Disease relevance of AHR

• Variability in the human AHR affinity exists, but differences in human risk of toxicity or cancer related to AHR activation remain unproven [1].
• In conclusion, the female reproductive tract expresses mRNA for the transcription factors AHR and ARNT, and changes in their expression at select target sites in specific pathological conditions such as endometriosis and uterine leiomyomas suggest a potential role for these factors in the pathogenesis of these conditions [2].
• However, there were no changes in the expression of AHR or ARNT mRNA in ovarian cancer [2].
• Leiomyomas expressed significantly less AHR and ARNT mRNA compared with normal myometrium [2].
• Endometriotic ovarian cysts expressed more AHR but not more ARNT mRNA compared with healthy ovarian tissue [2].
• These findings suggest that AHR polymorphisms and potential gene-smoking interaction may be involved in the etiology of lung cancer [3].

Psychiatry related information on AHR

• Individual difference in expression levels of Ahr and Arnt mRNA was observed in liver, lung and blood [4].
• The basic helix-loop-helix PAS (bHLH-PAS) transcription factors SIM1 and arylhydrocarbon receptor (AHR) are involved in the control of feeding behavior [5].
• However, it did not support the association of Ahr gene polymorphism with higher risk of senile dementia [6].
• Polymorphism of alpha-estrogen receptor and aryl hydrocarbon receptor genes in dementia patients in Shanghai suburb [6].
• The prototype AHR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin) did not affect the rates of chronic alcohol consumption in B6 or D2 mice, suggesting that dioxin-inducible metabolism does not play a major role in alcohol drinking preference [7].

High impact information on AHR

• Reconstitution of STAT6 only in epithelial cells was sufficient for IL-13-induced AHR and mucus production in the absence of inflammation, fibrosis or other lung pathology [8].
• In animal models of allergic asthma, blockade of IL-13 markedly inhibits allergen-induced AHR, mucus production and eosinophilia [8].
• The requirement for this factor distinguishes the Ah receptor from the glucocorticoid receptor, to which the Ah receptor has been presumed to be similar [9].
• The ability of the AhR to bind and be activated by a range of structurally divergent chemicals suggests that the AhR contains a rather promiscuous ligand binding site [10].
• Two regulatory proteins, the aromatic (aryl) hydrocarbon receptor (AhR) and the AhR nuclear translocator (Arnt), mediate induction [11].

Chemical compound and disease context of AHR

• Curcumin activates the aryl hydrocarbon receptor yet significantly inhibits (-)-benzo(a)pyrene-7R-trans-7,8-dihydrodiol bioactivation in oral squamous cell carcinoma cells and oral mucosa [12].
• Dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin) induces cleft palate and hydronephrosis in mice, when exposed in utero; these effects are mediated by the aryl hydrocarbon receptor [13].
• Aryl hydrocarbon receptor mediates sensitivity of MCF-7 breast cancer cells to antitumor agent 2-(4-amino-3-methylphenyl) benzothiazole [14].
• Estrogen and aryl hydrocarbon receptor expression and crosstalk in human Ishikawa endometrial cancer cells [15].
• Our data suggest for the first time that CYP1A1 and 1B1 expressions in human medulloblastoma cells are AhR-independent and have no direct links with resveratrol-induced differentiation and apoptosis [16].

Biological context of AHR

• Specific transcriptional activation mediated by AHR/ARNT heterodimer, which is a functional indicator of receptor expression, was assessed by beta-galactosidase activity produced from a reporter plasmid [17].
• Sequential two-step ChIP assays were performed which demonstrate that AHR and ER alpha are present together at the same time on the Cyp1a1 enhancer during transrepression [18].
• AHR target gene activation can be repressed by estrogen and estrogen-like compounds [18].
• In conclusion, these results demonstrate the existence of AHR- and CYP1A1-independent mechanisms of PAH metabolic activation in mouse liver, a phenomenon that may have important implications for PAH-mediated carcinogenesis [19].
• Thus, no polymorphisms in the AHR, ARNT or CYP1A1 genes were identified that could be responsible for the non/low inducibility phenotype observed [20].

Anatomical context of AHR

• The LS180 cell line should constitute a good model for further mechanistic studies on AHR-regulated CYP1A2 expression [21].
• However, post-menopausal women on continuous hormone replacement therapy had greater expression of AHR but not of ARNT in the endometrium and myometrium when compared with women not taking hormones [2].
• Transfection in HuH7 human liver cells confirmed previously reported ERalpha enhancement of AhR activity [22].
• We studied the AhR-dependent pathway in lymphocytes from 62 subjects randomly sampled from the highest exposed zones and 59 subjects from the surrounding non-contaminated area, frequency matched for age, gender and smoking [23].
• Identification of BCRP as transporter of benzo[a]pyrene conjugates metabolically formed in Caco-2 cells and its induction by Ah-receptor agonists [24].
• In human placentas, the AhR was primarily present in syncytiotrophoblasts and also in endothelium of large blood vessels in villi and endothelium of umbilical cord arteries and veins. In fetal tissues (from 4 to 7 months), the AhR was localized in lung, kidney, esophagus, pancreas, liver, testicle, thymus gland, retina, and choroid, mainly in epithelial cells, whereas it was absent in heart, brain, sclera, and thoracic aorta [25].

