Plant Occurring Flavonoids As Modulators of the Aryl Hydrocarbon Receptor

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Review Plant Occurring Flavonoids as Modulators of the Aryl Hydrocarbon Receptor

Elizabeth Goya-Jorge 1,2 , María Elisa Jorge Rodríguez 3, Maité Sylla-Iyarreta Veitía 4 and Rosa M. Giner 1,*

1 Departament de Farmacologia, Facultat de Farmàcia, Universitat de València. Av. Vicente Andrés Estellés, s/n, Burjassot, 46100 Valencia, Spain; [email protected] 2 ProtoQSAR SL., CEEI (Centro Europeo de Empresas Innovadoras), Av. Benjamin Franklin 12, Parque Tecnológico de Valencia, Paterna, 46980 Valencia, Spain 3 Departamento de Farmacia, Facultad de Química-Farmacia, Universidad Central “Marta Abreu” de las Villas, 1 C. Camajuaní km 5 ⁄2, Santa Clara 54830, Villa Clara, Cuba; [email protected] 4 Equipe de Chimie Moléculaire du Laboratoire Génomique, Bioinformatique et Chimie Moléculaire (EA 7528), Conservatoire National des Arts et Métiers (Cnam), 2 Rue Conté, HESAM Université, 75003 Paris, France; [email protected] * Correspondence: [email protected]; Tel.: +34-963-543-609

Abstract: The aryl hydrocarbon receptor (AhR) is a transcription factor deeply implicated in health and diseases. Historically identified as a sensor of xenobiotics and mainly toxic substances, AhR has recently become an emerging pharmacological target in cancer, immunology, inflammatory conditions, and aging. Multiple AhR ligands are recognized, with plant occurring flavonoids being the largest group of natural ligands of AhR in the human diet. The biological implications of the modulatory effects of flavonoids on AhR could be highlighted from a toxicological and environmental concern and for the possible pharmacological applicability. Overall, the possible AhR-mediated Citation: Goya-Jorge, E.; Jorge harmful and/or beneficial effects of flavonoids need to be further investigated, since in many cases Rodríguez, M.E.; Veitía, M.S.-I.; Giner, they are contradictory. Similar to other AhR modulators, flavonoids commonly exhibit tissue, organ, R.M. Plant Occurring Flavonoids as and species-specific activities on AhR. Such cellular-context dependency could be probably beneficial Modulators of the Aryl Hydrocarbon in their pharmacotherapeutic use. Flavones, flavonols, flavanones, and isoflavones are the main Molecules 26 Receptor. 2021, , 2315. subclasses of flavonoids reported as AhR modulators. Some of the structural features of these groups https://doi.org/10.3390/ of flavonoids that could be influencing their AhR effects are herein summarized. However, limited molecules26082315 generalizations, as well as few outright structure-activity relationships can be suggested on the AhR

Academic Editors: Roberto Fabiani agonism and/or antagonism caused by ﬂavonoids. and Eliana Pereira Keywords: ﬂavonoids; phytochemicals; phytocompounds; Ah receptor; dioxin receptor; polyphenols;

Received: 16 March 2021 transcription factor; bioactive; xenobiotics; functional food Accepted: 13 April 2021 Published: 16 April 2021

Publisher’s Note: MDPI stays neutral 1. Introduction with regard to jurisdictional claims in Flavonoids are the largest class of phenolic compounds found in nature, particularly published maps and institutional affil- important in the plant kingdom. In multiple plants, flavonoids are responsible for the color iations. and flavor [1]. The aglycone and glycoside (i.e., glucosides, rhamnoglucosides, and rutino- sides) forms of flavonoids are found in the human daily diet like fruits, vegetables, grains, seeds, bark, herbs, roots, flowers, stems, and spices. The natural distribution of these plant secondary metabolites, their inherent structural diversity, chemical properties, and ability Copyright: © 2021 by the authors. to interact with biological systems modifying multiple target receptors in mammalians, Licensee MDPI, Basel, Switzerland. have attracted attention during decades to their study in pharmacological and toxicological This article is an open access article contexts [2,3]. distributed under the terms and Among the wide range of biological properties referable to flavonoids are included conditions of the Creative Commons antioxidant, anti-inflammatory, antitumor, antiviral, hypolipidemic, antithrombotic, estro- Attribution (CC BY) license (https:// genic, and antiallergic activities. Moreover, numerous pre-clinical and epidemiological creativecommons.org/licenses/by/ studies reveal that flavonoids may exert protective effects against chronic conditions such 4.0/).

Molecules 2021, 26, 2315. https://doi.org/10.3390/molecules26082315 https://www.mdpi.com/journal/molecules Molecules 2021, 26, 2315 2 of 20

as cancer, diabetes, and cardiovascular and neurodegenerative diseases, supporting the concept of a beneficial role for dietary flavonoids in human health [4–7]. The cellular detection of chemical signals from exogenous or endogenous sources can occur through chemoreceptors that commonly have cytoplasmic or transmembrane locations. The cytosolic chemosensor AhR is an evolutionarily conserved protein and a pleiotropic transcription factor with a key role in both health and diseases [8,9]. The signaling pathways of the formerly known as “dioxin receptor” have explained the mode of action of highly toxic chemicals, particularly 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and derivatives [10]. Recently, there is increasing attention on AhR as an attractive target in cancer, immunology, inflammatory bowel diseases, and aging [11]. However, much about the molecular mechanisms and the activation/inactivation patterns of AhR upon ligand binding is pending closer analyses [12]. Multiple and structurally diverse chemicals including polyhydroxyalkanoates, poly- chlorinated biphenyls, bisphenols, polyphenols, benzothiazoles, and triarylmethanes have been evaluated as AhR ligands [13–15]. Plant flavonoids are considered the main group of natural dietary ligands of the AhR [16,17]. Hence, several well-known activators and inhibitors of AhR-mediated effects are flavonoids, with the flavonol quercetin being a prototypical representative. Depending on the cell context, quercetin has shown agonist and/or antagonist activities on AhR transcriptional activation [18]. This could suggest selective AhR modulation in which agonism or antagonism must be confirmed, as it is not clearly predictable [19]. This literature review provides a summary and update of the most recent state of the art on AhR and its natural flavonoid modulators. First, a detailed introduction is given on AhR’s molecular characteristics and signaling pathways, including the main physiological effects associated with its transcriptional activity. Next, plant occurring flavonoids that have been evaluated as AhR modulators, and their AhR agonism and/or antagonism, are presented. Finally, some chemical-structural features and substitution patterns of flavonoids that could be contributing to their AhR activity, are suggested.

2. Aryl Hydrocarbon Receptor 2.1. Functional Domains The transcription factor AhR was originally discovered in hepatocytes in the 1970s. Half a century later, multiple studies have confirmed that AhR signaling affects virtually every animal cell-type and organ in vertebrates and in many invertebrates [8]. The highest AhR expression has been reported in the liver, kidney, thymus, lung, spleen, and pla- centa [20]. Moreover, AhR is constitutively allocated in the nucleus of aggressive malignancies, where its target genes are widely expressed [21]. Figure1 is a schematic representation of the AhR functional domains and binding sites. The AhR and its nuclear translocator (ARNT) belong to the bHLH-PAS superfamily of transcription factors, the acronym for basic Helix-Loop-Helix and Periodic (PER)-ARNT- Single minded (SIM) [22]. Protein subfamilies may be stratified into two classes, with Class I including bHLH-PAS proteins such as the AhR, hypoxia-inducible factors, clock circadian regulators, and neuronal PAS protein, while Class II includes the ARNT subfamily of proteins located inside the nucleus and can heterodimerize with the cytosolic Class I members such as AhR. Both AhR and ARNT include an (N-) terminal bHLH domain, two PAS domains named A and B, and a transactivation domain carboxy (C-) terminal [23,24]. The PAS A domain controls dimerization through its connector helix and strengthens the binding to a distinct DNA motif in which bHLH plays the main role. With a three-loop insertion difference from PAS A, the PAS B is the AhR ligand-binding domain (LBD) [25]. In the transactivation domain, the Q-rich (Glutamine-rich) subdomain is the key region for transcriptional activation of xenobiotic response elements (XRE) in the DNA [26]. The binding to coactivators during the transcriptional process regulates the wide diversity and tissue specific AhR effects [27]. Molecules 2021, 26, 2315 3 of 20 Molecules 2021, 26, x FOR PEER REVIEW 3 of 21

FigureFigure 1. Schematic1. Schematic domain domain organization organization of the of arylthe hydrocarbonaryl hydrocarbon receptor receptor (AhR) (AhR) and its and binding its binding sites. sites. 2.2. Cytoplasmic Complex and Signaling Pathways 2.2.The Cytoplasmic cytoplasmic Complex inactive and Signaling form of AhRPathways (monomer) is found to be associated with two moleculesThe cytoplasmic of the 90-kDa inactive heat form shock of AhR protein (monomer) (HSP90) is chaperone, found to be a co-chaperoneassociated with p23, two a termedmolecules X-associated of the 90-kDa protein heat 2 (XAP2), shock protein and a protein (HSP90) kinase chaperone, SRC. While a co-chaperone one of the HSP90 p23, a interactstermed withX-associated both the protein bHLH 2 and (XAP2), PAS regions,and a pr theotein other kinase unit SRC. is only While bound one of to the the HSP90 PAS domaininteracts [28 with]. The both HSP90 the bHLH is a protein and PAS folding regions, tool the found other also unit in is steroid only bound receptors to the such PAS asdomain estrogen, [28]. progesterone, The HSP90 andis a protein glucocorticoid folding receptors.tool found The also resistance in steroid to receptors salt treatment such as andestrogen, the absence progesterone, of molybdate and glucocorticoid led to suggestions receptors. that HSP90/AhRThe resistance binding to salt treatment may be the and mostthe absence stable binding of molybdate known led for to that suggestion chaperone.s that However, HSP90/AhR inter-species binding may differences be the formost HSP90/AhRstable binding binding known have for been that identiﬁed chaperone. [29,30 ].However, The co-chaperone inter-species p23 isdifferences a commonly for foundHSP90/AhR protein inbinding HSP90 have complexes, been identified where it [2 contributes9,30]. The toco-chaperone the ligand binding p23 is a and commonly to the releasefound from protein HSP90 in HSP90 chaperone complexes, machinery where [31 it,32 co].ntributes More recently, to the ligand a protecting binding role and of p23to the 0 againstrelease AhR’s from degradationHSP90 chaperone independent machinery of HSP90 [31,32].s functions More recently, has been a protecting acknowledged role of [33 p23]. Meanwhile,against AhR’s XAP2 degradation presents a discreteindependent domain of organization HSP90′s functions with a tetratricopeptidehas been acknowledged repeat motif[33]. whose Meanwhile, carboxyl-terminal XAP2 presents domain a discrete is responsible domain fororganization the interaction with with a tetratricopeptide AhR protein. Inrepeat the AhR motif core whose complex, carboxyl-terminal XAP2 positively domain or negatively is responsible modulates for the the receptor’s interaction sensitivity with AhR toprotein. ligands In and the the AhR transcriptional core complex, responses XAP2 positi [34–36vely]. The or negatively c-SRC tyrosine modulates kinase the contributes receptor’s tosensitivity ligand recognition to ligands andand indirectlythe transcriptional ensures responses the transcriptional [34–36]. The process c-SRC [37 tyrosine]. Figure kinase2 representscontributes some to ligand of the molecularrecognition consequences and indirectly upon ensures ligand the binding transcriptional to the AhR process complex. [37]. Figure 2 represents some of the molecular consequences upon ligand binding to the AhR complex.

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FigureFigure 2. 2.Schematic Schematic representation representation of of AhR-mediated AhR-mediated pathways. pathways. LigandsLigands bindbind toto thethe cytoplasmiccytoplasmic AhR, where it forms a complex with HSP90, p23, XAP2, and SRC. (I) Agonist ligands promote con- AhR, where it forms a complex with HSP90, p23, XAP2, and SRC. (I) Agonist ligands promote formational changes and the exposure of NLS, allowing the nuclear translocation mediated by im- conformational changes and the exposure of NLS, allowing the nuclear translocation mediated by portin β through the NPC. (II) Once in the nucleus, the heterodimer AhR-ARNT can bind to differ- importinent sequencesβ through in the the DNA NPC. and (II) trigger Once the in thesynthesis nucleus, of proteins the heterodimer (e.g., CYP1A1, AhR-ARNT UGT1A6), can which bind tois differentadditionally sequences regulated in the by DNA coactivators. and trigger (III) the Crosstalk synthesis interactions of proteins with (e.g., other CYP1A1, signaling UGT1A6), pathways which are isacknowledged additionally regulated (e.g., ESRs, by coactivators.AR). Moreover, (III) the Crosstalk Ah receptor interactions can be repressed with other by signaling AhRR, and pathways its deg- areradation acknowledged is mainly (e.g., mediated ESRs, by AR). 26S Moreover, proteasome. the Ah receptor can be repressed by AhRR, and its degradation is mainly mediated by 26S proteasome. Genomic and non-genomic pathways are suggested for AhR signaling, as repre- sentedGenomic in Figure and non-genomic2. The genomic pathways induction are of suggested target genes forAhR is the signaling, fundamental as represented and best- inknown Figure mechanism2. The genomic of AhR-mediated induction of signaling. target genes The is genomic the fundamental pathway (I) and starts best-known once AhR mechanismagonists bind of AhR-mediated to the LBD, causing signaling. conformati The genomiconal changes pathway in (I) the starts PAS once A that AhR trigger agonists the bindexposure to the of LBD, nuclear causing localization conformational sequences changes (NLS) in[38,39]. the PAS The A SRC that is trigger then released the exposure from ofthe nuclear AhR-chaperone localization complex sequences to the (NLS) cytosol, [38 ,tr39iggering]. The SRC phosphorylatio is then releasedn processes from the [40]. AhR- The chaperoneentrance complexto the nucleus to the cytosol,is facilitated triggering by importins phosphorylation that recognize processes the [NLS.40]. The Specifically, entrance toimportin the nucleus β isis the facilitated direct mediator by importins that facilitates that recognize the passage the NLS. to the Specifically, cytoplasmic importin face ofβ theis thenuclear direct pore mediator complex that (NPC) facilitates [41]. the passage to the cytoplasmic face of the nuclear pore complexAfter (NPC) the [AhR-chaperone41]. complex is translocated to the nucleus, the receptor heter- odimerizesAfter the with AhR-chaperone ARNT, losing complex the chaperone is translocated proteins to in the the nucleus, process theand receptorforming het-the erodimerizesAhR/ARNT withcomplex ARNT, (II in losing Figure the 2) chaperone[42]. Depending proteins on inthe the target process genes and involved forming in thethe AhR/ARNTsubsequent complextranscriptional (II in activity Figure2 triggere)[ 42].d Depending by the AhR/ARNT, on the target the genomic genes involved signaling inis theclassified subsequent as canonical transcriptional when it activity is mediated triggered by XRE by or the else AhR/ARNT, as non-canonical the genomic or no consen- signal- ingsus is classifiedXRE (NC-XRE) as canonical responses when (Figure it is mediated 2). The bycanonical XRE or elsesignaling as non-canonical starts when or the no consensusAhR/ARNT XRE complex (NC-XRE) binds responses to the XRE (Figure identifi2).ed The by canonical the DNA signalingconsensus starts motif when sequence the AhR/ARNT complex binds to the XRE identified by the DNA consensus motif sequence 50- TNGCGTG-30 [43,44]. The NC-XREs, sometimes referred to as AhR Responsive Elements-II,

