*2.1.2 Naturally occurring dietary AhR-ligands*

*Immune Response Activation and Immunomodulation*

affects inflammation, and autoimmunity.

**2. Categories of AhR-ligands**

**2.1 Exogenous AhR-ligands**

*2.1.1 Synthetic AhR-ligands*

will start.

body [7].

in the translocation of the complex into the nucleus [5]. The ligand:AhR will then be released from this complex and bind to a related nuclear protein called AhR nuclear translocator (ARNT), which converts the AhR into its high-affinity DNA-binding form [6]. The ligand:AhR:ARNT complex binds to its specific DNA recognition site, the dioxin response elements (DREs), resulting in stimulation of the transcription of cytochrome P450 (CYP1A1) and other AhR-responsive genes. Once the AhR-ligand binds to its receptor, the AhR:ligand complex will translocate into the nucleus. The ligand:AhR will then be released from this complex and bind to ARNT, which converts the AhR into its high-affinity DNAbinding form, and then the ligand:AhR:ARNT complex will bind to the DRE, and as a result, transcription of cytochrome P450 and other AhR-responsive genes

The present chapter highlights the effects of some AhR-ligands both exogenous

and endogenous, on the secretion of pro- and/or anti-inflammatory cytokines which control the production of different T helper cell subsets, and consequently

There are two major categories of AhR-ligands: exogenous and endogenous ligands. Exogenous ligands are those that are synthetic (formed as a result of nonbiological activity) and/or naturally occurring dietary AhR-ligands. Endogenous ligands are those formed in biological systems as a result of natural processes in the

The synthetic AhR-ligands are in general high-affinity ligands and include halogenated aromatic hydrocarbons (HAHs) such as poly-halogenated dibenzo*p*-dioxins. Synthetic ligands include also polycyclic aromatic hydrocarbons (PAHs) such as benzathracenes and related compounds [8]. HAHs represent the most potent type of AhR-ligands, with binding affinities in the pM to nM range. In contrast, PAHs bind to the AhR with lower affinity in the nM to μM range. The dioxin 2,3,7,8-tetrachlorodibenzo*-p-*dioxin (TCDD), which is a member of the HAH group, is considered as one of the most potent AhR agonists known. The potency of TCDD is about 1000-fold greater than that of PAH compounds [9]. It was observed that aryl hydrocarbon receptor-deficient mice, loss of responsiveness to TCDD and related chemicals [10]. Many genes are regulated by the AhR, especially those encoding xenobiotic metabolizing enzymes, such as cyp1a1. The induction of cyp1a1 is AhR-dependent response that has been observed in most species [11]. The physiological role of the AhR remains a key question, and to date no high-affinity endogenous ligand has been identified. The detailed analysis of AhR-ligand binding has mainly focused on the structurally related HAHs and PAHs. However, recent studies have demonstrated the ability of a structurally diverse range of chemicals to bind and/or activate AhR-dependent gene expres-

These results suggest that AhR has a ligand-binding site with special characteristics. The identification and characterization of variety of naturally occurring AhR-ligands has started to redefine our ideas as to the structural specificity of

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sion [12, 13].

AhR-ligand binding.

The major source of exposure of animals and humans to AhR-ligands both synthetic and natural comes from the diet. A number of studies have described and characterized a variety of naturally occurring dietary chemicals that can directly activate and/or inhibit the AhR signaling pathway. Many studies have documented a variety of naturally occurring dietary chemicals that can act as agonist/antagonist to AhR. It was reported that extracts of vegetables or vegetable-derived materials could induce CYP1A1 activity, the hallmark of AhR activation [14]. The ability of several dietary plant compounds, including 7,8-dihydrorutacarpine, indole 3-carbinol (I3C), indolo [3,2-b]carbazole (ICZ), dibenzoylmethanes, curcumin, quercetin, carotinoids (e.g., canthaxanthin and astaxanthin), pro-carotinoid, and *β*-apo-8'carotenal, to competitively bind to the AhR and stimulate AhR-dependent gene expression was also reported [15, 16]. Flavonoids are the largest group of naturally occurring dietary AhR-ligands which include flavones, flavanols, flavanones, and isoflavones. Flavonoids are found in dietary vegetables, fruits, and teas. These chemicals have strong antioxidative activity, anticarcinogenicity, and the ability to inhibit several enzymes such as protein kinases and cytochrome P450 [10, 17]).

Quercetin (3, 3′4′,5,7-pentahydroxy flavonol) is an AhR-ligand which could have both agonist and antagonist activity to AhR depending on the cell context and the experimental conditions [10]. The continuous administration of quercetin following TCDD exposure in C57Bl/6J mice prevented the reduction in body weight due to dioxin exposure [18], and quercetin treatment for 30 days was found to reduce hepatomegaly. Moreover, treating endothelial cells with 100-μM quercetin, following the treatment with the AhR-ligand polychlorinated biphenyls, was found to significantly reduce cyp1a1 mRNA level [19]. In addition to the ability of flavonoids to interact with the AhR, many of these flavonoids are also substrates of the CYP1A1 enzyme [20]. Flavonoid levels in human blood are usually in the μM concentration range, and this amount was reported to be sufficient to either inhibit or activate the AhR [21]. These findings suggest that quercetin could antagonize AhR causing significant suppression in the production of cyp1a1.

Curcumin [1,7-bis(4-hydrosy-3-methoxyphenyl)-1,6-hepta-diene-3,5-dione] is a naturally occurring dietary ligand of AhR. It is the main component (70–75%) of turmeric herb (*Curcuma longa*). Curcumin has a powerful anti-inflammatory, antioxidant, and antimicrobial activities [22, 23]. It has this ability because it can act through many cellular pathways including many transcription factors, hormones, growth factors, and their associated receptors. Also, curcumin is a powerful antitumor agent, due to its ability to dissociate the AhR/ARNT complex inside the nucleus [24]. The administration of curcumin suppresses cyp1a1 and 1b1 mRNA, induced by TCDD treatment. TCDD was reported to enhance AhR/ ARNT-mediated cyp1a1 induction, and the expression of indoleamine-2,3-dioxygenase (IDO), which could enhance malignant transformation. In contrast, curcumin was observed to attenuate AhR/ARNT-mediated CYP induction by TCDD; thus, this mode of action may be the reason why curcumin could prevent malignant transformation, suggesting that curcumin could be used as a chemopreventive or anticancer agent.

Thus, plant-derived materials and extracts contain AhR-ligands or products that can promptly be converted into AhR-ligands. They are perhaps the largest class of natural AhR-ligands to which humans and animals are exposed. These chemicals are capable of binding to AhR as ligands, and suppress the transformation of the receptor by simply inhibiting the phosphorylation of AhR and Arnt, by protein kinase C, which is responsible for this process.
