Plant Occurring Flavonoids as Modulators of the Aryl Hydrocarbon Receptor
Abstract
:1. Introduction
2. Aryl Hydrocarbon Receptor
2.1. Functional Domains
2.2. Cytoplasmic Complex and Signaling Pathways
2.3. AhR Effects and Modulators
3. Flavonoids: Generalities and Modulating Effects of AhR
- The modulation of AhR by aglycones and glycosides analogous does not seem to differ significantly, noticeable when compare flavone luteolin vs. luteolin 7,3′-diglucoside (Table 2), that both display blockage effect on AhR transcriptional activation, although luteolin also exhibited agonist effects. In flavonols, the prototypical AhR modulator quercetin is reported as an agonist and as an antagonist of the receptor (Table 3), while its glycoside analogous guaijaverin is described as agonist, quercitrin as antagonist, and rutin has shown both agonist and antagonist effects. The flavanone aglycone hesperetin is reported as AhR antagonist, while exhibited also AhR agonist effects as the glycoside hesperidin. Naringenin differs from naringin in the agonist capacity, reported only for the glycoside derivative (Table 4).
- Comparing the flavone apigenin vs. the isoflavone analogous genistein, the modification from position 2 to position 3 appears to lead to the loss of agonist effects (Table 2 and Table 5). Similarly, a loss of agonism is observed when compared to unsaturated analogous (apigenin and kaempferol) vs. the saturated flavanone naringenin (Table 2, Table 3 and Table 4).
- In flavone derivatives, the 7-methoxy substitution causes a loss of agonist capacity noticeable when compared genkwanin vs. the tri-hydroxy substituted apigenin (Table 2). In flavanones (naringenin vs. sakuranetin) (Table 4) and isoflavones (genistein vs. prunetin) (Table 5), 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.
- The 4-methoxy substitution does not seem to affect the AhR agonist potential in flavones (acacetin vs. apigenin) (Table 2).
- In isoflavones, 4′-methoxy substitution confers AhR agonist activity (daidzein vs. formononetin and biochanin A vs. genistein) (Table 5).
4. Conclusions
5. Search Methodology
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Flavonoids | Bioassays a | Cell lines & Tissues b | [μM] | Reference |
---|---|---|---|---|
Flavones Acacetin, Apigenin, Baicalin, Chrysin, Flavone, Genkwanin, Luteolin, Luteolin 7,3′-diglucoside, Scutellarein, Tangeretin, Tricetin, 4′,7-dimethoxy-5-hydroxyflavone, 4′,5,7-trimethoxyflavone, 3′,4′,5,7-tetramethoxyflavone. | RT-qPCR, PCR, LucRGA, ChIP, WB, IF, IHC | Caco2, YAMC, DLN, HepG2 AhR-Lucia, H1L6.1c2, 3T3-L1 (AhR) HCT116, MDA-MB-231, Hepatic tissue (rats), Myocardial tissue (mice) | 10–100 | [128,129,130,131,132,133,134,135,136,137] |
Flavonols Fisetin, Flavonol, Galangin, Gossypetin, Guaijaverin, Icaritin, Isorhamnetin, Kaempferol, Morin, Myricetin, Quercetin, Quercitrin, Robinetin, Rutin. Tamarixetin, 3,6,2′,3′-Tetrahydroxyflavone, 3,6,2′,4′-Tetrahydroxyflavone. | RT-qPCR, ChIP, WB, LucRGA | LNCaP, CWR22Rv1, Caco2, H1L6.1c2, 3T3-L1 (AhR), PBMEC/C1-2, HepG2 AhR-Lucia | 10–100 | [128,129,135,136,138,139] |
Dihydroflavonols Taxifolin, Dihydromyricetin | RT-qPCR, ChIP, WB, LucRGA | Caco2, HepG2 | 0.1–100 | [135,140] |
Flavolignane Silymarin | LucRGA | H1L6.1c2 | 25 | [139] |
Flavanones Alpinetin, Eriodictyol, Flavanone, Hesperetin, Hesperidin, Isoxanthohumol, Naringenin, Naringin, Naringenin Trimethyl Ether, Sakuranetin, 6-Prenylnaringenin, 8-Prenylnaringenin | LucRGA, RT-qPCR, WB, ChIP, Co-IP, EROD | HepG2, MCF-7, HepG2 AhR-Lucia, H1L6.1c2, Caco2, YAMC, PBMEC/C1-2, EL-4 | 0.1–100 | [136,137,139,141,142] |