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are recognized by the consensus promoter region 50-CATG{N6}C[T|A]TG-30 [45]. A scaf- fold is formed upon binding to AhR core regions, inducing the recruitment of multiple coactivators that ultimately regulate the transcriptional process [27]. In addition, similar to other PAS proteins involved in critical signaling functions, AhR expression is controlled by a transcriptional repressor (AhRR) with a similar N-terminal region sequence [46]. Thus, the AhRR is an AhR competitor in that it may form the heterodimeric AhRR/ARNT complex, which binds to the XRE, and consequently repress the transcription. The AhRR effects mediate key processes such as inflammation and tumor growth that have led to its consideration as a drug target [47,48]. The repression pathway is also controlled by the receptor itself and its transcriptional outcomes forming a regulatory circuit [49]. The prototypical canonical target gene identified for AhR determines the induction of cytochrome P450 from family 1, subfamily A, polypeptide 1 (CYP1A1) xenobiotic- metabolizing enzyme [50,51]. At the same time, AhR regulates the basal CYP1A1 expression through elements such as the so-called special protein family, and particularly the specificity protein 1 [52]. Moreover, AhR signaling through XRE has been associated with other family members such as CYP1A2 and CYP1B1 as well as phase II enzymes such as the UGT1A6 [53,54]. The understanding of the AhR complexity has been further expanded with the discovery of multiple nonclassical target genes in the past decades [55]. Some of the most important NC-XRE pathways are related to the tumor suppressor Kruppel-like factor 6 and the recruitment of flanking target genes such as the plasminogen activator inhibitor 1 and the p21cip1 protein [56]. Among the non-genomic mechanisms that AhR activation could trigger is the above- commented phosphorylation induced by the c-SRC of multiple key protein substrates such as the epidermal growth factor receptor (EGFR) [57,58]. Furthermore, c-SRC, the mitogen- activated protein kinases, reactive oxygen species (ROS), and AhR-dependent paths have been recently associated with the apoptosis of neuronal cells through the stress of the endoplasmic reticulum [59]. The proteasome-mediated degradation of ubiquitinated proteins is another important non-genomic pathway of AhR activation, which has been linked to the inflammatory process [60,61]. Thus, AhR can act as a ligand-dependent ubiquitin protein ligase (E3), promoting the proteolysis of other transcription factors [62,63]. Furthermore, AhR controls the levels of intracellular calcium and the induction of enzymes such as the cytosolic phospholipase A2 and cyclooxygenase 2 [64,65]. On the other hand, AhR modulation intervenes in the signaling networks of many other crucial cellular entities [66]. The crossroad with estrogen receptors (ESRα and ESRβ) is among the best-studied and it has been shown to lead to transcriptional activation of estrogen-responsive gene promoters and the consequent estrogenic effects [67]. Besides, AhR has proven to interact with the canonical Wnt/β-catenin pathway possibly mediated by some other entities such as R-spondin 1 [68], which is an important element in cellular proliferation as well as in sexual organ’s development and differentiation [69,70]. Such an interaction associates the receptor with the regulation of organogenesis and other key biological processes such as cell polarity and migration attributed to the glycoproteins Wnts [71]. AhR crosstalk interactions include effects on the transforming growth factor-β/bone morphogenetic protein (TGFβ/BMP) pathway. TGFβ/BMP is a target of drugs currently in phase I or phase II clinical trials for the treatment of ovarian cancer, hepatocellular carcinoma, glioblastoma, and melanoma [72]. In addition, the subunit RelB of NF-kB transcription factor family has shown to be functionally associated with AhR-mediated transcription. The resulting RelB/AhR complexes play an important role as inducers of pro-inflammatory chemokines such as IL-8, and this crosstalk mechanism is critically involved in immunity, cell proliferation, and apoptosis [73,74]. Lastly, the downregulation of AhR is described as a rapid crucial attenuation of AhR effects on gene transcription. The proteolytic degradation is a terminal step mainly ubiquitin-mediated through the 26S proteasome. It could be triggered if the receptor complex has a misfolded conformation prior to entry to the nucleus. Otherwise, after the Molecules 2021, 26, 2315 6 of 20

signaling processes, AhR is ubiquitinated and degraded inside the nucleus or transferred to the cytoplasm via the Exportin 1 (or CRM-1) that recognizes the nuclear export signals (NES). In the cytosol, AhR is targeted and degraded by 26S proteasome [75,76]. Recently, lysosomal degradation of AhR via chaperone-mediated autophagy has been identiﬁed in triple-negative breast cancer cells [77].

2.3. AhR Effects and Modulators The ligand, cell, tissue-specific, and pleiotropic effects of AhR-mediated activity are still puzzling and, in many cases, poorly understood [78]. Human diet and gut microbiome are tremendous sources of AhR modulators that trigger complex and fundamental processes in health and diseases [79,80]. It is believed that at least the downstream effects of dietary AhR inducers fit the renowned quote of the father of toxicology Paracelsus that “Sola dosis facit venenum” (the dose makes the poison) [12]. However, the receptor’s occupancy and the persistence of modulators are suggested to be, in many cases, far more relevant than the dosage. Low dosage effects still are underestimated and not fully understood by current science. Overall, AhR pathways intricacies have led some to consider that many of its adverse health consequences could be an exacerbated cellular response to its endogenous roles [66,81]. The truth is that these contradictory statements remain to be clarified on this fascinating transcription factor [10]. Toxicologists have been for decades interested in AhR-dependent signaling as a key intermediate step in the toxic responses to dioxin-like compounds [10]. Immunological, hepatic, and endocrine disruptions, as well as carcinogenic effects, are attributed to AhR- mediated activity [55]. However, the proven AhR physiological functions, particularly important in barrier organs as the gut or the skin, are nowadays driving a new line of research for the formerly known as “dioxin receptor” [9]. AhR has been associated with key processes such as development, cell cycle regulation, immunity, resilience against stress, homeostasis, and metabolism [82]. Potential therapeutic uses of AhR modulation include maintenance of lung health [83], control of the inflammatory process in vascular tissues [84], treatment of liver and cystic fibrosis [85,86], control of the antioxidant response [87], and regulation of neural functions in both vertebrates and invertebrates [88]. Numerous and structurally diverse chemical entities have been identified as AhR agonist and/or antagonist modulators (Figure3). Hence, the receptor has been considered a “promiscuous” sensor of chemical entities [89]. Endogenous entities such as the tryptophan derivative 6-formylindolo [3, 2-b]carbazole (FICZ) [90] and the neurotransmitter serotonin [91], are AhR modulators. Exogenous compounds exhibiting AhR modulatory effects include the toxicant TCDD, the synthetic alpha-Naphthoflavone and the drug Phorthress, as well as naturally occurring compounds such as berberine, quercetin, and resveratrol. Discovering chemical entities acting as AhR agonists and antagonists contribute to a better understanding of the molecular interactions as well as the toxicological and therapeutic roles of the receptor [92]. In toxicology, this has helped to identify potential high concern substances and environmental contaminants, particularly persistent organic pollutants whose exacerbated effects could trigger the adverse outcomes associated with AhR transcriptional activity [93]. Inflammatory and immunological diseases could be modulated through AhR expression and particularly those affecting gut and intestinal tissues [79,80,94]. Thus, promising drug candidates such as the designed AhR ligands NPD-0414-2 and NPD-0414-24, have been recently suggested in the therapy of colitis [95]. However, probably the most significant pharmacological applications of targeting AhR are in the treatment of malignancies. Hence, the chemotherapy of CYP1A1-positive tumors includes AhR agonists such as Phortress (NSC 710305) [96] and Aminoflavone (NSC 686288) [97], with demonstrated antiproliferative activity through AhR activation. Molecules 2021, 26, 2315 7 of 20 Molecules 2021, 26, x FOR PEER REVIEW 7 of 21

Figure 3. Examples of AhR endogenous and exogenous modulators (structures, common names, Figure 3. Examples of AhR endogenous and exogenous modulators (structures, common names, and and CAS numbers are shown). CAS numbers are shown).

SomeDiscovering authors suggestchemical the entities term ofacting selective as Ah AhRR agonists modulators and antagonists (SAhRMs) contribute instead of to a commonbetter understanding categorizations of based the molecular on their bindinginteractio affinity,ns as well structural as the toxicological similarities, origins,and thera- or toxicity.peutic roles Such of a the consideration receptor [92]. is basedIn toxicology, on the tissue, this has organ, helped and to species-specific identify potential activ- high itiesconcern exhibited substances by most and AhR environmental ligands, but particularly contaminants, by particularly non-dioxin-like persistent ligands organic such as pol- flavonoids.lutants whose Deeper exacerbated investigations effects that could focus trigge onr thethe selectivityadverse outcomes patterns associated and the agonist with AhR andtranscriptional antagonist responses activityof [93]. AhR modulators could significantly contribute to their clinical applicationsInflammatory and to the and control immunological of their toxicity diseases [19]. could be modulated through AhR expression and particularly those affecting gut and intestinal tissues [79,80,94]. Thus, promising 3. Flavonoids:drug candidates Generalities such as the and designed Modulating AhR Effects ligands of NPD-0414-2 AhR and NPD-0414-24, have beenFlavonoids recently aresuggested secondary in the metabolites therapy of widely colitis distributed[95]. However, throughout probably the the plant most king- signif- domicant in bothpharmacological edible and non-edibleapplications species. of targeting Countless AhR are literature in the treatment reports indicate of malignancies. a link betweenHence, flavonoid’s the chemotherapy consumption of CYP1A1-positive and health benefits tumors (or risks), includes due toAhR their agonists antioxidant, such as antiproliferative,Phortress (NSC estrogenic,710305) [96] or and anti-estrogenic Aminoflavone properties (NSC 686288) [98,99 [97],]. As with a largedemonstrated reservoir an- of chemicaltiproliferative diversity, activity plant through polyphenols AhR activation. are involved in a varied spectrum of gene and enzymaticSome regulation authors mechanismssuggest the [term100– 102of selective]. AhR modulators (SAhRMs) instead of common categorizations based on their binding affinity, structural similarities, origins, or toxicity. Such a consideration is based on the tissue, organ, and species-specific activities

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exhibited by most AhR ligands, but particularly by non-dioxin-like ligands such as flavonoids. Deeper investigations that focus on the selectivity patterns and the agonist and antagonist responses of AhR modulators could significantly contribute to their clinical applications and to the control of their toxicity [19].

3. Flavonoids: Generalities and Modulating Effects of AhR Flavonoids are secondary metabolites widely distributed throughout the plant kingdom in both edible and non-edible species. Countless literature reports indicate a link between flavonoid’s consumption and health benefits (or risks), due to their antioxidant, Molecules 2021, 26, 2315 antiproliferative, estrogenic, or anti-estrogenic properties [98,99]. As a large reservoir8 of 20of chemical diversity, plant polyphenols are involved in a varied spectrum of gene and en- zymatic regulation mechanisms [100–102]. Structurally, flavonoids are characterized by their basic skeleton arranged in the form Structurally, flavonoids are characterized by their basic skeleton arranged in the form C6-C3-C6, which corresponds to two benzene rings linked by a unit of three carbon atoms, C6-C3-C6, which corresponds to two benzene rings linked by a unit of three carbon atoms, which may or may not give rise to a third ring. Despite the various criteria regarding their which may or may not give rise to a third ring. Despite the various criteria regarding theirclassification, classification, three three general general classes classes are recognized are recognized according according to the to linkage the linkage position position of the ofaromatic the aromatic ring with ring respect with respect to the benzopyrane to the benzopyrane (chromane) (chromane) moiety: moiety: flavonoids flavonoids (2-phenyl (2-- phenyl-1,4-benzopyrones),1,4-benzopyrones), isoflavonoids isoflavonoids (3-phenyl (3-phenyl-1,4-benzopyrones),-1,4-benzopyrones), and and neoflavonoids neoflavonoids (4- (4-phenyl-1,2-benzopyrones)phenyl-1,2-benzopyrones) [101]. [101 Moreover,]. Moreover, they they can can be besubclassified subclassified into into subgroups subgroups ac- accordingcording to to the the degree degree of of oxidation oxidation of of the the pyranic pyranic ring, ring, which can be opened andand recycledrecycled inin thethe furan furan cycle cycle and and linking linking chain chain unsaturation: unsaturation: 2-phenylchromones 2-phenylchromones (flavones, (flavones, flavonols, flavo- flavanones,nols, flavanones, and dihydroflavonols); and dihydroflavonols); 2-phenylchromanes 2-phenylchromanes (flavans, (flavans, flavan-3-ols, flavan flavan-3,4--3-ols, fla- diols),van-3,4 chalcones-diols), chalcones (represented (represented in Figure4 in), andFigure some 4), othersand some such others as anthocyanins such as anthocyanins (2-phenyl- benzopyrilium)(2-phenyl-benzopyrilium) and aurones and [2, 3aurones,103,104 [2,3,103,104]]. .

