Crosstalk Between the Aryl Hydrocarbon Receptor and Hypoxia on the Constitutive Expression of Cytochrome P4501A1 mRNA

Zhang, Nan; Walker, Mary

doi:10.1007/s12012-007-9007-6

Cited by 43 publications

(38 citation statements)

References 36 publications

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“…Successful AHR inactivation was confirmed using methods reported elsewhere. 12 Inactivation of AHR in human microvascular endothelial cells isolated from lung significantly reduced prepro-ET-1 mRNA expression under normoxic conditions ( Figure 5A) but failed to alter hypoxia-induced expression ( Figure 5B) and had no effect on hypoxia-induced ET-1 secretion (data not shown). Similar results were obtained in studies conducted with human umbilical vein endothelial cells (data not shown).…”

Section: Lund Et Almentioning

confidence: 88%

Loss of the Aryl Hydrocarbon Receptor Induces Hypoxemia, Endothelin-1, and Systemic Hypertension at Modest Altitude

et al. 2008

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Abstract-The aryl hydrocarbon receptor (AHR) is a basic helix-loop-helix Per-Arnt-Sim transcription factor that mediates induction of metabolic enzymes and toxicity of certain environmental pollutants. Although AHR knockout (KO) mice develop cardiac hypertrophy, conflicting reports associate this pathology with hypotension or endothelin (ET)-1-dependent hypertension. Because hypertension occurred at modest altitude, we tested the hypothesis that loss of AHR increases the sensitivity to hypoxia-induced ET-1, contributing to systemic hypertension. We found that AHR KO mice were hypertensive at modest altitude (1632 m) but hypotensive at low altitude (225 m). When AHR KO mice residing at 1632 m were exposed to the partial pressure of inspired oxygen (PIO 2 ) at sea level for 11 days, blood pressure declined to levels measured at 225 m. Although plasma ET-1 in AHR KO mice was significantly elevated at 1632 m and decreased at 225 m and sea level PIO 2 , pulmonary prepro-ET-1 mRNA was significantly reduced at 1632 m and decreased further at 225 m and sea level PIO 2 . Blood gas analysis revealed that AHR KO mice were hypoxemic, hypercapnic, and acidotic at 1632 m, values that were attenuated and normalized after 24 hours and 11 days under sea level PIO 2 , respectively. Lastly, AHR inactivation in endothelial cells by small interfering RNA significantly reduced basal prepro-ET-1 mRNA but did not alter hypoxia-induced expression. Our studies establish the AHR KO mouse as a model in which modest decreases in PIO 2 lead to hypoxemia, increased plasma ET-1, and systemic hypertension without increased pulmonary prepro-ET-1 mRNA expression. Key Words: blood pressure Ⅲ hypertension Ⅲ endothelin Ⅲ oxygen Ⅲ gene regulation T he aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor belonging to the basic helix-loophelix Per-Arnt-Sim family of DNA binding proteins, which also includes hypoxia-inducible factors. 1 Although the AHR is known to mediate induction of drug-metabolizing enzymes and toxicity after exposure to 2,3,7,8-tetrachlorodibenzo-pdioxin, recent evidence has revealed a physiological role for AHR in cardiovascular homeostasis. AHR knockout (KO) mice develop cardiac hypertrophy, 2,3 which is mediated, in part, by elevated plasma angiotensin II and endothelin-1 (ET-1). 4,5 There are conflicting reports, however, of whether the cardiac hypertrophy is associated with systemic hypertension. Lund et al 4,5 reported that cardiac hypertrophy in AHR KO mice is preceded by hypertension, whereas Vasquez et al 6 and Ichihara et al 7 reported that AHR KO mice are hypotensive and normotensive, respectively. The explanation for the disparate blood pressure values among these studies is unclear.AHR and hypoxia-inducible factor-1␣ share a common dimerization partner, AHR nuclear translocator (hypoxiainducible factor-1␤), as well as other transactivators, and studies have shown that these 2 signal transduction pathways can exhibit reciprocal inhibitory cross-talk. 8,9 The mechanism by which this functional inter...

