Comparison of the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced CYP1A1 gene expression profile in lymphocytes from mice, rats, and humans: Most potent induction in humans

Nohara, Keiko; Ao, Kana; Miyamoto, Yuri; Ito, Tomohiro; Suzuki, Takehiro; Toyoshiba, Hiroyoshi; Tohyama, Chiharu

doi:10.1016/j.tox.2006.06.005

Cited by 32 publications

(19 citation statements)

References 48 publications

(56 reference statements)

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“…In addition, examination of hAHR ligand specificity compared with those of zebrafish and rainbow trout AHRs revealed that mono-ortho polychlorinated biphenyls activated hAHR but were not very effective in activating either zebrafish or rainbow trout AHRs (Abnet et al, 1999), suggesting that the hAHR may specifically bind a structurally unique subset of ligands. It is noteworthy that CYP1A1 induction in response to TCDD treatment was also shown to be most potent in human lymphocytes compared with mouse and rat lymphocytes (Nohara et al, 2006). Conversely, using a "knock-in" hAHR mouse, Moriguchi et al (2003) demonstrated that the hAHR was resistant to TCDDmediated toxicity compared with the mAHR d , suggesting that indeed, humans might also be resistant to TCDD-mediated toxicity.…”

Section: Discussionmentioning

confidence: 99%

Ligand Selectivity and Gene Regulation by the Human Aryl Hydrocarbon Receptor in Transgenic Mice

Flaveny¹,

Murray²,

Chiaro³

et al. 2009

Mol Pharmacol

119

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The aryl hydrocarbon receptor (AHR) is a ligand-inducible transcription factor that displays interspecies differences with the human and mouse AHR C-terminal region sequences sharing only 58% amino acid sequence identity. Compared with the mouse AHR (mAHR), the human AHR (hAHR) displays ϳ10-fold lower relative affinity for prototypical AHR ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin, which has been attributed to the amino acid residue valine 381 (alanine 375 in the mAHR) in the ligand binding domain of the hAHR. We investigated whether the 10-fold difference in ligand-binding affinity between the mAHR and hAHR would be observed with a diverse range of AHR ligands. To test this hypothesis, ligand binding assays were performed using the photo-affinity ligand 2-azido-3-[125 I]iodo-7,8-dibromodibenzo-p-dioxin and liver cytosol isolated from hepatocyte-specific transgenic hAHR mice and C57BL/6J mice. It is noteworthy that competitive ligand-binding assays revealed that, compared with the mAHR, the hAHR has a higher relative affinity for certain compounds, including indirubin [(2Z)-2,3-biindole-2,3 (1ЈH,1ЈH)-dione and quercetin (2-(3,4dihydroxyphenyl)-3,5,7-trihydroxy-4H-chromen-4-one]. Electrophoretic mobility shift assays revealed that indirubin was more efficient at transforming the hAHR compared with the mAHR. Indirubin was also a more potent inducer of Cyp1a1 expression in transgenic hAHR mouse hepatocytes compared with C57BL/6J mouse hepatocytes. These observations suggest that indirubin is a potent hAHR ligand that is able to selectively bind to and activate the hAHR. These discoveries imply that there may be a significant degree of structural divergence between mAHR and hAHR ligands and highlights the importance of the hAHR transgenic mouse as a model to study the hAHR in vivo.

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Section: Discussionmentioning

confidence: 99%

Ligand Selectivity and Gene Regulation by the Human Aryl Hydrocarbon Receptor in Transgenic Mice

Flaveny¹,

Murray²,

Chiaro³

et al. 2009

Mol Pharmacol

119

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“…Expression of target genes and rRNA (rRNA) was quantified by real-time PCR on LightCycler instrument (Roche Diagnostics) as described previously. 60 Amplification in experimental samples during the log linear phase was compared with the standard curve from the dilution series of a control cDNA using LightCycler quantification software (Version 3.5). The control cDNA to make a standard curve was prepared from the livers of C57BL/6 mice.…”

Section: Discussionmentioning

confidence: 99%

Diurnal expression ofDnmt3bmRNA in mouse liver is regulated by feeding and hepatic clockwork

et al. 2012

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“…Other tryptophan derivatives, the kynurenines, and further downstream products such as the newly identified cinnabarinic acid (stimulates IL-22) display large potential as well (Mezrich et al, 2010;Lowe et al, 2014). Although global gene expression profiles and promoter studies have shed some light on the activities of SAhRMs, AhR antagonists and agonists, and selective modulators for other receptors (Sun et al, 2004;Nohara et al, 2006;Suzuki and Nohara, 2007;Nault et al, 2013), the factors important for the selectivity of a specific AhR ligand are not well understood and require further investigation.…”

Section: Therapeutic Potential Of Aryl Hydrocarbon Receptor Ligandsmentioning

confidence: 99%

The Aryl Hydrocarbon Receptor in Barrier Organ Physiology, Immunology, and Toxicology

2015

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Comparison of the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced CYP1A1 gene expression profile in lymphocytes from mice, rats, and humans: Most potent induction in humans

Cited by 32 publications

References 48 publications

Ligand Selectivity and Gene Regulation by the Human Aryl Hydrocarbon Receptor in Transgenic Mice

Ligand Selectivity and Gene Regulation by the Human Aryl Hydrocarbon Receptor in Transgenic Mice

Diurnal expression ofDnmt3bmRNA in mouse liver is regulated by feeding and hepatic clockwork

The Aryl Hydrocarbon Receptor in Barrier Organ Physiology, Immunology, and Toxicology

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