Glucocorticoid-Enhanced Expression of Dioxin Target Genes through Regulation of the Rat Aryl Hydrocarbon Receptor

Sonneveld, Edwin; Jonas, A.; Meijer, Onno C.; Brouwer, Abraham; Burg, Bart van der

doi:10.1093/toxsci/kfm176

Cited by 45 publications

(42 citation statements)

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“…26) Two GRE-like sequences have been reported to be present in the promoter region of rat AhR gene; that one of the glucocorticoids, dexamethasone, induced AhR mRNA expression via GR in rat H4IIE cells. 15) AhR mRNA expression had a tendency to decrease in ADX rats (Fig. 3), indicating that decreased glucocorticoid levels in ADX rats may suppress the signal transduction via GR, which causes the tendency to reduce transcriptional activation for AhR.…”

Section: Discussionmentioning

confidence: 98%

“…A GRE-like sequence has been identified in the 5′-flanking region of the rodent AhR gene. 15) Glucocorticoids increased AhR mRNA levels and binding of ligand to AhR, and enhanced expression on CYP1A1 as AhR target gene in H4IIE rat hepatoma cells. 15,16) A GRE is located between base pair −141 and the promoter in the rat UGT1A6 gene.…”

mentioning

confidence: 93%

“…15) Glucocorticoids increased AhR mRNA levels and binding of ligand to AhR, and enhanced expression on CYP1A1 as AhR target gene in H4IIE rat hepatoma cells. 15,16) A GRE is located between base pair −141 and the promoter in the rat UGT1A6 gene. 17) A previous study using rat hepatocytes treated with dexamethasone indicated that glucocorticoids induced the expression of UGT1A6 and p-nitrophenol glucuronidation.…”

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Effect of Adrenalectomy on Expression and Induction of UDP-Glucuronosyltransferase 1A6 and 1A7 in Rats

Sakakibara

Katoh

Suzuki

et al. 2014

Biological & Pharmaceutical Bulletin

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Uridine 5′-diphosphate (UDP)-glucuronosyltransferase 1A (UGT1A), which catalyzes major phase II reactions, is regulated by endogenous and exogenous factors via nuclear receptors such as the aryl hydrocarbon receptor (AhR). Glucocorticoid, one of the adrenocortical hormones, regulates AhR and UGT1A expression. We examined the effects of adrenalectomy on the expression and induction of UGT1A via AhR in the rat liver and small intestine. Rats were adrenalectomized bilaterally (ADX) or sham-operated (SHAM) and received intraperitoneal treatment with β-naphthoflavone (BNF) for 4 d. Hepatic UGT1A6 and UGT1A7 mRNA levels were altered by ADX (0.1-fold and 1.6-fold, respectively). BNF treatment increased UGT1A6 and UGT1A7 mRNA expression and the intrinsic clearance of acetaminophen (APAP) glucuronidation, which is primarily catalyzed by UGT1A6 and UGT1A7, in both SHAM and ADX rats. Therefore, ADX rats maintained a functional AhR signaling pathway in the presence of BNF, expressed UGT1A6 and UGT1A7 mRNA, and showed APAP glucuronidation, namely induction by BNF via AhR was not abolished. Our results indicate that adrenal-dependent factors such as glucocorticoids are partially involved in the basal regulation of UGT1A6 and UGT1A7 transcription.

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Section: Discussionmentioning

confidence: 98%

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confidence: 93%

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confidence: 93%

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Effect of Adrenalectomy on Expression and Induction of UDP-Glucuronosyltransferase 1A6 and 1A7 in Rats

Sakakibara

Katoh

Suzuki

et al. 2014

Biological & Pharmaceutical Bulletin

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“…The first major finding of our dmd.aspetjournals.org remains unclear how these effects are produced in the absence of a decrease in AHR protein levels. Sonneveld et al (2007) found that DEX acts via the GR to augment the induction by TCDD of AHRactivated luciferase reporters, EROD activity, and several endogenous AHR target genes in rodent cells (rat H4IIE and mouse Hepa-1) but not human cells (HepG2 and T47D breast carcinoma cells). DEX increased AHR mRNA levels in rat H4IIE cells but not in human cells.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Aryl Hydrocarbon Receptor Expression and Function by Glucocorticoids in Mouse Hepatoma Cells