FigureFigure 4.4. GeneralGeneral classesclasses ofof ﬂavonoidsflavonoids andand somesome relevantrelevant subclassiﬁcations.subclassifications.

RegardingRegarding their their chemical chemical reactivity, reactivity, flavonoids flavonoids occur occur as hydroxylated, as hydroxylated, methylated, methylated, and prenylatedand prenylated aglycones aglycones or glycosylated or glycosylated derivatives, derivatives, either O -glycosides either O-glycosides formed via formed linkage via of thelinkage sugar of unit theto sugar the hydroxyls, unit to the or hydroxyls, C-glycosides or C directly-glycosides to the directly carbon atomto the of carbon the flavonoid atom of skeletonthe flavonoid [2,105 skeleton]. In the [2,105]. cytosol In (pH the 7.4),cytosol most (pH flavonoids 7.4), most form flavonoids a mixture form of a phenolatemixture of anions and neutral phenols. Their proportion depends on the pKa of each phenolic group in the structure. Since most flavonoids are weak hydrophobic acids, depending on their lipophilicity, they have the potential to cross cellular and mitochondrial membranes and act as protonophores. Sometimes even minimal structural modifications alter the solubility, reactivity, and stability of flavonoids that ultimately lead to their bioavailability differences and the diversity of biological effects across the groups [106,107]. The current uses of plant flavonoids cover cosmetic, nutraceutical, and pharmaceutical industries [3,108,109]. Their prophylactic efficacy against neoplastic [110–112], cardiovascular [113–115], bone [116], and neurological disorders [117] are among the most widespread. Pharmacological studies have revealed also anti-inflammatory [118,119] and antibacterial potential [102] of flavonoids, as well as their applications in the prevention and treatment of obesity [120] and diabetes [121,122]. Besides, antioxidant effects have been attributed Molecules 2021, 26, 2315 9 of 20

to all flavonoid subclasses [7]. Thus, most of the anticancer properties ascribed to plants and natural extracts from traditional medicine are explained through flavonoids’ ability to scavenge free radicals and other ROS, modulate ROS-scavenging enzymes, chelate metal ions, and prevent oxidative stress-related conditions [104,123]. However, the mechanisms mediating the diverse bioactivity profiles of flavonoids, which are determined by minimal structural differences, still are pending further investigations [2,6]. A wide variety of flavonoids are suggested to be modulators of AhR function. The complexity of the role of AhR in physiology and in pathological conditions, lead to discrepancies in the positive or negative molecular consequences of the AhR transcriptional modulation caused by flavonoids [11,16,124]. Furthermore, it is recognized that beyond a dose dependence of food flavonoids when acting on AhR, these ligands could display different activities depending on the exposure time, and their effects are variable among species and tissues [125–127]. Table1 shows the list of flavonoids studied as AhR modulators, the main bioassays used, and the common range of concentrations tested.

Table 1. Plant occurring ﬂavonoids studied as aryl hydrocarbon receptor (AhR) modulators through different bioassays.

Flavonoids Bioassays a Cell lines & Tissues b [µM] Reference Flavones Acacetin, Apigenin, Baicalin, Chrysin, Caco2, YAMC, Flavone, Genkwanin, Luteolin, RT-qPCR, PCR, DLN, HepG2 AhR-Lucia, Luteolin 7,30-diglucoside, Scutellarein, LucRGA, H1L6.1c2, 3T3-L1 (AhR) 10–100 [128–137] Tangeretin, Tricetin, ChIP, WB, HCT116, MDA-MB-231, 40,7-dimethoxy-5-hydroxyflavone, IF, IHC Hepatic tissue (rats), 40,5,7-trimethoxyflavone, Myocardial tissue (mice) 30,40,5,7-tetramethoxyflavone. Flavonols Fisetin, Flavonol, Galangin, Gossypetin, LNCaP, CWR22Rv1, Guaijaverin, Icaritin, Isorhamnetin, RT-qPCR, Caco2, H1L6.1c2, Kaempferol, Morin, Myricetin, Quercetin, [128,129,135, ChIP, WB, 3T3-L1 (AhR), 10–100 Quercitrin, Robinetin, 136,138,139] LucRGA PBMEC/C1-2, Rutin. Tamarixetin, HepG2 AhR-Lucia 3,6,20,30-Tetrahydroxyflavone, 3,6,20,40-Tetrahydroxyflavone. Dihydroflavonols RT-qPCR, ChIP, WB, Caco2, HepG2 0.1–100 [135,140] Taxifolin, Dihydromyricetin LucRGA Flavolignane LucRGA H1L6.1c2 25 [139] Silymarin Flavanones Alpinetin, Eriodictyol, Flavanone, HepG2, MCF-7, LucRGA, Hesperetin, Hesperidin, Isoxanthohumol, HepG2 AhR-Lucia, RT-qPCR, [136,137,139, Naringenin, Naringin, H1L6.1c2, Caco2, 0.1–100 WB, ChIP, 141,142] Naringenin Trimethyl Ether, YAMC, PBMEC/C1-2, Co-IP, EROD Sakuranetin, 6-Prenylnaringenin, EL-4 8-Prenylnaringenin Flavan 3-ol 3T3-L1 (AhR), WB, LucRGA 30–100 [128,136] Epigallocatechin gallate HepG2 AhR-Lucia Chalcone qPCR, WB THP-1 3.0–30 [143] Cardamonin Isoflavones Caco2, YAMC, Biochanin A, Daidzein, Formononetin, H1L6.1c2, MCF-7, Genistein, Puerarin, Prunetin, RT-qPCR, LucRGA, [136,137,139, HC-04, HepG2 (AZ-AhR), 0.1–1000 40,7-dimethoxy-5-hydroxyisoflavone, WB 144–146] Hepa-1c1c7, 40,5,7-trimethoxyisoflavone, HepG2 AhR-Lucia 30,40,5,7-tetramethoxyisoflavone a Bioassays: Chromatin immunoprecipitation (ChIP), Co-immunoprecipitation (Co-IP), EROD, ethoxyresorufin-O-deethylase (EROD), Immunofluorescence (IF), Immunohistochemical (IHC), Luciferase reporter gene assay (LucRGA), reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR), western blotting (WB). b Cell Lines: draining lymph node (DLN), human breast adenocarcinoma (MCF-7), human colon cancer (HCT116), human epithelial colorectal adenocarcinoma (Caco2), human hepatocyte (HC-04), human hepatoma (HepG2), human monocytic leukemia (THP-1), human prostate carcinoma (LNCaP, CWR22Rv1), mouse adipocytes (3T3-L1), mouse colonic epithelium (YAMC), mouse hepatoma (H1L6.1c2, Hepa-1c1c7), mouse lymphoblast (EL-4), porcine brain microvascular endothelium (PBMEC/C1-2). MoleculesMolecules 2021Molecules, 26 2021Molecules, x FOR, 262021, PEERx 2021 ,FOR 26, ,REVIEWx 26PEER FOR, x FOR PEERREVIEW PEER REVIEW REVIEW 10 of 2110 of 2110 of10 21 of 21

MoleculesMolecules 2021Molecules , 26Molecules2021, x ,FOR2021 26, x ,PEER2021 26FOR, x, 26FORPEERREVIEW, x FORPEER REVIEW PEER REVIEW REVIEW 10 of 2110 of10 21 of 1021 of 21