Flavan 3-ol Epigallocatechin gallate | WB, LucRGA | 3T3-L1 (AhR), HepG2 AhR-Lucia | 30–100 | [128,136] |
Chalcone Cardamonin | qPCR, WB | THP-1 | 3.0–30 | [143] |
Isoflavones Biochanin A, Daidzein, Formononetin, Genistein, Puerarin, Prunetin, 4′,7-dimethoxy-5-hydroxyisoflavone, 4′,5,7-trimethoxyisoflavone, 3′,4′,5,7-tetramethoxyisoflavone | RT-qPCR, LucRGA, WB | Caco2, YAMC, H1L6.1c2, MCF-7, HC-04, HepG2 (AZ-AhR), Hepa-1c1c7, HepG2 AhR-Lucia | 0.1–1000 | [136,137,139,144,145,146] |
Flavones | |||
---|---|---|---|
Flavone | Chrysin | Apigenin | Luteolin |
Agonist [139] Antagonist [129] | Agonist [133,139] Antagonist [129] | Agonist [135,136,139] Antagonist [129] | Agonist [135] Antagonist [147] |
Tricetin | Scutellarein | Acacetin | Genkwanin |
Agonist [135] | Agonist [136] | Agonist [137] | Non-agonist [137] |
4′,7-Dimethoxy-5-hydroxyflavone | 4′,5,7-Trimethoxyflavone | 3′,4′,5,7-tetramethoxyflavone | Tangeretin |
Agonist [137] | Non-agonist [137] | Agonist [137] | Antagonist [132] |
Baicalin | Luteolin 7,3′-diglucoside | ||
Agonist [131,139] Antagonist [130] | Antagonist [128] |
Flavonols | |||
---|---|---|---|
Flavonol | Galangin | Kaempferol | Fisetin |
Agonist [128] Antagonist [128] | Antagonist [128] | Agonist [135] Antagonist [128,135] | Agonist [135,139] Antagonist [128,135] |
3,6,2′,3′-Tetrahydroxyflavone | 3,6,2′,4′-Tetrahydroxyflavone | Morin | Quercetin |
Agonist [135] | Agonist [135] Antagonist [135] | Agonist [135] Antagonist [129] | Agonist [135,139] Antagonist [128] |
Robinetin | Gossypetin | Myricetin | Isorhamnetin |
Agonist [135] | Agonist [135] | Agonist [135] Antagonist [129] | Antagonist [129] |
Tamarixetin | Icaritin | Guaijaverin | Quercitrin |
Agonist [128], Antagonist [129] | Agonist [138] | Agonist [136] | Antagonist [128] |
Rutin Agonist [139] Antagonist [128] |
Flavanones | ||
---|---|---|
Flavanone | Naringenin | Eriodictyol |
Antagonist [129] Agonist [128] | Antagonist [129] Non-agonist [137] | Antagonist [128] |
Alpinetin | Sakuranetin | Hesperetin |
Agonist [148,149] | Non-agonist [136] | Agonist [139] Antagonist [142] |
Naringenin Trimethyl Ether | Hesperidin | Naringin |
Non-agonist [137] | Agonist [136,139] | Agonist [139] Antagonist [128] |
6-Prenylnaringenin | 8-Prenylnaringenin | Isoxanthohumol |
Agonist [141] | Agonist [141] | Non-agonist [141] |
Isoflavones | |||
---|---|---|---|
Daidzein | Genistein | Formononetin | Biochanin A |
Antagonist [144] Non-agonist [145] | Antagonist [144,146] Non-agonist [136,137] | Agonist [144,145] | Agonist [139,144,145] |
Prunetin | 4′,7-dimethoxy-5-hydroxyisoflavone | 4′,5,7-trimethoxyisoflavone | 3′,4′,5,7-tetramethoxyisoflavone |
Non-agonist [137] | Non-agonist [137] | Agonist [137] | Non-agonist [137] |
Puerarin | |||
Non-antagonist [128] |
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Goya-Jorge, E.; Jorge Rodríguez, M.E.; Veitía, M.S.-I.; Giner, R.M. Plant Occurring Flavonoids as Modulators of the Aryl Hydrocarbon Receptor. Molecules 2021, 26, 2315. https://doi.org/10.3390/molecules26082315
Goya-Jorge E, Jorge Rodríguez ME, Veitía MS-I, Giner RM. Plant Occurring Flavonoids as Modulators of the Aryl Hydrocarbon Receptor. Molecules. 2021; 26(8):2315. https://doi.org/10.3390/molecules26082315
Chicago/Turabian StyleGoya-Jorge, Elizabeth, María Elisa Jorge Rodríguez, Maité Sylla-Iyarreta Veitía, and Rosa M. Giner. 2021. "Plant Occurring Flavonoids as Modulators of the Aryl Hydrocarbon Receptor" Molecules 26, no. 8: 2315. https://doi.org/10.3390/molecules26082315