Bielefeld¹,

Lee²,

Riddick³

2007

Drug Metab Dispos

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ABSTRACT:The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates most biological responses to 2,3, 7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related aromatic hydrocarbons. Although the role of the AHR in control of drug metabolism and endocrine disruption is partly understood, we know little about the regulation of the AHR itself by endocrine factors. Our work with hypophysectomized rats suggested that hepatic AHR protein level is positively regulated by pituitary-dependent factors. A current hypothesis is that adrenal glucocorticoids elevate AHR expression and enhance responsiveness to AHR agonists. Dexamethasone ( The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates most biological responses to halogenated aromatic hydrocarbons (HAHs) such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and polycyclic aromatic hydrocarbons (PAHs) such as 3-methylcholanthrene (MC). The most fully understood AHR-mediated biological response is the induction of cytochrome P450 genes belonging to the CYP1A subfamily. Binding of ligand to the cytoplasmic AHR complex triggers the translocation of the receptor into the nucleus, dimerization with the AHR nuclear translocator, and binding of the AHR ⅐ AHR nuclear translocator heterodimer to dioxin-responsive elements (DREs) in regulatory regions of genes subject to transcriptional up-regulation such as CYP1A1 (Riddick et al., 1994). Although the role of the AHR in control of drug metabolism and endocrine disruption is partly understood (Safe, 1995), we know little about the regulation of the AHR itself by endocrine and other factors (Harper et al., 2006).Our interest in endocrine control of AHR expression and function was stimulated by our observation that hypophysectomy results in a significant loss of hepatic AHR protein and TCDD-binding capacity in male rats without decreasing CYP1A1 induction in response to MC treatment (Timsit et al., 2002). This finding suggested that pituitary hormones and/or pituitary-dependent factors may act as positive regulators of hepatic AHR levels and aromatic hydrocarbon responsiveness. We are interested in identifying the pituitary-dependent factors that modulate hepatic AHR expression and function and determining the molecular mechanisms by which they act.Our initial focus has been on adrenal glucocorticoids as potential candidates for the pituitary-dependent endocrine factors involved in modulation of AHR levels and activity. Several lines of evidence suggest that glucocorticoids can augment aromatic hydrocarbon responsiveness. Elevated levels of endogenous corticosterone (CORT) induced by stress result in enhanced induction of hepatic CYP1A1-catalyzed 7-ethoxyresorufin O-deethylation (EROD) in response to PAH exposure in rats (Konstandi et al., 2000). The in vivo induction of rat hepatic CYP1A1 and/or associated catalytic activities by MC is potentiated by the synthetic glucocorticoid dexamethasone (DEX) (Sherratt et al., 1989) and diminished by adrenalectomy (Nebert and Gel...

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“…A potent and synergistic interaction has been found to occur between TCDD and glucocorticoid hormones [11]. It has been reported that glucocorticoids influence TCDD action in porcine and human aorta endothelial cells, and rat, mouse, or human hepatoma cells in vitro [9,[12][13][14]. Recently, we have reported that low dose of TCDD caused testicular oxidative stress under the influence of increased level of corticosterone [15].…”

Section: Introductionmentioning

confidence: 98%

Effects of corticosterone and 2,3,7,8‐tetrachloro‐ dibenzo‐p‐dioxin on epididymal antioxidant system in adult rats

Dhanabalan

D’Cruz

Mathur

2010

J Biochem & Molecular Tox

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2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), an endocrine disruptor, causes epididymal toxicity by inducing oxidative stress. Glucocorticoids have been found to influence TCDD action in vitro and in vivo. The present experiments were set up to analyze the effects of TCDD on rat epididymal antioxidant system under the influence of increased corticosterone level. Adult male Wistar/NIN rats (70-80 days old) numbering 24 (six per group) were used in the study. Corticosterone (3 mg/kg body weight per day) or TCDD (100 ng/kg body weight per day) were administered or coadministered to rats for 15 days. Treatment with corticosterone or TCDD decreased the levels of serum testosterone significantly. In caput, corpus, and cauda fractions, administration of corticosterone or TCDD increased the levels of lipid peroxidation and hydrogen peroxide and decreased the activities of superoxide dismutase and catalase significantly. Coadministration of corticosterone and TCDD to rats decreased the levels of serum testosterone significantly as compared with rats treated with TCDD alone. In caput, corpus, and cauda fractions, the levels of lipid peroxidation and hydrogen peroxide were increased and activities of superoxide dismutase and catalase were decreased significantly as compared with rats treated with TCDD alone. Stress, characterized by increased glucocorticoid levels and activity, may enhance TCDD-induced epididymal toxicity.

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Glucocorticoid-Enhanced Expression of Dioxin Target Genes through Regulation of the Rat Aryl Hydrocarbon Receptor

Cited by 45 publications

References 46 publications

Effect of Adrenalectomy on Expression and Induction of UDP-Glucuronosyltransferase 1A6 and 1A7 in Rats

Effect of Adrenalectomy on Expression and Induction of UDP-Glucuronosyltransferase 1A6 and 1A7 in Rats

Regulation of Aryl Hydrocarbon Receptor Expression and Function by Glucocorticoids in Mouse Hepatoma Cells

Effects of corticosterone and 2,3,7,8‐tetrachloro‐ dibenzo‐p‐dioxin on epididymal antioxidant system in adult rats

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