Disease relevance of Ahr

• Signal transduction-mediated activation of the aryl hydrocarbon receptor in rat hepatoma H4IIE cells [1].
• Hepatic upregulation of the aryl hydrocarbon receptor may modulate the potential for benzo(a)pyrene toxicity via the activation of cytochrome P450 and the subsequent deposition of lipophillic metabolites to developing central nervous system structures such as cerebral cortex and hippocampus [2].
• This study indicates that the enhancement of DMBA-induced mammary carcinogenicity in a relatively low PCB126 dose group might partially involve the higher expression of CYP1B1 and AhR in these carcinomas [3].
• Both antagonists inhibited the induction of genes under the control of the CYP1A1 and mouse mammary tumor virus promoters, which indicates that the alpha NF- and MCDF-mediated antagonism of TCDD-induced, aryl hydrocarbon receptor-dependent gene transcription does not depend on promoter context [4].
• Identification of 3'-methoxy-4'-nitroflavone as a pure aryl hydrocarbon (Ah) receptor antagonist and evidence for more than one form of the nuclear Ah receptor in MCF-7 human breast cancer cells [5].

High impact information on Ahr

• The aryl hydrocarbon receptor (AHR) is a ligand-inducible transcription factor that is best known because it mediates the actions of polycyclic and halogenated aromatic hydrocarbon environmental toxicants such as 3-methylcholanthrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin [6].
• In a reporter gene assay, this ligand activates the AHR with a potency five times greater than that of beta-naphthoflavone, a prototypical synthetic AHR ligand [6].
• 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester competes with 2,3,7,8-[(3)H]tetrachlorodibenzo-p-dioxin for binding to human, murine, and fish AHRs, thus showing that AHR activation is caused by direct receptor binding, and that recognition of this endogenous ligand is conserved from early vertebrates (fish) to humans [6].
• Down-regulation of nuclear aryl hydrocarbon receptor DNA-binding and transactivation functions: requirement for a labile or inducible factor [7].
• H/W rats are exceptionally resistant to induction of AHF by TCDD, and the resistance is associated with an altered transactivation domain of the aryl hydrocarbon receptor [8].

Chemical compound and disease context of Ahr

• We have investigated mechanisms of omeprazole (OME)-mediated induction of CYP1A1 and CYP3A, using the rat hepatoma H4IIE cell line, in comparison with mechanisms exerted by traditional aryl hydrocarbon receptor (AhR) ligands such as benso(a)pyrene (B(a)P) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) [1].
• The dependency of the cytostatic effects of five flavonoids (flavone, alpha-naphthoflavone, apigenin, 3'-methoxy-4'-nitroflavone and 2'-amino-3'-methoxyflavone) on a functional AHR was examined in AHR-containing rat hepatoma 5L cells and an AHR-deficient cell line (BP8) derived from the 5L line [9].
• Sucrose gradient analyses using rat liver and murine hepatoma 1c1c7 extracts demonstrated that SP600125 competed with TCDD for binding to the AhR [10].
• Thus, DIM represents a new class of relatively non-toxic AhR-based antiestrogens that inhibit E2-dependent tumor growth in rodents and current studies are focused on development of analogs for clinical treatment of breast cancer [11].
• Coordinate responses of UGT activity after treatment with TCDD or tBHQ were also observed in rat hepatoma 5L cells, mutants without the AhR and with recomplemented AhR [12].

Biological context of Ahr

• The data are consistent with a mechanism for OME-mediated induction of CYP1A1 that involves activation of the AhR complex via intracellular signal transduction systems and that is distinct from induction mediated by AhR ligands [1].
• Multiple mechanisms are involved in Ah receptor-mediated cell cycle arrest [13].
• The aryl hydrocarbon receptor (AhR) agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can disrupt the regenerative process, as evidenced by suppression of DNA synthesis in rat primary hepatocytes in culture and in vivo liver regeneration after partial hepatectomy [13].
• Our findings suggest that the cancer preventive effect of soy-based diets is mediated in part by reduction in AhR protein level posttranslationally, which reduces procarcinogen-induced CYP1A1 induction and metabolic activation [14].
• Strain differences in cytochrome P4501A1 gene expression caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin in the rat liver: role of the aryl hydrocarbon receptor and its nuclear translocator [15].