FlavanonesFlavanonesF lavanonesFlavanones FlavanonesFlavanones Alpinetin,Alpinetin,F Alpinetin,Eriodictyol,lavanonesAlpinetin,Flavanones Eriodictyol, Eriodictyol, Flavanone, Eriodictyol, Flavanone, Flavanone, Hes- Flavanone, Hes- Hes- Hes- HepG2,HepG2, MCF-7,HepG2, HepG2,MCF-7, MCF-7, MCF-7, Alpinetin,Alpinetin,Alpinetin, Eriodictyol,Alpinetin, Eriodictyol, Eriodictyol, Flavanone,Eriodictyol, Flavanone, Flavanone, Hes- Flavanone, Hes- Hes-LucRGA, Hes-LucRGA, LucRGA,LucRGA, HepG2, HepG2, MCF-7,HepG2, HepG2,MCF-7, MCF-7, MCF-7, peretin,peretin, Hesperidin,peretin, peretin,Hesperidin, Hesperidin, Isoxanthohumol, Hesperidin, Isoxanthohumol, Isoxanthohumol, Isoxanthohumol, LucRGA, LucRGA, LucRGA, LucRGA, HepG2 HepG2 AhR-Lucia,HepG2 AhR-Lucia,HepG2 AhR-Lucia, AhR-Lucia, peretin,peretin, Hesperidin,peretin, peretin,Hesperidin, Hesperidin, Isoxanthohumol,Hesperidin, Isoxanthohumol, Isoxanthohumol, Isoxanthohumol, RT-qPCR, RT-qPCR, RT-qPCR, RT-qPCR, HepG2 HepG2 AhR-Lucia,HepG2 AhR-Lucia,HepG2 AhR-Lucia, AhR-Lucia, [136,137,139,14[136,137,139,14[136,137,139,14[136,137,139,14 Naringenin,Naringenin,Naringenin, Naringin,Naringenin, Naringin, Naringin, Naringin, RT-qPCR,RT-qPCR,RT-qPCR, RT-qPCR, H1L6.1c2, H1L6.1c2, Caco2,H1L6.1c2,H1L6.1c2, Caco2, Caco2, Caco2,0.1–100 0.1–100 0.1–100[136,137,139,14 0.1–100[136,137,139,14 [136,137,139,14[136,137,139,14 Naringenin,Naringenin,Naringenin, Naringin,Naringenin, Naringin, Naringin, Naringin, WB, ChIP,WB, WB,ChIP,WB, ChIP, ChIP, H1L6.1c2, H1L6.1c2,H1L6.1c2, Caco2,H1L6.1c2, Caco2, Caco2, Caco2, 0.1–100 0.1–100 0.1–100 0.1–1001,142] 1,142] 1,142] 1,142] NaringeninNaringeninNaringenin TrimethylNaringenin Trimethyl Ether,Trimethyl Trimethyl Ether, Ether, Ether, WB, ChIP,WB,WB, ChIP, WB, ChIP, YAMC, ChIP, YAMC, PBMEC/C1-2,YAMC, YAMC,PBMEC/C1-2, PBMEC/C1-2, PBMEC/C1-2, 1,142]1,142] 1,142] 1,142] NaringeninNaringeninNaringenin TrimethylNaringenin Trimethyl Trimethyl Ether, Trimethyl Ether, Ether, Ether, Co-IP, Co-IP, ERODCo-IP, EROD Co-IP, EROD ERODYAMC, YAMC, PBMEC/C1-2,YAMC, YAMC,PBMEC/C1-2, PBMEC/C1-2, PBMEC/C1-2, Sakuranetin,Sakuranetin,Sakuranetin, 6-PrSakuranetin,enylnaringenin, 6-Prenylnaringenin, 6-Pr 6-Prenylnaringenin,enylnaringenin, Co-IP, Co-IP, ERODCo-IP, ERODCo-IP, EROD EROD EL-4 EL-4 EL-4EL-4 Sakuranetin,Sakuranetin, 6-Prenylnaringenin, 6-Prenylnaringenin, EL-4 EL-4 EL-4 8-Prenylnaringenin8-PrenylnaringeninSakuranetin,8-Prenylnaringenin8-PrenylnaringeninSakuranetin, 6-Pr 6-Prenylnaringenin, enylnaringenin, EL-4 8-Prenylnaringenin8-Prenylnaringenin8-Prenylnaringenin8-Prenylnaringenin FlavanFlavan 3-olFlavan Flavan3-ol 3-ol 3-ol 3T3-L13T3-L1 (AhR),3T3-L1 (AhR),3T3-L1 (AhR), (AhR), FlavanFlavan 3-olFlavan Flavan3-ol 3-ol 3-ol WB, LucRGAWB, WB,LucRGA WB, LucRGA LucRGA 3T3-L1 3T3-L1 (AhR),3T3-L1 (AhR),3T3-L1 (AhR), (AhR), 30–100 30–100 30–100 30–100 [128,136] [128,136] [128,136] [128,136] EpigallocatechinEpigallocatechinEpigallocatechinEpigallocatechin gallate gallate gallate gallate WB, LucRGAWB,WB, LucRGAWB, LucRGA LucRGA HepG2 HepG2 AhR-LuciaHepG2 AhR-LuciaHepG2 AhR-Lucia AhR-Lucia 30–100 30–100 30–100 30–100 [128,136] [128,136] [128,136] [128,136] EpigallocatechinEpigallocatechinEpigallocatechinEpigallocatechin gallate gallate gallate gallate HepG2HepG2 AhR-LuciaHepG2 AhR-LuciaHepG2 AhR-Lucia AhR-Lucia ChalconeChalconeChalcone Chalcone ChalconeChalconeChalcone Chalcone qPCR,qPCR, WB qPCR, WBqPCR, WB WB THP-1 THP-1 THP-1 THP-1 3.0–30 3.0–30 3.0–30 3.0–30 [143] [143] [143] [143] CardamoninCardamoninCardamonin Cardamonin qPCR,qPCR, WBqPCR, WBqPCR, WB WB THP-1 THP-1 THP-1 THP-1 3.0–30 3.0–30 3.0–30 3.0–30 [143] [143] [143] [143] CardamoninCardamoninCardamonin Cardamonin IsoflavonesIsoflavonesIsoflavones Isoflavones IsoflavonesIsoflavonesIsoflavonesIsoflavones Caco2,Caco2, YAMC,Caco2, YAMC,Caco2, YAMC, YAMC, BiochaninBiochanin BiochaninA, Daidzein,Biochanin A, Daidzein, A, Formononetin, Daidzein,A, Daidzein, Formononetin, Formononetin, Formononetin, Caco2,Caco2, YAMC,Caco2, YAMC,Caco2, YAMC, YAMC, BiochaninBiochaninBiochanin A,Biochanin Daidzein, A, Daidzein, A, Daidzein, A,Formononetin, Daidzein, Formononetin, Formononetin, Formononetin, H1L6.1c2,H1L6.1c2, MCF-7,H1L6.1c2,H1L6.1c2, MCF-7, MCF-7, MCF-7, Genistein,Genistein, Genistein,Puerarin,Genistein, Puerarin, Prunetin, Puerarin, Puerarin, Prunetin, 4 Prunetin,′,7-di- Prunetin, 4′,7-di- 4′RT-qPCR,,7-di- 4′,7-di-RT-qPCR, Lu-RT-qPCR,RT-qPCR, Lu- Lu-H1L6.1c2, Lu-H1L6.1c2,H1L6.1c2, MCF-7,H1L6.1c2, MCF-7, MCF-7, MCF-7, [136,137,139,14[136,137,139,14[136,137,139,14[136,137,139,14 Genistein,Genistein,Genistein, Puerarin,Genistein, Puerarin, Puerarin, Prunetin, Puerarin, Prunetin, Prunetin, 4′,7-di- Prunetin, 4′,7-di- 4′,7-di-RT-qPCR, 4′,7-di-RT-qPCR,RT-qPCR, Lu-RT-qPCR, Lu-HC-04, Lu-HC-04, Lu- HepG2HC-04, HepG2HC-04, (AZ-AhR), HepG2 (AZ-AhR),HepG2 (AZ-AhR), (AZ-AhR),0.1–1000 0.1–1000 0.1–1000[136,137,139,140.1–1000 [136,137,139,14 [136,137,139,14 [136,137,139,14 methoxy-5-hydroxyisoflavone,methoxy-5-hydroxyisoflavone,methoxy-5-hydroxyisoflavone,methoxy-5-hydroxyisoflavone, 4′,5,7- 4′,5,7- 4′,5,7-cRGA, 4′,5,7-cRGA, WBcRGA, WBcRGA, HC-04,WB WB HC-04, HepG2HC-04, HepG2HC-04, (AZ-AhR), HepG2 (AZ-AhR),HepG2 (AZ-AhR), (AZ-AhR), 0.1–1000 0.1–1000 0.1–10000.1–1000 4–146] 4–146] 4–146] 4–146] methoxy-5-hydroxyisoflavone,methoxy-5-hydroxyisoflavone,methoxy-5-hydroxyisoflavone,methoxy-5-hydroxyisoflavone, 4′,5,7- 4′,5,7- 4′,5,7- cRGA,4′,5,7-cRGA, WBcRGA, WBcRGA, WB WBHepa-1c1c7, Hepa-1c1c7,Hepa-1c1c7, Hepa-1c1c7, 4–146]4–146] 4–146] 4–146] trimethoxyisoflavone,trimethoxyisoflavone,trimethoxyisoflavone,trimethoxyisoflavone, 3′,4′,5,7-tetra- 3′,4′,5,7-tetra- 3′,4 ′3,5,7-tetra-′,4′,5,7-tetra- Hepa-1c1c7,Hepa-1c1c7,Hepa-1c1c7, Hepa-1c1c7, trimethoxyisoflavone,trimethoxyisoflavone,trimethoxyisoflavone,trimethoxyisoflavone, 3′,4′,5,7-tetra- 3′,4 ′3,5,7-tetra-′,4′ ,5,7-tetra-3′,4′,5,7-tetra- HepG2HepG2 AhR-LuciaHepG2 AhR-LuciaHepG2 AhR-Lucia AhR-Lucia methoxyisoflavonemethoxyisoflavonemethoxyisoflavonemethoxyisoflavone HepG2HepG2 AhR-LuciaHepG2 AhR-LuciaHepG2 AhR-Lucia AhR-Lucia methoxyisoflavone methoxyisoflavonea Bioassays:methoxyisoflavonea Bioassays:methoxyisoflavonea ChromatinBioassays:a Bioassays: Chromatin Chromatinimmunoprecipitation Chromatin immunoprecipitation immunoprecipitation immunoprecipitation (ChIP), (ChIP), Co-i (ChIP),mmunoprecipitation Co-i(ChIP), mmunoprecipitationCo-i Co-immunoprecipitationmmunoprecipitation (Co-IP), (Co-IP), EROD, (Co-IP), (Co-IP),EROD, ethoxyresorufin-O- EROD, ethoxyresorufin-O-EROD, ethoxyresorufin-O- ethoxyresorufin-O- a a deethylase Bioassays:deethylase Bioassays: a(EROD),deethylase Bioassays: Chromatindeethylasea Bioassays:(EROD), ImmunofluorescenceChromatin (EROD), Chromatin (EROD),Immunofluorescenceimmunoprecipitation Chromatin Immunofluorescenceimmunoprecipitation Immunofluorescenceimmunoprecipitation immunoprecipitation (IF), Immunohistochemical (I(ChIP),F), Immunohistochemical(I (ChIP),F), (I Co-iImmunohistochemicalF),(ChIP), Immunohistochemical mmunoprecipitationCo-i(ChIP), Co-immunoprecipitation (IHC), mmunoprecipitationCo-i (IHC),mmunoprecipitationLuciferase (IHC), Luciferase(Co-IP), (IHC), reporter Luciferase(Co-IP), Luciferase EROD, (Co-IP),reporter gene (Co-IP), EROD,reporter ethoxyresorufin-O-assay EROD,genereporter ethoxyresorufin-O-EROD, gene(LucRGA),assay ethoxyresorufin-O- gene assay (LucRGA),ethoxyresorufin-O- assay (LucRGA), (LucRGA), reversedeethylasereversedeethylase transcriptase-quantitativedeethylasereverse (EROD), transcriptase-quantitativereversedeethylase (EROD), transcriptase-quantitative Immunofluorescence(EROD), transcriptase-quantitative (EROD),Immunofluorescence Immunofluorescence polymerase Immunofluorescence polymerase (I F),polymerasechai Immunohistochemicalpolymerase(InF), reactionchai (IImmunohistochemicalF),n chai (IreactionImmunohistochemicalF), (RT-qPCR), chain Immunohistochemical reactionn (RT-qPCR),reaction 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Molecules 2021, 26, 2315 As presentedAs presentedAs inpresentedAs Table presented in Table1, in Tablerecent in1, Tablein recent1, years, in 1, recent in years, accurate recent years, accurate years, and accurate informative accurate and informativeand and informative techniques informative techniques techniques10 such of techniques 20 as such suchas such as as RT-qPCR,RT-qPCR,As presented RT-qPCR,LucRGA,As RT-qPCR,presentedAs LucRGA, presentedAs in ChIP,LucRGA, presentedTable LucRGA,in ChIP, Co-IP,Table 1,in inTableChIP, in Co-IP,recent1, EROD, ChIP, Tablein 1, Co-IP,recent inyears,EROD, Co-IP, 1, recentIF, in EROD,years,IHC, recentaccurate IF, EROD,years, andIHC,accurate IF,years, accurate andWBIHC,IF, and accurateIHC,informative haveand WBand and informative and beenhaveWB andinformative WB have usedbeen techniquesinformative have been tousedtechniques assessbeen techniques used to such techniquesusedassess the to suchas assessto thesuch assessas suchthe as the as modulatoryRT-qPCR,modulatoryRT-qPCR,RT-qPCR,modulatory LucRGA,capacitymodulatoryRT-qPCR, LucRGA, capacity LucRGA,of ChIP, capacity flavon LucRGA, capacity ofChIP, Co-IP, flavonoids ChIP, of Co-IP, flavon on ChIP,ofEROD,oids Co-IP,flavonAhR. onoidsEROD, Co-IP, Meanwhile,IF,AhR. oidsEROD, on IHC, AhR.IF,EROD, onMeanwhile, AhR.IHC,IF,and Meanwhile, theIHC, IF, WBMeanwhile,and testedIHC, and havetheWB testedand concentrationsWB thehavebeen thetestedWBhave concentrations beenused tested have been concentrations usedto concentrationsbeen assessareused to com- usedassess areto the assess com- to are the assess arecom- the com- the monlymodulatorymonlymodulatory betweenmodulatorymonly between capacitymonlymodulatoryAs 10 between presented capacity μ Mbetween 10ofcapacity and flavonμ capacityM 10inof 100 Table andflavonμ10 ofoidsM μ μ flavon1M.100and ,Mof on inoids Theflavon and recent μAhR.100M.oids on main100 μThe AhR. years,oids Meanwhile,onM. μ AhR.mainsubclassesM.The on Meanwhile, accurate TheAhR. main Meanwhile,subclasses main the Meanwhile, and subclassesof tested informativetheflavonoidssubclasses of testedthe concentrations flavonoids testedtheof concentrations techniques flavonoids oftestedstudied concentrationsflavonoids studied concentrations as suchare studiedAhR com- arestudiedas AhRcom-are as com- are AhRas com-AhR as RT-qPCR, LucRGA, ChIP, Co-IP, EROD, IF, IHC, and WB have been used to assess modulatorsmonlymodulatorsmonly betweenmonlymodulators are betweenmodulatorsmonly flavones, between 10are μ betweenflavones, Mare10 andflavonols, μ areflavones,10M μ100flavones, and10 Mflavonols, μandμ 100M M. flavanones,flavonols, and 100 Theμflavonols,M. flavanones, 100 μ mainTheM. flavanones,μ TheandM.main subclassesflavanones, Themainisoflavones. andsubclasses main subclassesisoflavones.and of andsubclasses isoflavones.flavonoids Inof isoflavones. these flavonoids of In flavonoids fourtheseof studied Inflavonoids theseclasses, In fourstudied these as studiedfourclasses, AhRag- four studiedas classes, AhR asag-classes, AhR as ag- AhR ag- modulatorsmodulatorsmodulatorsthe aremodulators modulatory flavones, are flavones,are capacity flavones, areflavonols, flavones, flavonols, of flavonoids flavonols, flavanones, flavonols, flavanones, on flavanones, AhR. and flavanones, Meanwhile, isoflavones.and and isoflavones. and theisoflavones. tested Inisoflavones. these concentrationsIn these fourIn these Inclasses,four these four areclasses, ag-four classes, classes,ag- ag- agonist and/oronistonist commonlyand/or antagonistonist and/or antagonistand/or between antagonistactivities, antagonist 10 activities,µM as andactivities, wellactivities, 100 as µ aswellM. asinactivity The wellas main inactivitywell as subclasses oninactivityas AhR-mediatedinactivity on ofAhR-mediated on flavonoids AhR-mediatedon AhR-mediated effects studied effects are as effectsre- are effects re-are arere- re- onist onistand/or and/or antagonist antagonist activities, activities, as well as wellas inactivity as inactivity on AhR-mediated on AhR-mediated effects effects are re- are reported,ported, as onistported,summarizedAhR asported,onist modulatorsand/or summarized as and/or summarizedas antagonist insummarized are Tableantagonist flavones, in Table2 activities,in(Flavones), flavonols, Table in activities,2 (Flavones),Table 2 as flavanones,(Flavones), Table 2well (Flavones),as well Table3as (Flavonols), andinactivity asTable 3 isoflavones. inactivity(Flavonols),Table 3 (Flavonols),on 3Table (Flavonols), InAhR-mediatedon these TableAhR-mediated4 (Flavanones), four Table 4 classes, (Flavanones),Table 4 effects (Flavanones), 4 effects(Flavanones), are re-are re- andported, Tableandported, as ported,Table5andagonist (Isoflavones).summarized andported,as Table 5 summarized and/or(Isoflavones).asTable summarized5 as (Isoflavones). 5 antagonistsummarizedin (Isoflavones). Table in Table in2 activities, (Flavones),Table in 2 Table(Flavones), 2 as (Flavones), well 2 Table (Flavones), as inactivityTable 3 (Flavonols),Table 3 Table(Flavonols), on 3 AhR-mediated(Flavonols), 3 Table(Flavonols), Table 4 (Flavanones),Table effects 4 Table(Flavanones), are4 (Flavanones), 4 (Flavanones), and Tableandand Tablereported, 5 (Isoflavones). andTable 5 (Isoflavones).Table as 5 summarized(Isoflavones). 5 (Isoflavones). in Table 2 (Flavones), Table3 (Flavonols), Table4 (Flavanones), Table Table2. StructuresTable 2. StructuresTable 2. and andStructures 2. AhRStructures Table and activity5 AhR (Isoflavones).and andactivityAhR reported AhR activity reported activity for reported the reportedfor flavone the for flavone classthefor flavonethe of class flavonecompounds. ofclass compounds. class of compounds. of compounds. TableTable 2. StructuresTable 2. TableStructures 2. Structures and 2. Structures AhR and activityandAhR AhRand activity reported AhR activity reported activity forreported the reported for flavone the for flavonethe for class flavone the ofclass flavone compounds. class of compounds. class of compounds. of compounds. Table 2. Structures and AhR activity reported for the flavone class of compounds. FlavonesFlavones FlavonesFlavones FlavonesFlavonesFlavones Flavones FlavoneFlavoneFlavones Flavone Flavone ChrysinChrysin Chrysin Chrysin ApigeninApigenin ApigeninApigenin LuteolinLuteolin LuteolinLuteolin Apigenin Luteolin FlavoneFlavone Flavone Flavone Flavone ChrysinChrysin Chrysin ChrysinChrysin ApigeninApigeninApigenin Apigenin LuteolinLuteolin LuteolinLuteolin