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Section: Lund Et Almentioning

confidence: 88%

Loss of the Aryl Hydrocarbon Receptor Induces Hypoxemia, Endothelin-1, and Systemic Hypertension at Modest Altitude

et al. 2008

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“…Because AhR is reported to be involved in the constitutive expression of CYP1A1 (Zhang and Walker, 2007), the effect of SWCNTs on expression of AhR mRNA was investigated. However, the effect of SWCNTs on basal AhR expression was negligible in NHBE and A549 cells, indicating that the down-regulatory effect of SWCNTs on CYP1A1 mRNA was not due to the suppression of AhR expression.…”

Section: Discussionmentioning

confidence: 99%

Changes in Expression of Drug-Metabolizing Enzymes by Single-Walled Carbon Nanotubes in Human Respiratory Tract Cells

Hitoshi¹,

Katoh²,

Suzuki³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Single-walled carbon nanotubes (SWCNTs) have attracted attention for biomedical and biotechnological applications, such as drug delivery. However, there are concerns about the safety of SWCNTs for use in humans. To investigate the potential use of SWCNTs for targeted drug delivery to the lung, we examined their effect on drug-metabolizing enzymes in primary normal human bronchial epithelial (NHBE) cells from two donors and the lung carcinoma A549 cell line. Exposure of NHBE and A549 cells to SWCNTs dysregulated some of the important drug-metabolizing enzymes expressed in the human respiratory organs. Exposure of NHBE cells to SWCNTs for 24 h had a pronounced effect on expression of CYP1A1 and CYP1B1 mRNAs, which were reduced to less than 1% of control cells. These effects were also observed in A549 cells. Exposure of A549, HepG2 hepatic carcinoma cells, and MCF-7 breast carcinoma cells to tetrachlorodibenzo-p-dioxin induced the expression and enzymatic activity of CYP1A1 and CYP1B1, which were also suppressed by SWCNTs, suggesting that SWCNTs down-regulated both basal and induced CYP1A1 and CYP1B1 activities. Chromatin immunoprecipitation assays revealed that the down-regulatory effect of SWCNTs may be due to inhibition of activated aryl hydrocarbon receptor binding to the enhancer regions of the CYP1A1 and CYP1B1 genes. Down-regulation of CYP1A1 and CYP1B1 genes by SWCNTs may affect the defense mechanisms by reducing procarcinogen bioactivation in the human lung.

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“…29) Our results indicate that the downregulatory effect of SWCNTs on CYP1A1 mRNA was not due to the suppression of AHR expression. Resveratrol, a phenolic phytoalexin, downregulates both constitutive and polycyclic aromatic hydrocarbon-induced CYP1A1 expression, leading to a chemopreventive effect by inhibiting procarcinogen activation.…”

Section: Discussionmentioning

confidence: 54%

Single-Walled Carbon Nanotubes Downregulate Stress-Responsive Genes in Human Respiratory Tract Cells

Hitoshi

Katoh

Suzuki

et al. 2012

Biological & Pharmaceutical Bulletin

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Carbon nanotubes (CNTs) are currently key promising materials of nanotechnology. However, elucidation of the possible effects of CNTs on the respiratory tract is urgently needed. The present study aimed to clarify the effect of single-walled CNTs (SWCNTs) on the expression of stress-responsive genes, using primary cultured normal human bronchial epithelial (NHBE), diseased HBE (DHBE) cells, and the human carcinoma cell lines A549 and FaDu. Purified SWCNTs were applied at concentrations of 0.1 or 1.0 mg/mL for 6 h, and a polymerase chain reaction (PCR) array was conducted to examine 84 stress-responsive genes. NHBE cell exposure to SWCNTs resulted in global downregulation of genes involved in inflammation, oxidative stress, and apoptosis. Further analysis using DHBE cells and carcinoma cell lines indicated a similar trend, although differences in sensitivity were observed. Downregulation of stress-responsive genes may be involved in the mechanism by which stress response protects against lung injury.Key words carbon nanotube; stress-responsive gene; human bronchial epithelial cell Nanotechnology has drastically emerged over the past 10 years, and a vast variety of nanomaterials, which can be employed in a wide range of applications in nanoscience, medicine, and engineering, have been created. Carbon nanotubes (CNTs), discovered by Iijima, are currently key promising materials of nanotechnology.

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Crosstalk Between the Aryl Hydrocarbon Receptor and Hypoxia on the Constitutive Expression of Cytochrome P4501A1 mRNA

Cited by 43 publications

References 36 publications

Loss of the Aryl Hydrocarbon Receptor Induces Hypoxemia, Endothelin-1, and Systemic Hypertension at Modest Altitude

Loss of the Aryl Hydrocarbon Receptor Induces Hypoxemia, Endothelin-1, and Systemic Hypertension at Modest Altitude

Changes in Expression of Drug-Metabolizing Enzymes by Single-Walled Carbon Nanotubes in Human Respiratory Tract Cells

Single-Walled Carbon Nanotubes Downregulate Stress-Responsive Genes in Human Respiratory Tract Cells

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