Associations of AHR with chemical compounds

• In contrast, strains with an intact pathway for tryptophan biosynthesis responded to AHR agonists and had lower levels of background beta-galactosidase activity [17].
• Indole-3-carbinol was an exceptionally potent AHR agonist (EC50 approximately 10 microM) in yeast [17].
• Tryptophan, indole, indole acetic acid, and tryptamine activated transcription in yeast coexpressing AHR and ARNT (EC50 values approximately 300 microM) [17].
• Hexachlorobenzene, benzo(a)pyrene, and beta-naphthoflavone were effective AHR agonists in the yeast system, and had EC50 values of 200, 40, and 20 nM, respectively, for beta-galactosidase activity induction [17].
• Transfection studies with a plasmid containing a luciferase reporter gene under control of two dioxin-responsive elements indicate an effect on AHR protein expression [26].
• Taken together, our studies show that recruitment of ARNT to the AhR after dioxin treatment can account for the antiestrogenic effect of dioxins [27].

Physical interactions of AHR

• This yeast system is useful for the study of AHR/ARNT protein complexes, and may be generally applicable to the investigation of other multiprotein complexes [17].
• Altogether, our data indicate that the RIP140 gene exhibits a complex structure with several noncoding exons and supports transcriptional cross-talk and feedback involving the ERalpha and AhR nuclear receptors [28].
• Nuclear receptor coactivator SRC-1 interacts with the Q-rich subdomain of the AhR and modulates its transactivation potential [29].
• We also report that AHR interacts with COUP-TF in transfected CV-1 cells [30].
• Indeed, some xenobiotics do activate CYP1A1 gene expression in spite of their inability to compete with TCDD for binding to the AhR [31].
• Inactivation or silencing of HDAC6 also led to reduced binding of ligand to the AhR and decreased translocation of the AhR from cytosol to nucleus in response to ligand [32].

Regulatory relationships of AHR

• The aryl hydrocarbon (or dioxin) receptor (AhR) is a ligand-activated basic helix-loop-helix (bHLH) protein that heterodimerizes with the bHLH protein AhR nuclear translocator (ARNT) to form a complex that binds to xenobiotic regulatory elements in the enhancers of target genes [33].
• CONCLUSIONS: In the absence of exogenous AhR ligands (such as cigarette smoke components), AhR overexpression up-regulated the expression of CYP1B1 in the early stage of lung adenocarcinoma [34].
• Individuals with at least one copy of the G1721A AhR variant allele showed a significantly higher level of induced CYP1A1 activity compared with individuals negative for the polymorphism (P = 0.0001) [35].
• The induction of BCRP (mRNA and protein expression) by indolo[3,2-b]carbazole was inhibited in Caco-2 cells by co-incubation with the AhR antagonist PD98059 (2'-amino-3'-methoxyflavone) [24].
• Aryl hydrocarbon receptor agonists directly activate estrogen receptor alpha in MCF-7 breast cancer cells [36].
• Binding of PDE2A to XAP2 inhibited TCDD- and cAMP-induced nuclear translocation of AhR in Hepa1c1c7 hepatocytes [37].

Other interactions of AHR

• Using chromatin immunoprecipitation assays, we studied the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-mediated recruitment of the aryl hydrocarbon receptor (AhR) and several co-regulators to the CYP1A1 promoter [22].
• We confirm the interactions of ARNT and AHR with SRC-1 with immunocytochemical techniques [38].
• Aryl hydrocarbon receptor-mediated transcription: ligand-dependent recruitment of estrogen receptor alpha to 2,3,7,8-tetrachlorodibenzo-p-dioxin-responsive promoters [22].
• These observations reveal that the Ah receptor is involved in human UGT1A1 induction [39].
• Requirement of Aryl Hydrocarbon Receptor Overexpression for CYP1B1 Up-Regulation and Cell Growth in Human Lung Adenocarcinomas [34].

Analytical, diagnostic and therapeutic context of AHR

• Co-immunoprecipitation and co-localization assays revealed that RIP140 interacted with AhR, but not with ARNT, both in vitro and in cells [40].
• EXPERIMENTAL DESIGN: AhR, CYP1B1, and CYP1A1 expression was examined in 107 lung adenocarcinomas and 57 BAC by immunohistochemistry [34].
• The expression of human Ahr and Arnt is reported here for the first time, providing a quantitative RT-PCR analysis as a useful tool for further studies [4].
• Regulation of cytochrome P450 enzymes by aryl hydrocarbon receptor in human cells: CYP1A2 expression in the LS180 colon carcinoma cell line after treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin or 3-methylcholanthrene [21].
• RESULTS: Immunoblotting of enriched prostatic epithelial cells (EC) and stromal cells revealed constitutive expression of bands at around 110 kDa and 90 kDa, using anti-AhR and anti-ARNT, respectively [41].

References