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Hydrocarbon Receptor (hydrocarbon + receptor)
Kinds of Hydrocarbon Receptor Selected AbstractsEnvironmental Toxicants May Modulate Osteoblast Differentiation by a Mechanism Involving the Aryl Hydrocarbon Receptor,,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 10 2007Elizabeth P Ryan Abstract The AHR mediates many of the toxicological effects of aromatic hydrocarbons. We show that AHR expression in osteoblasts parallels the induction of early bone-specific genes involved in maturation. The AHR may not only mediate the effects of toxicants, but with an as yet unidentified ligand, be involved in the differentiation pathways of osteoblasts. Introduction: Metabolic bone diseases arise as a result of an imbalance in bone cell activities. Recent evidence suggests that environmental toxicants may be contributing factors altering these activities. One candidate molecule implicated in mediating the toxic effects of exogenous compounds is the aryl hydrocarbon receptor (AHR). Materials and Methods: Osteoblasts isolated from neonatal rat calvaria were analyzed for AHR expression by quantitative PCR, Western blot, and immunohistochemistry. In addition, AHR activation was evaluated by electromobility gel shift assay and fluorescence microscopy. Results: Our findings showed AHR expression in mature osteoblasts in vivo. The pattern of AHR expression peaks after alkaline phosphatase and before induction of osteocalcin. We first show that AHR functions as a transactivating receptor in osteoblasts, as evidenced by its ligand-dependent migration to the nucleus and its association with known dioxin response elements. AHR activation by 2,3,7,8-tetrachlorodibenzo -p -dioxin (TCDD) mediated the induction of cytochrome p450 1A1 and cycloxygenase-2 protein levels. This effect could be inhibited by the potent AHR antagonist, 3,4 methoxynitroflavone. Furthermore, lead treatment of osteoblasts upregulates the expression of AHR mRNA and protein levels, supporting a novel mechanism whereby lead in the skeleton may increase the sensitivity of bone cells to toxicant exposure. Conclusions: These data imply that the AHR mediates the effects of aromatic toxicants on bone and that AHR expression is regulated during osteoblast differentiation. [source] Interaction between halogenated aromatic compounds in the Ah receptor signal transduction pathwayENVIRONMENTAL TOXICOLOGY, Issue 5 2004Guosheng Chen Abstract Many toxic and biochemical responses to halogenated aromatic compounds (HACs) such as polychlorinated biphenyls (PCBs) and polychlorinated dibenzo- p -dioxins (PCDDs) are mediated through the aryl hydrocarbon receptor (AhR), which is an intracellular cytosolic target for HACs. Environmental exposure to HACs almost always involves complex mixtures of congeners, some of which can antagonize the action of potent HACs such as 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD). In this work we studied TCDD and representative PCB congeners, alone and in mixture, for their effect on CYP1A gene transcription and protein levels in primary rat hepatocytes. Together with our previous work, our results suggest that formation of the Ah receptor-ligand-DRE (dioxin response element) complex is the principal point of divergence in the mechanism between an AhR agonist and an AhR antagonist. The coplanar PCBs 77 and 126 and the mono- ortho PCB 156 were full agonists toward CYP1A1 gene transcription and CYP1A protein levels, showing typical additive behavior with TCDD to the target molecule AhR. In contrast, the nonplanar PCB 153 antagonized the action of TCDD, even at concentrations that occupied a significant fraction of AhR molecules. Competitive inhibition explains the commonly reported decrease of ethoxyresorufin- O -deethylase (EROD) activity when PCBs are present in high concentrations and the antagonism of PCBs to the EROD activity of TCDD. The result is that Western blotting offers a much more reliable measure of CYP1A protein concentration than does the EROD assay, despite the greater convenience of the latter. © 2004 Wiley Periodicals, Inc. Environ Toxicol 19: 480,489, 2004. [source] Polychlorinated naphthalenes and other dioxin-like compounds in Elbe River sedimentsENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 3 2008Werner Brack Abstract Contamination of Elbe River (Germany) sediments with dioxin-like toxicants was investigated following the 500-year flood (flood that