Aryl Hydrocarbon Receptor AhR

However, our current understanding of these regulatory pathways is largely based on molecular mechanisms, and data from in vitro studies may only be extrapolated with caution to complex situations in humans in vivo. Especially, NR interaction and cross talk make the prediction of in vivo responses difficult. Further research is required for a better understanding of the detailed transcriptional mechanism for proper drug and therapeutics design. 

Handschin, C. and Meyer, U. A. (2003) Induction of drug metabolism the role of nuclear receptors. Pharmacol. Rev. 55, 649-673. 

Eloranta, J. J. and Kullak-Ublick, G. A. (2005) Coordinate transcriptional regulation of bile acid homeostasis and drug metabolism. Arch. Biochem. Biophys. 433, 397-412. 

Urquhart, B. L., Tirona, R. G., and Kim, R. B. (2007) Nuclear receptors and the regulation of drug-metabolizing enzymes and drug transporters implications for interindividual variability in response to drugs. J. Clin. Pharmacol. 47, 566-578. 

Stimmel, J. B., Willson, T. M., Zavacki, A. M., Moore, D. D., et al. (1999) Bile acids natural ligands for an orphan nuclear receptor. Science 284, 1365-1368. 

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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). 

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). 

An essential step of TCDD toxic effects, including its carcinogenic potential, is its binding to the aryl hydrocarbon receptor (AhR) at the pM range. Deletion of... 

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)... 

An additional screening test for TCDD-like (aryl hydrocarbon receptor, AhR, active) chemicals has been developed (Garrison et al. 1996) and is available commercially (Anonymous 1997). Dubbed the CALUX (for chemically activated luciferase gene expression) system, the assay is based on recombinant cell lines into which researchers have inserted a firefly luciferase gene. When exposed to dioxin-like compounds, the recombinant cells luminesce. The method is sensitive to ppt levels of 2,3,7,8-TCDD equivalents in blood, serum, and milk (Anonymous 1997). Samples testing positive can be subjected to more definitive and specific analytical testing. 

Table 2 Nuclear receptors (NR) for enzyme inducers. Enzyme inducers are now known to act as ligands to nuclear receptors, leading to gene activation and increased synthesis of the enzyme. Affinity of inducers to die receptors is now known to be responsible for the differential induction potential and can explain die observed species-differences in induction. The receptors tabulated are aryl hydrocarbon receptors (AhR), constituitively androstane receptor (CAR), pregnane X receptor (PXR), and glucocorticoid receptor (GR). The isoforms in bold type are the major isoform regulated by the corresponding receptors.

Figure 2.9. Luciferase reporter gene assay/promoter deletion analysis. Cells are transfected with the CYP1A1 promoter reporter (luciferase) constructs in which the promoter region is increasing deleted. The cells are then treated with benzo[a]pyrene (an inducer of CYP1A1), and cells are harvested 24-48hr later and luciferase activity is measured. Promoter deletion analysis revealed enhancer element between -1140 and -1029. Contained within this region is xenobiotic response element (XRE) to which the aryl hydrocarbon receptor (AHR) binds.

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