AgonistAgonist [139]Agonist Agonist[139] [139] [139] Agonist Agonist [133,139]Agonist Agonist[133,139] [133,139] [133,139] Agonist Agonist [135,136,139]Agonist Agonist[135,136,139] [135,136,139] [135,136,139] Agonist Agonist [135]Agonist Agonist[135] [135] [135] AgonistAgonist [139]AgonistAgonist [139]Agonist [139] [ 139[139] ] AgonistAgonist [133,139]AgonistAgonistAgonist [133,139] [[133,139] 133, 139[133,139] ] Agonist AgonistAgonist [135,136,139]AgonistAgonist [[135,136,139]135, 136[135,136,139],139 [135,136,139] ] AgonistAgonistAgonist [135 [135]Agonist] Agonist [135] [135] [135] AntagonistAntagonistAntagonist [129]AntagonistAntagonist [129] [129] [129 [129] ] Antagonist AntagonistAntagonist [129]AntagonistAntagonist [129] [129 [129] ] [129] Antagonist AntagonistAntagonistAntagonist [129]Antagonist [ 129 [129]] [129] [129] Antagonist AntagonistAntagonistAntagonist [ 147[147]Antagonist] [147] [147] [147] AntagonistAntagonistAntagonist [129]Antagonist [129] [129] [129] Antagonist AntagonistAntagonist [129]Antagonist [129] [129] [129] AntagonistAntagonistAntagonist [129]Antagonist [129] [129] [129] AntagonistAntagonistAntagonist [147]Antagonist [147] [147] [147] Tricetin TricetinTricetin ScutellareinScutellareinScutellarein Scutellarein AcacetinAcacetin GenkwaninGenkwanin Tricetin Tricetin Scutellarein Acacetin Acacetin GenkwaninGenkwanin Genkwanin TricetinTricetin Tricetin Tricetin ScutellareinScutellareinScutellarein Scutellarein AcacetinAcacetin AcacetinAcacetin GenkwaninGenkwaninGenkwanin Genkwanin

MoleculesMolecules 2021, 26 2021, x FOR, 26, xPEER FOR REVIEWPEER REVIEW 11 of 2111 of 21

MoleculesMolecules 2021 2021, 26, 26, x, FORx FOR PEER PEER REVIEW REVIEW 1111 of of 21 21 Molecules 2021, 26, x FOR PEER REVIEW 11 of 21

AgonistAgonist [135]Agonist Agonist[135]Agonist [135] [ 135[135] ] Agonist Agonist [136] Agonist Agonist Agonist[136] [ 136[136] ] [136] Agonist Ag Agonist [137]onist Ag [onist Ag137[137]]onist [137] [137] Non-agonist Non-agonist Non-agonist Non-agonist [ 137[137] Non-agonist] [137] [137] [137] 4′,7-Dimethoxy-5-Agonist4′,7-Dimethoxy-5-Agonist [135] [135] Agonist Agonist [136] [136] Ag0 0 onist Ag onist[137] [137] Non-agonist Non-agonist [137] [137] Agonist4′4,7-Dimethoxy-5-Agonist0′,7-Dimethoxy-5- [135] [135] 4′,5,7-Trimethoxyflavone 4′,5,7-Trimethoxyflavone Agonist Agonist [136] [136]3 ′,4 ′,5,7-tetramethoxyflavone 3′,43′,5,7-tetramethoxyflavone,4 ,5,7-tetramethoxyflavone Agonist Agonist [137] [137] TangeretinTangeretinTangeretin Non-agonist Non-agonist [137] [137] 44′,7-Dimethoxy-5-′,7-Dimethoxy-5-,7-Dimethoxy-5- 4′4,5,7-Trimethoxyflavone4′,5,7-Trimethoxyflavone0,5,7-Trimethoxyflavone 3′3,4′,4′,5,7-tetramethoxyflavone′,5,7-tetramethoxyflavone TangeretinTangeretin hydroxyflavonehydroxyflavonehydroxyflavone 4′,5,7-Trimethoxyflavone 3′,4′,5,7-tetramethoxyflavone Tangeretin hydroxyflavonehydroxyflavonehydroxyflavone

AgonistAgonistAgonist [[137]137 [137]] Non-agonist Non-agonist Non-agonist [137] [ 137[137]] Agonist Agonist [137] [137[137]] Antagonist Antagonist Antagonist [[132]132 [132]] AgonistAgonist [137] Agonist[137]Agonist [137] [137] Non-agonist Non-agonist Non-agonist Non-agonist [137] [137] [137] [137] Agonist Agonist Agonist Agonist [137] [137] [137] [137] Antagonist Antagonist Antagonist Antagonist [132] [132][132] [132] LuteolinLuteolin 7,3 7,3′-diglucoside′-diglucosideLuteolin 7,30-diglucoside Baicalin Baicalin Luteolin 7,3′-diglucoside BaicalinBaicalin LuteolinLuteolin 7,3′-diglucoside 7,3′-diglucoside BaicalinBaicalin

AgonistAgonist [131,139] [131,139] Agonist [131[131,139] ,139] AntagonistAntagonist [128] [128] AntagonistAntagonist [130] [130] AntagonistAntagonist [128] [ 128[128]] AntagonistAntagonist [130] [ 130[130]] AgonistAgonist [131,139] [131,139] TableTable 3. 3. Structures Structures and and AhR AhR activi activityty reported reported for for the theAntagonist flavon flavonAntagonistolol class class [128]of of compounds. compounds. [128] AntagonistAntagonist [130] [130]TableTable 3. 3. Structures Structures and and AhR AhR activi activityty reported reported for for the the flavon flavonolol class class of of compounds. compounds. Flavonols FlavonolsFlavonols FlavonolFlavonolTable Table 3. Structures 3. Structures and AhR andGalangin activi AhR tyactivi reportedty reported for the for flavonKaempferol the flavonol class ol ofclass compounds. of compounds.FisetinFisetin FlavonolFlavonol GalanginGalangin KaempferolKaempferol FisetinFisetin FlavonolsFlavonols FlavonolFlavonol GalanginGalangin KaempferolKaempferol FisetinFisetin

AgonistAgonist [128] [128] AgonistAgonist [135] [135] AgonistAgonist [135,139] [135,139] AgonistAgonist [128] [128] AntagonistAntagonist [128] [128] AgonistAgonist [135] [135] AgonistAgonist [135,139] [135,139] Antagonist [128] AntagonistAntagonist [128] [128] Antagonist [128,135] Antagonist [128,135] AntagonistAntagonist [128] [128] AntagonistAntagonist [128,135] [128,135] AntagonistAntagonist [128,135] [128,135] 3,6,23,6,2′,4′,4′-Tetrahydroxyflavone′-Tetrahydroxyflavone MorinMorin QuercetinQuercetin 3,6,2′,3′-Tetrahydroxyflavone 3,6,23,6,2′,4′,4′-Tetrahydroxyflavone′-Tetrahydroxyflavone MorinMorin QuercetinQuercetin 3,6,23,6,2′,3′′,3,3′-Tetrahydroxyflavone′′-Tetrahydroxyflavone-Tetrahydroxyflavone AgonistAgonist [128] [128] AgonistAgonist [135] [135] AgonistAgonist [135,139] [135,139] AntagonistAntagonist [128] [128] AntagonistAntagonist [128] [128] AntagonistAntagonist [128,135] [128,135] Antagonist Antagonist [128,135] [128,135] 3,6,2 ′,43,6,2′-Tetrahydroxyflavone′,4′-Tetrahydroxyflavone MorinMorin QuercetinQuercetin 3,6,2′,33,6,2′-Tetrahydroxyflavone′,3′-Tetrahydroxyflavone AgonistAgonist [135] [135] AgonistAgonist [135] [135] AgonistAgonist [135,139] [135,139] AgonistAgonist [135] [135] AgonistAgonist [135] [135] AgonistAgonist [135] [135] AgonistAgonist [135,139] [135,139] AgonistAgonist [135] [135] Antagonist [135] Antagonist [129] Antagonist [128] AntagonistAntagonist [135] [135] AntagonistAntagonist [129] [129] AntagonistAntagonist [128] [128] Robinetin IsorhamnetinIsorhamnetin RobinetinRobinetin Gossypetin MyricetinMyricetin IsorhamnetinIsorhamnetin GossypetinGossypetin Myricetin

AgonistAgonist [135] [135] AgonistAgonist [135] [135] AgonistAgonist [135,139] [135,139] AgonistAgonist [135] [135] AntagonistAntagonist [135] [135] AntagonistAntagonist [129] [129] AntagonistAntagonist [128] [128]

RobinetinRobinetin IsorhamnetinIsorhamnetin GossypetinGossypetin MyricetinMyricetin AgonistAgonist [135] [135] AgonistAgonist [135] [135] Agonist Agonist [135] [135] AgonistAgonist [135] [135] AntagonistAntagonist [129] [129] AgonistAgonist [135] [135] Agonist Agonist [135] [135] Antagonist [129] AntagonistAntagonist [129] [129] AntagonistAntagonist [129] [129] Tamarixetin IcaritinIcaritin TamarixetinTamarixetin Icaritin

Guaijaverin Quercitrin GuaijaverinGuaijaverin QuercitrinQuercitrin

AgonistAgonist [135] [135] AgonistAgonist [135] [135] Agonist Agonist [135] [135] AntagonistAntagonist [129] [129] AntagonistAntagonist [129] [129] TamarixetinTamarixetin IcaritinIcaritin

GuaijaverinGuaijaverin QuercitrinQuercitrin

MoleculesMoleculesMoleculesMolecules 2021 2021, ,2021 26 202126, ,x x, , FOR 26FOR26,, xx PEER FORPEERFOR PEERPEERREVIEW REVIEW REVIEWREVIEW 1111 of of 2111 1121 ofof 2121 Molecules Molecules Molecules 2021, , 2021 262021,, xx, ,FOR26FOR 26, ,x x PEERFORPEER FOR PEER PEERREVIEWREVIEW REVIEW REVIEW 11 of 112111 of of 21 21 Molecules Molecules MoleculesMolecules Molecules Molecules 2021 20212021, , 2021, 26 202126262021,, , x xx, , FOR26 ,FORFOR26 26, ,x ,x x PEERFOR PEERPEERFOR FOR PEER PEER REVIEW PEERREVIEWREVIEW REVIEW REVIEW REVIEW 111111 of ofof 1121 21112111 of of of 21 21 21

44′,7-Dimethoxy-5-′,7-Dimethoxy-5-44′′,7-Dimethoxy-5-,7-Dimethoxy-5- 4′′,7-Dimethoxy-5-,7-Dimethoxy-5-44′,7-Dimethoxy-5-′,7-Dimethoxy-5- 44′,5,7-Trimethoxyflavone′,5,7-Trimethoxyflavone44′′,5,7-Trimethoxyflavone,5,7-Trimethoxyflavone 33′,4 ′ ,4′,5,7-tetramethoxyflavone′3,5,7-tetramethoxyflavone3′′,4,4′′,5,7-tetramethoxyflavone,5,7-tetramethoxyflavone TangeretinTangeretinTangeretinTangeretin 444hydroxyflavone′′hydroxyflavone,7-Dimethoxy-5-′,7-Dimethoxy-5-,7-Dimethoxy-5-444hydroxyflavone′hydroxyflavone′,7-Dimethoxy-5-,7-Dimethoxy-5-′,7-Dimethoxy-5- 4′′,5,7-Trimethoxyflavone,5,7-Trimethoxyflavone44′′,5,7-Trimethoxyflavone,5,7-Trimethoxyflavone′,5,7-Trimethoxyflavone 3′ ′ ,4,4 ′′,5,7-tetramethoxyflavone,5,7-tetramethoxyflavone33′′,4,4′,4′′,5,7-tetramethoxyflavone,5,7-tetramethoxyflavone′,5,7-tetramethoxyflavone TangeretinTangeretinTangeretin hydroxyflavonehydroxyflavonehydroxyflavone 444′′,5,7-Trimethoxyflavone′,5,7-Trimethoxyflavone,5,7-Trimethoxyflavone44′,5,7-Trimethoxyflavone′,5,7-Trimethoxyflavone 333′′,4′,4 ,4 ′′,5,7-tetramethoxyflavone′,5,7-tetramethoxyflavone,5,7-tetramethoxyflavone33′,4′,4′,5,7-tetramethoxyflavone′,5,7-tetramethoxyflavone TangeretinTangeretinTangeretinTangeretinTangeretin hydroxyflavonehydroxyflavonehydroxyflavonehydroxyflavonehydroxyflavonehydroxyflavone