statistically occurs once in 500 years) of 2002. It was hypothesized that large amounts of particulate matter from river beds and associated dioxin-like toxicants were mobilized and transported during this flood event. The investigation focused on polychlorinated naphthalenes (PCNs) that have not been determined previously in the Elbe River. The in vitro H4IIE- luc assay was used as an overall measure for toxicants capable of binding to the aryl hydrocarbon receptor (AhR). The assay was combined with congener-specific instrumental analyses and fractionation to quantify PCN contributions to total AhR-mediated activity relative to polychlorinated dibenzo- p -dioxins and dibenzofurans (PCDD/Fs) and polychlorinated biphenyls (PCBs). Penta- to octachloron-aphthalene concentrations of 30 ng/kg dry weight up to 13 ,g/kg dry weight were found in Elbe River sediments downstream of Bitterfeld. Concentrations of penta- to octachloronaphthalenes, however, were only approximately 3 ,g/kg dry weight at a site in the vicinity of Bitterfeld, where a level of approximately 3 mg/kg dry weight was reported before the flood. Also, the congener pattern of PCNs at this site changed after the flood, and PCN patterns reported previously for Bitterfeld and assigned to chlor-alkali electrolysis with graphite electrodes could now be observed at the sites from downstream of Bitterfeld and Magdeburg. Whereas PCDD/Fs dominated the dioxin-like activity in the middle and lower Elbe River, PCNs contributed as much as 10% of the total AhR-mediated activity. The contribution of PCBs was less significant (maximum, 0.2%). Thus, in Elbe River sediments, PCNs should be considered as relevant contaminants and be included in future monitoring and risk assessment programs. [source] Aryl hydrocarbon bioaccessibility to small mammals from arctic plants using in vitro techniquesENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 3 2007Sarah A. Armstrong Abstract Through their diet, herbivores inhabiting contaminated sites may be chronically exposed to a variety of aryl hydrocarbons (e.g., dioxins and polycyclic aromatic hydrocarbons [PAHs]). However, little is known about how differences in morphology and physiology among plant species alter the environmental accumulation of aryl hydrocarbons or their release and subsequent activity in the gastrointestinal tract of herbivores after ingestion. In the present study, the activity of aryl hydrocarbons during digestion was examined using six Arctic plant species growing in impacted and reference sites near Inuvik, Northwest Territories, Canada. The plant species studied were black spruce (Picea mariana), labrador tea (Ledum groenlandicum), bog birch (Betula glandulosa), green alder (Alnus crispa), water sedge (Carex aquatilis), and little-tree willow (Salix arbusculoides). Plants were digested using a simulator of the upper digestive tract, and aryl hydrocarbon release was evaluated using an aryl hydrocarbon-receptor assay. Bioaccessible aryl hydrocarbon activity varied among the plant species tested. The species with the greatest activity was green alder, and the species with the least activity was black spruce. Further investigation revealed that digested plant extracts may antagonize the aryl hydrocarbon receptor and prevent bioactivation of the aryl compound benzo[a]pyrene. Thus, PAH risk from the ingestion of vegetation varies among plant species and may depend on antagonists present in the vegetation. [source] Interactions between metabolism of trace metals and xenobiotic agonists of the aryl hydrocarbon receptor in the antarctic fish Trematomus bernacchii: Environmental perspectivesENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 6 2005Francesco Regoli Abstract Although Antarctica is a pristine environment, organisms are challenged with contaminants either released locally or transported from industrialized regions through atmospheric circulation and marine food webs. Organisms from Terra Nova Bay also are exposed to a natural enrichment of cadmium, but to our knowledge, whether such environmental conditions influence biological responses to anthropogenic pollutants has never been considered. In the present study, the Antarctic rock cod (Trematomus bernacchii) was exposed to model chemicals, including polycyclic aromatic hydrocarbons (benzo[a]pyrene), persistent organic pollutants (2,3,7,8-tetrachlorodibenzo- p -dioxin [TCDD]), cadmium, and a combination of cadmium and TCDD. Analyzed