Anatomical context of Ahr

• OME did not bind specifically to AhR, and it could not activate the AhR complex in rat cytosol to a xenobiotic-responsive element (XRE)-binding form in vitro [1].
• Western blot analysis showed that the daily cycle of relative AhR protein expression exhibits a similar oscillation pattern in the liver, lungs, and thymus [16].
• AhR, ARNT, and CYP1B1 were only weakly expressed, even after 2,3,7,8-tetrachlorodibenzo-p-dioxin induction, when rat mammary epithelial cells (RMEC) were cultured on plastic [17].
• In summary, both AhR and ARNT were expressed in all organs of the adult male rat reproductive tract examined, and epithelial and/or endothelial cells within each of these organs (with the exception of the testis) were responsive to TCDD exposure in terms of CYP1A1 induction [18].
• Induction of detoxifying enzymes in rodent white adipose tissue by aryl hydrocarbon receptor agonists and antioxidants [19].

Associations of Ahr with chemical compounds

• Northern blotting demonstrated that, in the mediobasal hypothalamus, a subcutaneous injection of 20 microg estradiol benzoate (E(2)) significantly increased the expression of Arnt2 mRNA, but induced no significant changes in the expression of AhR and Arnt1 mRNAs [20].
• By using a compendium of gene expression profiles, FLU was shown to signal in rats similar to an AhR activator with additional CYP2B and CYP3A effects that most resembled the ADME gene expression pattern of the atypical CYP1A inducers I3C and OME [21].
• This preliminary report is the first study to suggest that the PAS proteins, AhR and Arnt, exhibit a daily oscillation pattern within multiple target tissues which may give insight into the tissue-specific toxic and biochemical responses mediated through this dimerization pair, as well as the physiological function of these proteins [16].
• These results suggest that the transient decreases in androgen-regulated prostatic mRNA abundance observed in response to in utero and lactational TCDD exposure were probably not the result of direct action of the activated AhR on these genes but instead were reflective of a TCDD-induced delay in prostate development [22].
• Profiling the hepatic effects of flutamide in rats: a microarray comparison with classical aryl hydrocarbon receptor ligands and atypical CYP1A inducers [21].

Physical interactions of Ahr

• The tryptophan photoproduct, FICZ, has previously been characterized to possess very high AhR binding affinity and to transiently induce CYP1A1 gene expression in cultured cells at picomolar concentrations [23].
• We recently demonstrated that the AhR interacts with the retinoblastoma protein (pRb) [24].

Co-localisations of Ahr

• There was no neuroanatomic evidence that AhR is preferentially colocalized with ARNT or ARNT2 [25].

Regulatory relationships of Ahr

• The down-regulation of AhR-regulated gene expression was previously shown to be dependent on cytochrome P450 1A1 (CYP1A1) [26].
• In conclusion, AhR signaling is activated in the ovary by TCDD and inhibition of COX-2 appeared to be a critical step in the TCDD blockage of ovulation because blockage or reduction of COX-2 expression is well known to be associated with failure of ovulation [27].
• Ornithine decarboxylase activity is induced by all aromatic amines tested irrespective of their Ah receptor affinity [28].

Other interactions of Ahr

• Gel shift analysis with radiolabeled XRE and specific peptide antibodies toward AhR and aryl hydrocarbon receptor nuclear translocator protein (Arnt) revealed an OME-mediated translocation of the AhR.Arnt complex into the nuclei [1].
• Assessment of metabolites and AhR and CYP1A1 mRNA expression subsequent to prenatal exposure to inhaled benzo(a)pyrene [2].
• These results suggest that both AhR and Nrf2 pathways are active in WAT and that lipophilic compounds accumulated in WAT can activate these transcription factors to increase detoxification capability in the tissue [19].
• Independent observations demonstrated that AhR-mediated G(1) phase cell cycle arrest depends on an interaction with the retinoblastoma tumor suppressor protein (pRb), but differences exist regarding proposed mechanisms of action [13].
• Also in the latter, in the vacuolated acinar cells, CYP1A1 was overexpressed, and statistically significant decreases in expressions of AhR, CCKAR, and amylase occurred [29].

Analytical, diagnostic and therapeutic context of Ahr

• Using reverse transcriptase-polymerase chain reaction (RT-PCR), mRNAs encoding the AhR and ARNT were detected in both ventral and dorsolateral prostates from control animals throughout postnatal development [22].
• In addition, a chromatin immunoprecipitation assay further confirmed that BDE-99 could bind to the AhR and activate the AhR nuclear translocation and dioxin responsive element (DRE) binding in the context of the CYP1A1 promoter [30].
• AhR-mediated change in expression of AhR target genes was measured by oligonucleotide microarrays and by reverse transcription-polymerase chain reaction in human and rat hepatocytes [31].
• In the present study, molecular cloning and sequencing of the H/W rat AhR revealed that the reason for its smaller size is a deletion/insertion-type change at the 3' end of exon 10 in the receptor cDNA [32].
• This up-regulation in vivo is in contrast to the sustained depletion of AHR caused by TCDD in cell culture [33].

References