AgonistAgonistAgonistAgonist [137] [137] [137] [137] Non-agonist Non-agonist Non-agonist Non-agonist [137] [137] [137] [137] Agonist Agonist Agonist Agonist [137] [137] [137] [137] Antagonist Antagonist Antagonist Antagonist [132] [132] [132] [132] AgonistAgonistAgonist [137] [137] [137] Non-agonist Non-agonist Non-agonist [137] [137] [137] Agonist Agonist Agonist [137] [137] [137] Antagonist Antagonist Antagonist [132] [132] [132] AgonistAgonistAgonistAgonistAgonist [137] [137][137] [137] [137] Non-agonist Non-agonist Non-agonist Non-agonist Non-agonist [137] [137][137] [137] [137] Luteolin LuteolinLuteolinLuteolin Agonist7,3 Agonist Agonist7,3′-diglucoside′ -diglucoside Agonist7,37,3 Agonist′ ′-diglucoside [137]-diglucoside [137][137] [137] [137] Antagonist Antagonist Antagonist Antagonist Antagonist [132] [132][132] [132] [132] BaicalinBaicalinBaicalinBaicalin LuteolinLuteolinLuteolin 7,3′′-diglucoside 7,3 7,3′-diglucoside′-diglucoside BaicalinBaicalinBaicalin LuteolinLuteolinLuteolinLuteolinLuteolinLuteolin 7,3 7,37,3′′-diglucoside′-diglucoside -diglucoside 7,3 7,37,3′′-diglucoside-diglucoside′-diglucoside BaicalinBaicalinBaicalinBaicalinBaicalinBaicalin

AgonistAgonistAgonistAgonist [131,139] [131,139] [131,139][131,139] Molecules 2021, 26,Agonist 2315AgonistAgonist [131,139] [131,139] [131,139] AntagonistAntagonistAntagonistAntagonist [128] [128] [128] [128] 11 of 20 AgonistAntagonistAgonistAgonistAntagonistAgonistAntagonistAgonistAntagonistAgonist [131,139] [131,139][131,139] [130] [130] [131,139] [131,139][131,139] [130] [130] AntagonistAntagonistAntagonist [128] [128] [128] AntagonistAntagonistAntagonist [130] [130] [130] AntagonistAntagonistAntagonistAntagonistAntagonistAntagonist [128] [128][128] [128] [128] [128] AntagonistAntagonistAntagonistAntagonistAntagonistAntagonist [130] [130][130] [130] [130] [130] TableTableTableTable 3. 3. Structures Structures 3.3. StructuresStructures and and AhR andAhRand AhRactivi AhRactivi activityactivity reported reportedtyty reportedreported for for the the forfor flavon flavon thethe flavonflavonolol class classolol classofclass of compounds. compounds. ofof compounds.compounds. TableTableTable 3. StructuresStructures 3. 3. Structures Structures andand AhRAhRand and AhR activiAhRactivi activi activity reportedtyty reported reported for the for for flavon the the flavon flavonol classolol class classof compounds. of of compounds. compounds. TableTableTableTableTable 3.TableTable 3. 3.3.Structures Structures StructuresStructures 3. 3.3. Structures StructuresStructures and and andand AhR AhR andAhRAhR andand activity AhR activi AhRactiviAhRactivi activiactivi tytyactivity reported reported reportedreportedtytyty reported reportedreported for for forfor the the the the for for ﬂavonolfor flavon flavon flavon the thethe flavon flavonflavonololol class class classclassololol of class classof ofclassof compounds. compounds. compounds.compounds. of ofof compounds.compounds. compounds. Flavonols FlavonolsFlavonolsFlavonolsFlavonols FlavonolsFlavonolsFlavonols FlavonolsFlavonolsFlavonolsFlavonolsFlavonols Flavonol Flavonol FlavonolFlavonol GalanginGalanginGalanginGalangin KaempferolKaempferolKaempferolKaempferol FisetinFisetinFisetinFisetin FlavonolFlavonolFlavonol GalanginGalanginGalangin KaempferolKaempferolKaempferol FisetinFisetinFisetin FlavonolFlavonolFlavonolFlavonol GalanginGalangin KaempferolKaempferol FisetinFisetinFisetinFisetinFisetinFisetin FlavonolFlavonolFlavonol GalanginGalanginGalanginGalangin KaempferolKaempferolKaempferolKaempferol Fisetin

AgonistAgonistAgonistAgonist [128] [128] [128] [128] AgonistAgonistAgonistAgonist [135] [135] [135] [135] AgonistAgonistAgonistAgonist [135,139] [135,139] [135,139][135,139] AgonistAgonistAgonistAgonist [128] [128] [[128] 128] AntagonistAntagonistAntagonistAntagonist [128] [128] [128] [128] AgonistAgonistAgonistAgonist [[135]135] [135] [135] AgonistAgonistAgonistAgonist [135,139] [135,139] [[135,139]135,139 ] AntagonistAntagonistAgonistAgonistAgonistAntagonistAntagonistAgonistAgonist [128] [128][128] [128] [128] [128] [128] [128] [128] AntagonistAntagonistAntagonistAntagonist [[128]128] [128] [128] AntagonistAntagonistAgonistAgonistAgonistAntagonistAntagonistAgonistAgonist [128,135] [135] [128,135][135][135] [128,135] [128,135] [135] [135] Antagonist AntagonistAgonistAgonistAgonistAntagonistAntagonistAgonistAgonist [135,139] [135,139][135,139] [128,135] [128,135] [135,139][135,139] [128,135][128,135] AntagonistAntagonistAntagonistAntagonist [128] [[128][128]128 ] AntagonistAntagonistAntagonistAntagonistAntagonistAntagonist [128] [128][128] [128] [128] [128] AntagonistAntagonistAntagonistAntagonist [[128,135]128, 135[128,135] [128,135]] Antagonist AntagonistAntagonistAntagonist [128,135] [[128,135] 128[128,135],135 ] AntagonistAntagonistAntagonistAntagonistAntagonistAntagonist [128] [128][128] [128] [128] [128] 3,6,23,6,2′,4′-Tetrahydroxyflavone′,4′-Tetrahydroxyflavone AntagonistAntagonistAntagonistAntagonistAntagonistAntagonistMorin Morin[128,135] [128,135][128,135] [128,135] [128,135][128,135] Antagonist Antagonist AntagonistAntagonistAntagonistAntagonistQuercetinQuercetin [128,135] [128,135][128,135] [128,135] [128,135][128,135] 3,6,2′3,6,2,40 ′-Tetrahydroxyflavone0 ′,4′-Tetrahydroxyflavone MorinMorin QuercetinQuercetin 3,6,23,6,23,6,2′3,6,2,3′,3′-Tetrahydroxyflavone′-Tetrahydroxyflavone′′,3,30 ′′-Tetrahydroxyflavone-Tetrahydroxyflavone0 3,6,23,6,23,6,2′′3,6,2,4,4,4′′-Tetrahydroxyflavone-Tetrahydroxyﬂavone′,4′,4′-Tetrahydroxyflavone′-Tetrahydroxyflavone MorinMorinMorin QuercetinQuercetinQuercetin 3,6,23,6,2′′3,6,2,3,33,6,2′′-Tetrahydroxyflavone′,3′,3,3′-Tetrahydroxyflavone′-Tetrahydroxyflavone-Tetrahydroxyﬂavone 3,6,23,6,23,6,23,6,2′3,6,2′,4′3,6,2,4,4′′-Tetrahydroxyflavone′-Tetrahydroxyflavone-Tetrahydroxyflavone′′,4,4′,4′′-Tetrahydroxyflavone-Tetrahydroxyflavone′-Tetrahydroxyflavone MorinMorinMorinMorinMorinMorin QuercetinQuercetinQuercetinQuercetinQuercetinQuercetin 3,6,23,6,23,6,23,6,2′3,6,2′,3′3,6,2,3,3′′-Tetrahydroxyflavone′-Tetrahydroxyflavone-Tetrahydroxyflavone′′,3,3′,3′′-Tetrahydroxyflavone-Tetrahydroxyflavone′-Tetrahydroxyflavone

AgonistAgonistAgonistAgonist [135] [135] [135] [135] AgonistAgonistAgonistAgonist [135] [135] [135] [135] AgonistAgonistAgonistAgonist [135,139] [135,139] [135,139][135,139] AgonistAgonistAgonistAgonist [135] [135] [135] [135] AgonistAgonistAgonistAgonist [[135]135 ][135] [135] AgonistAgonistAgonistAgonist [[135]135] [135] [135] AgonistAgonistAgonistAgonist [135,139] [[135,139][135,139]135,139 ] AgonistAgonistAgonistAgonist [135] [135] [[135] 135] AntagonistAgonistAgonistAgonistAntagonistAntagonistAgonistAgonistAgonist [135] [135][135] [135] [135] [135] [135] [135][135] AntagonistAgonistAgonistAgonistAntagonistAntagonistAgonistAgonistAgonist [135] [135][135] [129] [135] [135] [135] [129][129] AgonistAgonistAgonistAntagonistAgonistAntagonistAgonistAntagonistAgonist [135,139] [135,139][135,139] [128] [135,139] [135,139][135,139] [128][128] AgonistAgonistAgonistAgonistAgonistAgonist [135] [135][135] [135] [135] [135] AntagonistAntagonistAntagonistAntagonist [135][[135]135] [135] AntagonistAntagonistAntagonistAntagonist [[129] 129[129]] [129] AntagonistAntagonistAntagonist [128][128] [ 128 [128] ] AntagonistAntagonist [135] [135] AntagonistAntagonist [129] [129] AntagonistAntagonist [128] [128] RobinetinRobinetinRobinetinRobinetin AntagonistAntagonistAntagonistAntagonist [135] [135][135] [135] AntagonistAntagonistAntagonistMyricetinAntagonistMyricetinMyricetin [129] [129][129] [129] AntagonistAntagonistAntagonistIsorhamnetinIsorhamnetinAntagonistIsorhamnetinIsorhamnetin [128] [128][128] [128] RobinetinRobinetinRobinetinRobinetin GossypetinGossypetinGossypetinGossypetin MyricetinMyricetinMyricetin IsorhamnetinIsorhamnetinIsorhamnetin RobinetinRobinetinRobinetinRobinetinRobinetinRobinetin GossypetinGossypetinGossypetinGossypetin MyricetinMyricetin IsorhamnetinIsorhamnetinIsorhamnetinIsorhamnetinIsorhamnetinIsorhamnetin GossypetinGossypetinGossypetinGossypetinGossypetinGossypetin MyricetinMyricetinMyricetinMyricetin

MoleculesMolecules 2021, 262021, x ,FOR 26, x PEER FOR PEERREVIEW REVIEW 12 of 2112 of 21 Molecules 2021, 26, x FOR PEER REVIEW AgonistAgonistAgonistAgonist [[135]135[135]] [135] [135] 12 of 21 AgonistAgonistAgonistAgonist [135] [135] [[135]135 ] Agonist Agonist Agonist Agonist [[135]135 ] [135][135] AgonistAgonistAgonist [135] [135] [135] AntagonistAntagonistAntagonistAntagonist [129] [[129]129[129] ] AgonistAgonistAgonist [135][135] [135] Agonist Agonist Agonist [135][135] [135] AntagonistAgonistAgonistAgonistAgonistAgonistAgonist [135] [135][135] [129 [135] [135]] [135] AntagonistAntagonistAntagonist [129][129] [129] AgonistAgonist [135] [135] Agonist Agonist [135] [135] AntagonistAntagonistAntagonistAntagonist [129] [129] [129] [129] AntagonistAntagonist [129] [129] AgonistAgonistAgonistAgonist [135] [135][135] [135] Agonist Agonist Agonist Agonist [135] [135][135] [135] AntagonistAntagonistAntagonist [129] [129] [129] AntagonistAntagonistAntagonistAntagonist [129] [129][129] [129] IcaritinIcaritinIcaritinIcaritin AntagonistAntagonistAntagonistGuaijaverinAntagonistAntagonist [129] [129][129] [129] [129] Quercitrin TamarixetinTamarixetinTamarixetinTamarixetin IcaritinIcaritinIcaritin TamarixetinTamarixetinTamarixetin IcaritinIcaritinIcaritinIcaritinIcaritinIcaritin TamarixetinTamarixetinTamarixetinTamarixetinTamarixetinTamarixetinTamarixetin Icaritin GuaijaverinGuaijaverinGuaijaverinGuaijaverin QuercitrinQuercitrinQuercitrinQuercitrin GuaijaverinGuaijaverinGuaijaverin QuercitrinQuercitrinQuercitrin GuaijaverinGuaijaverinGuaijaverinGuaijaverinGuaijaverinGuaijaverin QuercitrinQuercitrinQuercitrinQuercitrinQuercitrinQuercitrin

Agonist [128], Antagonist AgonistAgonist [128], [128], Antagonist Antagonist [129] [129] AgonistAgonist Agonist [138] [138 ][138] Agonist Agonist Agonist [136] [136] [136] Antagonist Antagonist Antagonist [128] [[128] 128] Agonist [128], Antagonist[129] [129] Agonist [138] Agonist [136] Antagonist [128] RutinRutin

Rutin

AgonistAgonist [139] [139] Antagonist Antagonist [128] [128] AgonistAgonist [139] [139] Antagonist [128 [128]]

TableTable 4. Structures 4. Structures and AhR and activiAhR activity reportedty reported for the for flav theanone flavanone class classof compounds. of compounds. Table 4. Structures and AhR activity reported for the flavanone class of compounds. FlavanonesFlavanones Flavanones FlavanoneFlavanone NaringeninNaringenin EriodictyolEriodictyol Flavanone Naringenin Eriodictyol

AntagonistAntagonist [129] [129] AntagonistAntagonist [129] [129] Antagonist [129] Antagonist [129] AntagonistAntagonist [128] [128] AgonistAgonist [128] [128] Non-agonistNon-agonist [137] [137] Antagonist [128] Agonist [128] Non-agonist [137] AlpinetinAlpinetin SakuranetinSakuranetin HesperetinHesperetin Alpinetin Sakuranetin Hesperetin