parameters included chemical bioaccumulation, activity, and levels of biotransformation enzymes (cytochrome P4501A); metallothioneins and the efficiency of the antioxidant system measured as individual defenses (catalase, glutathione, glutathione reductase, glutathione S -transferases, and glutathione peroxidases); and total scavenging capacity toward peroxyl and hydroxyl radicals. Reciprocal interactions between metabolism of inorganic and organic pollutants were demonstrated. Dioxin enhanced the accumulation of cadmium, probably stored within proliferating endoplasmic reticulum, and cadmium suppressed the inducibility of cytochrome P4501A, allowing us to hypothesize a posttranscriptional mechanism as the depletion of heme group availability. Clear evidence of oxidative perturbation was provided by the inhibition of antioxidants and enhanced sensitivity to oxyradical toxicity in fish exposed to organic chemicals. Exposure to cadmium revealed counteracting responses of glutathione metabolism; however, these responses did not prevent a certain loss of antioxidant capacity toward peroxyl radicals. The pattern of antioxidant responses exhibited by fish coexposed to cadmium and TCDD was more similar to that observed for cadmium than to that observed for TCDD. The overall results suggest that elevated natural levels of cadmium in Antarctic organisms from Terra Nova Bay can limit biotransformation capability of polycyclic (halogenated) hydrocarbons, thus influencing the bioaccumulation and biological effects of these chemicals in key sentinel species. [source] In vitro assessment of potential mechanism-specific effects of polybrominated diphenyl ethersENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 11 2002Daniel L. Villeneuve Abstract This study examined the ability of environmentally relevant concentrations of 10 different polybrominated diphenyl ethers (PBDEs) to induce aryl hydrocarbon receptor (AhR)-and estrogen receptor (ER)-mediated gene expression in vitro. It also examined the ability of PBDEs to displace steroid hormones from serum proteins in vitro. At concentrations ranging up to 880 ng/ml, none of the PBDEs significantly displaced tritiated 17,-estradiol (E2) or testosterone from hormone-stripped carp serum. At concentrations ranging up to 500 ng/ml, 9 of 10 PBDEs tested failed to induce ER- or AhR-mediated gene expression in MVLN and H4IIE-luc cells, respectively. One congener, 3,3,,4,4,,5-pentabromodiphenylether (BDE 126), induced significant AhR-mediated gene expression at 500 ng/ml, but the magnitude of induction was only 13% of that caused by 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD). Overall, the PBDEs tested were found to be at least 200,000 times less potent than TCDD and 50,000 times less potent than E2 for inducing AhR- and ER-mediated gene expression, respectively. [source] Activation of the aryl hydrocarbon receptor reveals distinct requirements for IL-22 and IL-17 production by human T helper cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 9 2010Jean-Marie Ramirez Abstract Ligands of the aryl hydrocarbon receptor (AHR), a transcription factor mediating the effects of dioxin, favor Th17 differentiation and exacerbate autoimmunity in mice. We investigated how AHR ligands affected human T-cell polarization. We found that the high affinity and stable AHR-ligand dioxin as well as the natural AHR-ligand 6-formylinolo[3,2-b] carbazole induced the downstream AHR-target cytochrome P450A1, and without affecting IFN-,, they enhanced IL-22 while simultaneously decreasing IL-17A production by CD4+ T cells. The specific AHR-inhibitor CH-223191 abolished these effects. Furthermore, blockade of IL-23 and IL-1, important for Th17 expansion, profoundly decreased IL-17A but not IL-22 production. AHR agonists reduced the expression of the Th17 master transcription factor retinoic acid-related orphan receptor C (RORC), without affecting T-bet, GATA-3 and Foxp3. They also decreased the expression of the IL-23 receptor. Importantly, AHR-ligation did not only decrease the number of Th17 cells but also primed naïve CD4+ T cells to produce IL-22 without IL-17 and IFN-,. Furthermore, IL-22 single producers did not express CD161, which distinguished them from the CD161+ Th17 cells. Hence, our data provide compelling evidence that AHR activation participates in shaping human CD4+ T-cell polarization favoring the emergence of a distinct subset of IL-22-producing cells that are