many recent studies, since the discovery in the 1980s that 4 and several derivatives thereof are powerful aryl hydrocarbon receptor (AHR) ligands. The remaining three isomers have been more... 

The most recent synthetic efforts in this area have focused on the preparation of mono- and diformyl-substituted indolo[3,2-l)]carbazoles 202 and 203, which are potent aryl hydrocarbon receptor (AHR) ligands (cf. Section V,C). 

Corticosteroids are the most potent anti-inflammatory agents available for the treatment of asthma. The efficacy of corticosteroids is due to their ability to affect multiple inflammatory pathways, resulting in the suppression of inflammatory cell activation and function, prevention of microvascular leakage, decreased mucus production, and upregulation of P2-adrenergic receptors.10,18 Clinically, corticosteroids decrease airway inflammation, decrease AHR, decrease mucus production and secretion, and improve the response to P2-agonists.18 Corticosteroids for the treatment of asthma are available in inhaled, oral, and injectable dosage forms. 

AhR Aryl hydrocarbon receptor (also known as dioxin receptor)... 

Sunscreens and their degradation metabolites analyzed in this study are potential inducers of the oestrogen (ER) and aryl hydrocarbon receptors (AhR, also known as Dioxin Receptor). Ectopic activation of these pathways can cause severe damage to organisms and their ecosystem by altering reproduction, hormonal and/or circulatory systems [73-75] as well as they have been associated with carcinogenic and mutagenic effects [76-78]. 

Kerkvliet, N. I., Shepherd, D. M., and Baecher-Steppan, L., T lymphocytes are direct, aryl hydrocarbon receptor (AhR)-dependent targets of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) AhR expression in both CD4+ and CD8+ T cells is necessary for full suppression of a cytotoxic T lymphocyte response by TCDD, Toxicol. Appl. Pharmacol., 185, 146, 2002. 

Funatake, C., et. al., Cutting Edge Activation of the aryl hydrocarbon receptor (AhR) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) generates a population of CD4+CD25+ cells with characteristics of regulatory T cells, J. Immunol., 175, 4184, 2005. 

Weisner, L. et al., Does an aryl hydrocarbon receptor (AHR) like molecule exist in earthworms Some implications for immunity, Pedobiologia, 47, 646, 2003. 

As observed in mammalian models, the immune system of fishes is a sensitive target organ system to evaluate toxicity. For a more thorough review of environmental immunotoxicology in fishes, with reference to specific classes of xenobiotics, readers are referred to several reviews that deal with the subject over a span of nearly three decades [45-47, 54-57], While fish in the environment may be exposed to a variety of xenobiotics, the most frequently investigated xenobiotics are the polycyclic aromatic hydrocarbons (PAHs) and halogenated aromatic hydrocarbons (HAHs) due to the presence and activation of the aryl hydrocarbon receptor (AhR) in fish, and heavy metals due to their ubiquitous environmental distribution. 

Klinge, C. M., Bowers, J.L., Kulakosky, P. C., Kamboj, K.K. and Swanson, H.I. (1999) The aryl hydrocarbon receptor (AHR)/AHR nuclear translocator (ARNT) heterodimer interacts with naturally occurring estrogen response elements. 

In Table 14.1, a list of important NRs leading to P450 induction is given [1,11-13]. The transcription factor aryl hydrocarbon receptor (AhR) was also included because of its special role in P450 induction (especially of some P450 family 1 members). 

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