The Aryl Hydrocarbon Receptor

Nearly 50 years ago, it was noted that rats exposed to 3-methylcholanthrene (3-MC) displayed a marked increase in metabolic capacity toward that substrate and other polycyclic aromatic hydrocarbons (PAHs) . This enhanced metabolic activity was referred to as aryl hydrocarbon hydroxylase (AHH) based on the ability of these enzymes to efficiently hydroxylate aromatic hydrocarbons . It is now known that AHH activity is the collective activities of the CYPlAl, CYPl A2, and CYPIBI enzymes. 

Over the next 30 years, two lines of evidence led to the identification of the AHR, the protein that functioned as the PAH sensor and regulated AHH activity. The first indications that such a receptor existed came from genetic studies of inbred mouse strains. Early studies demonstrated that C57BL/6 mice were much more responsive 

It was many years before the AHR was cloned and characterized. Attempts to purify the receptor were initially hampered by its low cellular concentration and relative instability. The development of a photoaffinity ligand, 2-azido-3-[ I]iodo-7,8-dibromodibenzo-p-dioxin, was the essential step that allowed the eventual purification of the AHR . Once the receptor was purified, a partial amino acid sequence was obtained and this lead to the cloning of the AHR cDNA from mouse liver - . The deduced amino acid sequence revealed that the AHR was 

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C. Biological Effects 1. Background The Aryl Hydrocarbon Receptor... 

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Lawrence, B.P. and Vorderstrasse, B.A., Activation of the aryl hydrocarbon receptor diminishes the memory response to homotypic influenza virus infection but does not impair host resistance, Toxicol. Sci., 79, 304, 2004. 

Matsen, S. and Shiverick, K., Characterization of the aryl hydrocarbon receptor complex in humanB lymphocytes Evidence for a distinct nuclear DNA-binding form, A rch. Biochem. Biophys., 36, 1996. 

Yamaguchi, K., et. al., Activation of the aryl hydrocarbon receptor/transcription factor and bone marrow stromal cell-dependent pre-B cell apoptosis, J. Immunol., 158, 2165,1997. 

Carver, L. and Bradfield, C., Ligand-dependent interaction of the aryl hydrocarbon receptor with a novel immunophilin homolog in vivo, J. Biol. Chem., 272, 11452, 1997. 

Svensson, C., et. al., Dioxin-induced adseverin expression in the mouse thymus is strictly regulated and dependent on the aryl hydrocarbon receptor, Biochem. Biophys. Res. Comm., 291, 1194, 2002. 

Thurmond, T.S., et. al., The aryl hydrocarbon receptor has a role in the in vivo maturation of murine bone marrow B lymphocytes and their response to 2,3,7,8-tetrachlorodibenzo-p-dioxin, Toxicol. Appl. Pharmacol., 165, 227, 2000. 

Sulentic, C., Holsapple, M., and Kaminski, N., Putative link between transcriptional regulation of IgM expression by TCDD and the aryl hydrocarbon receptor/dioxin-responsive enhancer signaling pathway, J. Pharmacol. Exper. Therapeut., 295, 705, 2000. 

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. 

H. (2005) Role of the aryl hydrocarbon receptor in drug metabolism. Expert Opinion on Drug Metabolism ej Toxicology,... 

Okey, A.B., Franc, M.A., Moffat, I.D., Tijet, N., Boutros, P.C., Korkalainen, M., Tuomisto, J. and Pohjanvirta, R. (2005) Toxicological implications of polymorphisms in receptors for xenobiotic chemicals the case of the aryl hydrocarbon receptor. Toxicology and Applied Pharmacology, 207, S43-S51. 

Kato, T.-A., Matsuda, T., Matsui, S., Mizutani, T. and Saeki, K.-I. (2002) Activation of the aryl hydrocarbon receptor by methyl yellow and related congeners structure-activity relationships in halogenated derivatives. Biological e[ Pharmaceutical Bulletin, 25, 466 171. 

Pandini, A., Denison, M.S., Song, Y., Soshilov, A.A. and Bonati, L. (2007) Structural and functional characterization of the aryl hydrocarbon receptor ligand binding domain by homology modeling and mutational analysis. Biochemistry, 46, 696-708. 

Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the expression of cytochrome P450 lAl, the aryl hydrocarbon receptor, and the aryl hydrocarbon receptor nuclear translocator in rat brain and pituitary. Toxicol Appl Pharmacol 169 159-167. 

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... 

Hankinson O (1995) The aryl hydrocarbon receptor complex. Annu Rev Pharmacol Toxicol 35 307-340... 

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)... 

Nebert DW. Role of the aryl hydrocarbon receptor mediated induction of the CYP1 enzymes in environmental toxicity and cancer. J Biol Chem 2004 279 23847-23850. 

Ciolino HP, Daschner PJ, Yeh GC. 1998. Resveratrol inhibits transcription of CYP1A1 in vitro by preventing activation of the aryl hydrocarbon receptor. Cancer Res 58 5707-5712. 

Rinaldi AL, Morse MA, Fields HW, Rothas DA, Pei P, Rodrigo KA, Renner RJ, Mallery SR. 2002. Curcumin activates the aryl hydrocarbon receptor yet significantly inhibits (—)-benzo(a)pyrene-7R-trans-7,8-dihydrodiol bioactivation in oral squamous cell carcinoma cells and oral mucosa. Cancer Res 62 5451-5456. 

Many of the planar PAH compounds induce their own metabolism by inducing transcription of the aryl hydrocarbon receptor (Ah receptor). Although expression of CYP1A1 and 1A2 is often coordinately induced, there are clear differences in regulation, not only with respect to substrate specificity but also in their biological expression. For example, CYP1A1 does not appear to be expressed in human liver unless induced,... 

Hahn ME, Westler WM, Sicinski RR, De-Luca HF (2002) A ligand for the aryl hydrocarbon receptor isolated from lung. 

Fukunaga BN, Probst MR, Reisz-Porszasz S, et al. 1995. Identification of functional domains of the aryl hydrocarbon receptor. J Biol Chem 270 29270-29278. 

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