AgonistAgonist [139] [139] AgonistAgonist [148,149] [148,149] Non-agonist Non-agonist [136] [136] Agonist [139] Agonist [148,149] Non-agonist [136] AntagonistAntagonist [142] [142] Antagonist [142] NaringinNaringin Naringin Hesperidin NaringeninNaringenin Trimethyl Trimethyl Ether Ether Hesperidin Naringenin Trimethyl Ether Hesperidin

AgonistAgonist [139] [139] Non-agonistNon-agonist [137] [137] Agonist Agonist [136,139] [136,139] Agonist [139] Non-agonist [137] Agonist [136,139] AntagonistAntagonist [128] [128] Antagonist [128]

MoleculesMoleculesMolecules 2021 2021 2021, 26, ,26 x, 26 ,FOR x, FORx FOR PEER PEER PEER REVIEW REVIEW REVIEW 12 12of12 21of of 21 21 Molecules MoleculesMolecules 2021 20212021, 26,, , x 2626 FOR,, xx FORFOR PEER PEERPEER REVIEW REVIEWREVIEW 12 of1212 21 ofof 2121 MoleculesMolecules 2021 2021, 26,, ,26 x ,,FOR xx FORFOR PEER PEERPEER REVIEW REVIEWREVIEW 12 12of of21 21

AgonistAgonistAgonist [128], [128], [128], Antagonist Antagonist Antagonist [129] [129] [129] Agonist Agonist Agonist [138] [138] [138] Agonist Agonist Agonist [136] [136] [136] Antagonist Antagonist Antagonist [128] [128] [128] AgonistAgonistAgonistAgonist [128], [128], [128], [128], Antagonist Antagonist Antagonist Antagonist [129] [129] [129] [129] Agonist Agonist Agonist Agonist [138] [138] [138] [138][138] Agonist Agonist Agonist Agonist Agonist [136] [136] [136] [136][136] Antagonist Antagonist Antagonist Antagonist Antagonist [128] [128] [128] [128][128] RutinRutinRutin RutinRutinRutinRutin

Molecules 2021, 26, 2315 12 of 20 AgonistAgonistAgonist [139] [139] [139] Antagonist Antagonist Antagonist [128] [128] [128] AgonistAgonistAgonistAgonist [139] [139] [139] [139] Antagonist Antagonist Antagonist Antagonist [128] [128] [128] [128] Table 4. Structures and AhR activity reported for the flavanone class of compounds. TableTableTable 4. Structures4. 4. Structures Structures and and andAhR AhR AhR activi activi activity reportedtyty reported reported for for thefor the flavthe flav anoneflavanoneanone class class class of compounds.of of compounds. compounds. TableTableTableTableTable 4. 4.4. Structures Structures4. Structures4. Structures Structures and andand and and AhR AhRAhR AhR AhR activi activityactivi activi activityty reported reportedtyreportedty reported reported for for for thefor the the flavtheﬂavanone flav flav flavanoneanoneanoneanone class class class class of of compounds. of compounds.of compounds. compounds. FlavanonesFlavanonesFlavanones FlavanonesFlavanonesFlavanonesFlavanonesFlavanones FlavanoneFlavanoneFlavanone NaringeninNaringeninNaringenin EriodictyolEriodictyolEriodictyol FlavanoneFlavanoneFlavanoneFlavanone NaringeninNaringeninNaringeninNaringenin EriodictyolEriodictyolEriodictyolEriodictyol FlavanoneFlavanone Naringenin Eriodictyol

AntagonistAntagonistAntagonist [129] [129] [129] AntagonistAntagonistAntagonist [129] [129] [129] AntagonistAntagonistAntagonistAntagonist [129] [129] [[129] 129[129] ] AntagonistAntagonistAntagonistAntagonist [129] [129] [[129] 129[129] ] AntagonistAntagonistAntagonist [128] [128] [128] AgonistAgonistAgonist [128] [128] [128] Non-agonistNon-agonistNon-agonist [137] [137] [137] AntagonistAntagonistAntagonistAntagonistAntagonist [128] [128[128] [128] [128]] AgonistAgonistAgonistAgonist [128] [128] [ [128]128[128] ] Non-agonistNon-agonistNon-agonistNon-agonist [137] [137] [ 137[137][137] ] Agonist [128] Non-agonistSakuranetin [137] AlpinetinAlpinetinAlpinetin SakuranetinSakuranetinSakuranetinSakuranetin HesperetinHesperetinHesperetin AlpinetinAlpinetinAlpinetinAlpinetinAlpinetin SakuranetinSakuranetinSakuranetinSakuranetin HesperetinHesperetinHesperetinHesperetin

AgonistAgonistAgonistAgonist [[139]139 [139] ][139] AgonistAgonistAgonistAgonist [148,149] [[148,149]148 [148,149],149 ] Non-agonist Non-agonist Non-agonist Non-agonist [136] [[136]136 [136] ] AgonistAgonistAgonistAgonist [139] [139] [139] [139] AgonistAgonistAgonistAgonist [148,149] [148,149] [148,149] [148,149] Non-agonist Non-agonist Non-agonist Non-agonist [136] [136] [136] [136] AntagonistAntagonistAntagonistAntagonist [142[142] [142]] [142] AntagonistAntagonistAntagonistAntagonist [142] [142] [142] [142] NaringinNaringinNaringin NaringinNaringinNaringinNaringin HesperidinHesperidinHesperidin NaringeninNaringeninNaringenin Trimethyl Trimethyl Trimethyl Ether Ether Ether Ether HesperidinHesperidinHesperidin NaringeninNaringeninNaringeninNaringenin Trimethyl Trimethyl Trimethyl Trimethyl Ether Ether Ether Ether HesperidinHesperidin

MoleculesMoleculesMoleculesMolecules 202120212021 2021 20212021,,,, 26,2626 26,,,, x26,x26xx x FORFORFORFOR, , FOR xx FORFOR PEERPEERPEERPEER PEER PEERPEER REVIEWREVIEWREVIEWREVIEW REVIEW REVIEWREVIEW 13131313 ofofof13 13of 2121 21 ofof21 21 21

AgonistAgonistAgonistAgonist [[139]139 [139] ][139] Non-agonistNon-agonistNon-agonistNon-agonist [137] [[137]137 [137] ] Agonist Agonist Agonist Agonist [136,139] [[136,139]136 [136,139],139 ] AgonistAgonistAgonistAgonist [139] [139] [139] [139] Non-agonistNon-agonistNon-agonistNon-agonist [137] [137] [137] [137] Agonist Agonist Agonist Agonist [136,139] [136,139] [136,139] [136,139] AntagonistAntagonistAntagonistAntagonist [128[128] [128]] [128] AntagonistAntagonistAntagonistAntagonist [128] [128] [128][128] 8-Prenylnaringenin8-Prenylnaringenin8-Prenylnaringenin8-Prenylnaringenin IsoxanthohumolIsoxanthohumolIsoxanthohumolIsoxanthohumolIsoxanthohumolAntagonistIsoxanthohumolIsoxanthohumol [128] 6-Prenylnaringenin6-Prenylnaringenin6-Prenylnaringenin6-Prenylnaringenin6-Prenylnaringenin 8-Prenylnaringenin

AgonistAgonistAgonistAgonist [141][141] [141] [ 141[141] ] Agonist Agonist Agonist Agonist [141][141] [141] [ 141[141] ] Non-agonist Non-agonist Non-agonist Non-agonist [ [141]141[141] [141] [141]]

TableTableTableTable 5.5.5. 5. Structures StructuresStructures 5.Structures StructuresStructures andandand and andand AhRAhRAhR AhR AhRAhR activityactivityactivity activity activityactivity reportedreportedreported reported reportedreported for forforfor for for the forthethethe the the the isoﬂavone isoflaisoflaisofla isofla isoflaisoflavonevonevonevone class classclass class class of ofof of compounds. compounds. compounds.of compounds. compounds.

IsoflavonesIsoflavonesIsoflavonesIsoflavonesIsoﬂavonesIsoflavonesIsoflavones DaidzeinDaidzeinDaidzeinDaidzein GenisteinGenisteinGenisteinGenistein FormononetinFormononetinFormononetinFormononetin BiochaninBiochaninBiochaninBiochaninBiochanin A AA A A

AntagonistAntagonistAntagonistAntagonist [ [144]144[144] [144] [144]] AntagonistAntagonistAntagonistAntagonist [[144,146][144,146] 144[144,146] [144,146],146] AgonistAgonistAgonistAgonist [144,145] [[144,145] 144[144,145] [144,145],145] Agonist Agonist Agonist Agonist [139,144,145] [[139,144,145]139[139,144,145] [139,144,145],144,145] Non-agonistNon-agonistNon-agonistNon-agonist [ [145]145[145] [145] [145]] Non-agonistNon-agonistNon-agonistNon-agonist [[136,137][136,137] 136[136,137] [136,137],137] 444′′′,7-dimethoxy-5-,7-dimethoxy-5-,7-dimethoxy-5-′,7-dimethoxy-5-4′′,7-dimethoxy-5-,7-dimethoxy-5- 333′′′,4,4,4′,43′′′,5,7-′,5,7-′,5,7-′,4,4,5,7-′′,5,7-,5,7- PrunetinPrunetinPrunetinPrunetin 444′′′,5,7-trimethoxyisoflavone,5,7-trimethoxyisoflavone,5,7-trimethoxyisoflavone′,5,7-trimethoxyisoflavone4′′,5,7-trimethoxyisoflavone,5,7-trimethoxyisoflavone hydroxyisoflavonehydroxyisoflavonehydroxyisoflavonehydroxyisoflavone tetramethoxyisoflavonetetramethoxyisoflavonetetramethoxyisoflavonetetramethoxyisoflavonetetramethoxyisoflavonetetramethoxyisoflavone

Non-agonistNon-agonistNon-agonistNon-agonist [137][137] [137] [137] Non-agonist Non-agonist Non-agonist Non-agonist [137][137] [137] [137] Agonist Agonist Agonist Agonist Agonist Agonist [137][137][137] [137] [137][137] Non-agonist Non-agonist Non-agonist Non-agonist Non-agonist Non-agonist [137][137][137] [137] [137][137]

PuerarinPuerarinPuerarinPuerarin

Non-antagonistNon-antagonistNon-antagonistNon-antagonistNon-antagonistNon-antagonist [128][128][128] [128] [128][128]

AsAsAs As shown shownshown shown in inin inTables TablesTables Tables 2–5, 2–5,2–5, 2–5, generalizations generalizationsgeneralizations generalizations of ofof ofstructure-activity structure-activitystructure-activitystructure-activity structure-activitystructure-activity relationships relationshipsrelationshipsrelationships relationshipsrelationships are areareare areare not notnotnot notnot possiblepossiblepossiblepossible when whenwhen when studying studyingstudying studying flavonoids flavonoidsflavonoids flavonoids as asas asAh AhAh AhRRR modulators. modulators.Rmodulators. modulators. AhR AhRAhR AhR agonism agonismagonism agonism and andand and antagonism antagonismantagonism antagonism and,and,and,and, in inin manyin manymany many cases, cases,cases, cases, both bothboth both effects effectseffects effects have havehave have been beenbeen been reportedreported reportedreported reportedreported forfor forfor for for flavones,flavones, flavones,flavones, flavones,flavones, flavonols,flavonols, flavonols,flavonols, flavonols,flavonols, flavanones,flavanones, flavanones,flavanones, flavanones,flavanones, andandandand isoflavones.isoflavones. isoflavones. isoflavones. Nevertheless,Nevertheless, Nevertheless, Nevertheless, thethe the the followingfollowing following following patternspatterns patterns patterns emerge.emerge. emerge. emerge. 1.1.1. 1. TheTheTheThe modulation modulationmodulation modulation of ofof ofAhR AhRAhR AhR by byby by aglycones aglyconesaglycones aglycones and andand and glycosides glycosidesglycosides glycosides analogous analogousanalogous analogous does doesdoes does not notnot not seem seemseem seem to toto to differdifferdifferdiffer significantly,significantly, significantly, significantly, noticeablenoticeable noticeable noticeable whenwhen when when comparecompare compare compare flavoneflavone flavone flavone luteolinluteolin luteolin luteolin vs.vs. vs. vs. luteolinluteolin luteolin luteolin 7,37,3 7,3 7,3′′′-diglu--diglu--diglu-′-diglu-′′-diglu--diglu- cosidecosidecosidecosidecosidecoside (Table(Table (Table(Table (Table(Table 2),2), 2),2), 2), 2),thatthat thatthat thatthat bothboth bothboth bothboth displaydisplay displaydisplay displaydisplay blockageblockage blockageblockage blockageblockage effecteffecteffect effect effecteffect ononon on on onAhRAhRAhR AhR AhRAhR transcriptionaltranscriptionaltranscriptional transcriptional transcriptionaltranscriptional activation,activation,activation, activation, activation,activation, althoughalthoughalthoughalthough luteolin luteolinluteolin luteolin also alsoalso also exhibited exhibitedexhibited exhibited agonist agonistagonist agonist ef efeffects. fects.fects.effects.fects.fects. In InInIn Inflavonols,Inflavonols, flavonols,flavonols, flavonols,flavonols, the thethethe thethe prototypicalprototypical prototypicalprototypical prototypicalprototypical AhRAhR AhRAhR AhRAhR modulatormodulatormodulatormodulator quercetin quercetinquercetin quercetin is isis reported reportedisreported reported as asas asan anan an agonist agonistagonist agonist and andand and as asas asan anan an antagonist antagonistantagonist antagonist of ofof theof thethe the receptor receptorreceptor receptor (Table(Table(Table(Table(Table(Table 3),3),3), 3), 3), while3),whilewhile while whilewhile itsitsits its itsglycosideitsglycosideglycoside glycoside glycosideglycoside analogousanalogousanalogous analogous analogousanalogous guaijaveringuaijaveringuaijaverin guaijaverin guaijaveringuaijaverin isisis is describeddescribed describedisisdescribed describeddescribed asasas as agonist,asagonist,asagonist, agonist, agonist,agonist, quercitrinquercitrinquercitrin quercitrin quercitrinquercitrin asasas antagonist,asantagonist, antagonist, antagonist, andand and and rutinrutin rutin rutin hashas has has shownshown shown shown bothboth both both agonistagonist agonist agonist andand and and antagonistantagonist antagonist antagonist effects.effects. effects. effects. TheThe The The flavanoneflavanone flavanone flavanone aglyconeaglyconeaglyconeaglycone hesperetinhesperetin hesperetin hesperetin isis is reported reported isreported reported asas as AhRasAhR AhR AhR antagonist,antagonist, antagonist, antagonist, whilewhile while while exhibitedexhibited exhibited exhibited alsoalso also also AhRAhR AhR AhR agonistagonist agonist agonist effectseffectseffectseffectseffects as asas astheas thethe thethe glycoside glycosideglycoside glycosideglycoside hesperidin. hesperidin.hesperidin. hesperidin.hesperidin. Naringenin NaringeninNaringenin NaringeninNaringenin differs differsdiffers differsdiffers from fromfrom fromfrom naringin naringinnaringin naringinnaringin in inin thein inthethe thethe agonist agonistagonist agonistagonist capacity,capacity,capacity,capacity,capacity,capacity, reportedreportedreported reported reportedreported onlyonly onlyonly onlyonly forfor forfor for for thethe thethe thethe glycosideglycoside glycosideglycoside glycosideglycoside derivativederivative derivativederivative derivativederivative (Table(Table(Table (Table (Table(Table 4).4).4). 4). 4). 4). 2.2.2. 2. FlavoneFlavoneFlavoneFlavone and andand and flavonol flavonolflavonol flavonol analogues analoguesanalogues analogues (Tables (Tables(Tables (Tables 2 22 and and2and and 3) 3)3) do3) dodo do not notnot not display displaydisplay display substantial substantialsubstantial substantial differ- differ-differ- differ- encesencesencesencesences ininin inin theirtheirtheir theirtheir effectseffectseffects effectseffects deduceddeduceddeduced deduceddeduced whenwhenwhen whenwhen compcompcomp compcompareareareare flavoneflavoneflavone flavone vs.vs.vs. vs. flavonol,flavonol,flavonol, flavonol, apigeninapigeninapigenin apigenin vs.vs.vs. vs.

MoleculesMolecules 20212021,,, 2626,,, xxx FORFORFOR PEERPEERPEER REVIEWREVIEWREVIEW 1313 ofof 2121

Isoxanthohumol 8-Prenylnaringenin8-Prenylnaringenin Isoxanthohumol 6-Prenylnaringenin6-Prenylnaringenin

AgonistAgonist [141][141] Agonist Agonist [141][141] Non-agonist Non-agonist [141][141]

TableTable 5.5. StructuresStructures andand AhRAhR activityactivity reportedreportedreported forforfor thethethe isoflaisoflaisoflavonevone classclass ofof compounds.compounds.

IsoflavonesIsoflavones DaidzeinDaidzein GenisteinGenistein FormononetinFormononetin BiochaninBiochanin AA

Molecules 2021, 26, 2315 13 of 20

Table 5. Cont. AntagonistAntagonist [144][144] AntagonistAntagonist [144,146][144,146] AgonistAgonist [144,145][144,145] Agonist Agonist [139,144,145][139,144,145] IsoflavonesNon-agonistNon-agonist [145][145] Non-agonistNon-agonist [136,137][136,137] 44′′′,7-dimethoxy-5-,7-dimethoxy-5-,7-dimethoxy-5-0 33′′0′,4,4,4′′0′,5,7-,5,7-,5,7- PrunetinPrunetin 4 ,7-dimethoxy-5- 44′′′,5,7-trimethoxyisoflavone,5,7-trimethoxyisoflavone0 3 ,4 ,5,7- Prunetin 4′4,5,7-trimethoxyisoflavone,5,7-trimethoxyisoflavone hydroxyisoflavonehydroxyisoflavonehydroxyisoflavone tetramethoxyisoflavonetetramethoxyisoflavonetetramethoxyisoflavone

Non-agonistNon-agonistNon-agonist [ [137]137[137]] Non-agonist Non-agonist Non-agonist [ [137]137[137]] Agonist Agonist Agonist Agonist [[137][137][137]137] Non-agonist Non-agonist Non-agonist Non-agonist [ [137][137]137[137]]

PuerarinPuerarin

Non-antagonistNon-antagonistNon-antagonistNon-antagonist[ [128]128[128][128]]

AsAs shownshown inin TablesTables2 2–5,–2–5,5, generalizations generalizationsgeneralizations of ofof structure-activity structure-activitystructure-activitystructure-activity relationships relationshipsrelationshipsrelationships are areareare not notnotnot possiblepossible whenwhen studyingstudying flavonoidsflavonoidsflavonoids asas AhRAhAhRR modulators.modulators.modulators. AhRAhR agonismagonism andandand antagonismantagonismantagonism and,and, ininin many manymany cases, cases,cases, both bothboth effects effectseffects have havehave been beenbeen reported reportedreported for forfor flavones, flavones,flavones, flavonols, flavonols,flavonols, flavanones, flavanones,flavanones, and andisoflavones.and isoflavones.isoflavones. Nevertheless, Nevertheless,Nevertheless, the following thethe followingfollowing patterns patternspatterns emerge. emerge.emerge. 1.1. TheThe modulationmodulation of ofof AhR AhRAhR by byby aglycones aglyconesaglycones and andand glycosides glycosidesglycosides analogous analogousanalogous does doesdoes not seem notnot seem toseem differ toto differdiffersignificantly, significantly,significantly, noticeable noticeablenoticeable when when comparewhen comparecompare flavone flavoneflavone luteolin luteolinluteolin vs. luteolin vs.vs. luteolinluteolin 7,30-diglucoside 7,37,3′′′-diglu--diglu- cosidecoside(Table2 (Table(Table), that both2),2), thatthat display bothboth blockagedisplaydisplay blockageblockage effect on effect AhReffecteffect transcriptional ononon AhRAhRAhR transcriptionaltranscriptionaltranscriptional activation, activation,activation,activation, although althoughalthoughluteolin also luteolinluteolin exhibited alsoalso exhibited agonistexhibited effects. agonistagonist In flavonols,efeffects.fects. InIn theflavonols,flavonols, prototypical thethe prototypicalprototypical AhR modulator AhRAhR modulatormodulatorquercetin is quercetinquercetin reported asisis anreportedreported agonist asas and anan as agonistagonist an antagonist andand asas ofanan the antagonistantagonist receptor (Tableofof thethe3 receptorreceptor), while (Table(Tableits glycoside 3),3), whilewhile analogous itsits glycosideglycoside guaijaverin analogousanalogous is described guaijaveringuaijaverin as isis agonist, describeddescribed quercitrin asas agonist,agonist, as antagonist, quercitrinquercitrin asasand antagonist,antagonist, rutin has andand shown rutinrutin both hashas shown agonistshown bothboth and agonistagonist antagonist andand effects.antagonistantagonist The effects.effects. flavanone TheThe flavanoneflavanone aglycone aglyconeaglyconehesperetin hesperetinhesperetin is reported isis asreportedreported AhR antagonist, asas AhRAhR antagonist,antagonist, while exhibited whilewhile exhibitedexhibited also AhR also agonistalso AhRAhR effects agonistagonist as effectseffectsthe glycoside asas thethe glycosideglycoside hesperidin. hesperidin.hesperidin. Naringenin NaringeninNaringenin differs from differsdiffers naringin fromfrom naringin innaringin the agonist inin thethe capacity, agonistagonist capacity,capacity,reported reported onlyreported for the onlyonly glycoside forfor thethe glycosideglycoside derivative derivativederivative (Table4). (Table(Table 4).4). 2.2. FlavoneFlavone andand flavonolflavonol flavonol analoguesanalogues (Tables(Tables (Tables 222 andandand3 3))3) do dodo not notnot display displaydisplay substantial substantialsubstantial differ- differ-differ- encesences inin their their effects effects deduceddeduced whenwhen comparecompcompareare flavoneflavoneflavone vs.vs.vs. flavonol, flavonol,flavonol, apigenin vs. vs. kaempferol, and luteolin vs. quercetin. Most of them have shown AhR agonism and AhR antagonism. 3. Comparing the flavone apigenin vs. the isoflavone analogous genistein, the mod-

ification from position 2 to position 3 appears to lead to the loss of agonist effects (Tables2 and5) . Similarly, a loss of agonism is observed when compared to unsatu- rated analogous (apigenin and kaempferol) vs. the saturated flavanone naringenin (Tables2–4). 4. The hydroxy-analogous derivatives representing the four classes of flavonoids: apigenin kaempferol, naringenin, and genistein have displayed AhR antagonist activity (Tables2–5). 5. In flavone derivatives, the 7-methoxy substitution causes a loss of agonist capacity noticeable when compared genkwanin vs. the tri-hydroxy substituted apigenin (Table2). In flavanones (naringenin vs. sakuranetin) (Table4) and isoflavones (genistein vs. prunetin) (Table5), 7-methoxy derivatives and 7-hydroxy derivatives are all reported as non-agonist of AhR. The 7-hydroxy flavanone naringenin and the 7-hydroxy isoflavone genistein have shown AhR antagonism. 6. The 4-methoxy substitution does not seem to affect the AhR agonist potential in flavones (acacetin vs. apigenin) (Table2). Molecules 2021, 26, 2315 14 of 20

7. In isoflavones, 40-methoxy substitution confers AhR agonist activity (daidzein vs. formononetin and biochanin A vs. genistein) (Table5). 8. Compounds 40,5,7-trimethoxy flavone (Table2) and 4 0,5,7-trimethoxy flavanone (Table4) both lack AhR agonist effects. However, the analogous 4 0,5,7-trimethoxy isoflavone (Table5) is an AhR agonist. 9. The 40,7-dimethoxy substitution is positive for AhR agonism in flavones compared to 40,5,7-trimethoxy substitution (Table2). The opposite occurs in isoflavones (Table5). 10. The 30,40,5,7-tetramethoxyflavone is AhR agonist (Table2), but the analogous 3 0,40,5,7- tetramethoxyisoflavone does not activate the receptor (Table5). 11. Most of the prenylated flavonoids are described as AhR agonists, such as the flavonol icaritin (Table3) and the flavanones 6-prenylnaringenin and 8-prenylnaringenin (Table4). However, this is not the case of the flavanone isoxanthohumol (Table4). Historically, the effect of flavonoids on AhR was associated with their capacity to suppress the receptor transcriptional activity [150]. However, as demonstrated in this review, the range of AhR agonist and antagonist effects of flavonoids have been shown to be much more complex and diverse than previously thought. The analysis of the structural substitution patterns of flavonoids does not appear to lead to general predictions of their potential AhR modulation. Differences in bioassays and experimental conditions and laboratories could be playing an important role in the AhR activity profile reported in the literature for flavonoids. Furthermore, as previously mentioned, several AhR, including some flavonoids, are considered to be SAhRMs. That is, the type of tissue and organ in which the AhR effects caused by these ligands are evaluated largely determines their behavior on the receptor [19,151]. Such selectivity on AhR could probably contribute to the therapeutical applicability of flavonoids as AhR mediators, as it has been suggested for the isoflavones biochanin A and formononetin used to ameliorate menopausal complaints [151]. However, the complexity and broad-based evidence required to ensure optimal ligand effects, in the absence of readily predictive AhR agonism and/or antagonism, is a matter that should be extensively studied. Therefore, further investigations on AhR transcriptional modulation caused by flavonoids need to be conducted in order to regulate their harmful consequences and get the most of their therapeutical potential through this pathway.

4. Conclusions Despite several decades of research on flavonoid derivatives, these ubiquitous con- stituents of food remain surprising for their bioactivity profiles. AhR is a pleiotropic chemosensor with toxicological and pharmacological implications. Therefore, AhR modulation caused by flavonoids could impact several fields including food science, nutrition, drug discovery, agronomy, and environmental research. Basic research on AhR and its multiple modulators, including the diet-incorporated flavonoids, could provide useful premises to health care, adequate nutrition, and risk assessment in the translational science paradigm.

5. Search Methodology The data collected in this review article aimed to concisely summarize the structural characteristics and functions of the transcription factor AhR (from 1990–2020), as well as to identify all plant flavonoids that have been evaluated as AhR modulators (from 2000– 2020). The most common and accurate sources were used to run the search including the scientific databases PubMed, Scopus, Web of Science, Science Direct, and Google Scholar. Keywords used to carry out the search included “dioxin receptor”, “ah receptor”, “aryl hydrocarbon receptor”, and “flavonoid”. The search syntaxes for the different databases were considered. Results of the search strategies implemented independently by two researchers were contrasted. Molecules 2021, 26, 2315 15 of 20

Author Contributions: Conceptualization, Investigation, Writing—original Draft, E.G.-J.; Investi- gation: Data/evidence collection, M.E.J.R.; Formal analysis & SAR suggestions, M.S.-I.V.; Formal Analysis, Supervision, Project administration, R.M.G. All authors have read and agreed to the published version of the manuscript. Funding: The preparation of this bibliographic review was financially supported by “PROTECTED” project (http://protected.eu.com/), that has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 722634. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: Not applicable. Acknowledgments: Authors acknowledge the website SMART (Servier Medical Art) https://smart. servier.com (accessed on 7 July 2020) for supplying some of the structures used in Figure2. Conflicts of Interest: The authors declare no conflict of interest.

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