independent from the Th17 lineage. [source] Context-specific regulation of LINE-1GENES TO CELLS, Issue 10 2007Ivo Teneng The present study was conducted to evaluate the contextual specificity of long interspersed nuclear element-1 (LINE-1 or L1) activation by cellular stress and the role of the aryl hydrocarbon receptor (AHR) transcription factor and oxidative stress in the gene activation response. Activation of the AHR by the genotoxic carcinogen benzo(a)pyrene (BaP) increased L1 expression in human cervical carcinoma (HeLa) cells, human microvascular endothelial cells (HMEC), mouse vascular smooth muscle cells (mVSMC) and mouse embryonic kidney cells (mK4). In contrast, challenge with a different AHR ligand 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD), or UV irradiation (10,20 J/m2), induced L1 only in HeLa cells. Transactivation of the mouse L1Md-A5 promoter was observed in all cell types challenged with BaP, while TCDD was without effect, and UV only activated L1 in HeLa cells. Genetic and pharmacological experiments implicated the AHR and oxidative stress as contextual determinants of L1 inducibility by cellular stress. [source] Chronic effects of polychlorinated dibenzofurans on mink in laboratory and field environmentsINTEGRATED ENVIRONMENTAL ASSESSMENT AND MANAGEMENT, Issue 2 2009Matthew J Zwiernik Abstract Mink are often used as a sentinel species in ecological risk assessments of chemicals such as polychlorinated biphenyls (PCBs), dibenzo- p -dioxins (PCDDs), and dibenzofurans (PCDFs) that cause toxicity mediated through the aromatic hydrocarbon receptor. Considerable toxicological information is available on the effects of PCBs and PCDDs on mink, but limited toxicological information is available for PCDFs. Thus, exposure concentrations at which adverse effects occur could not be determined reliably for complex mixtures in which PCDFs dominate the total calculated concentration of 2,3,7,8-tetrachlorodibenzo- p -dioxin equivalent (TEQ). Two studies were conducted to evaluate the potential toxicity of PCDFs to mink. The first was a chronic exposure, conducted under controlled laboratory conditions, in which mink were exposed to 2,3,7,8-tetrachlorodibenzofuran (2,3,7,8-TCDF) concentrations as great as 2.4 × 103 ng 2,3,7,8-TCDF/kg wet-weight (ww) diet or 2.4 × 102 ng TEQ2006-WHO-mammal/kg ww diet. In that study, transient decreases in body masses of kits relative to the controls was the only statistically significant effect observed. The second study was a 3-y field study during which indicators of individual health, including hematological and morphological parameters, were determined for mink exposed chronically to a mixture of PCDDs and PCDFs under field conditions. In the field study, there were no statistically significant differences in any of the measured parameters between mink exposed to a median estimated dietary dose of 31 ng TEQ2006-WHO-mammal/kg ww and mink from an upstream reference area where they had a median dietary exposure of 0.68 ng TEQ2006-WHO-mammal/kg ww. In both studies, concentrations of TEQ2006-WHO-mammal to which the mink were exposed exceeded those at which adverse effects, based on studies with PCDD and PCB congeners, would have been expected. Yet in both instances where PCDF congeners were the sole or predominant source of the TEQ2006-WHO-mammal, predicted adverse effects were not observed. Taken together, the results of these studies suggest that the values of the mammalian-specific toxicity equivalency factors suggested by the World Health Organization overestimate the toxic potency of PCDFs to mink. Therefore, hazard cannot be accurately predicted by making comparisons to toxicity reference values derived from exposure studies conducted with PCBs or PCDDs in situations where mink are exposed to TEQ mixtures dominated by PCDFs. [source] Correlation between the high expression of C/EBP, protein in F442A cells and their relative resistance to antiadipogenic action of TCDD in comparison to 3T3-L1 cellsJOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 2 2002Phillip C. C. Liu Abstract We compared the ability of two clonally derived murine preadipocyte cell lines, 3T3-L1(L1) and 3T3-F442A (F442A), to differentiate after treatment by 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD), and found that the former cell line was clearly suppressed by TCDD but the latter was not. It was initially postulated that the easiest way to explain the lack of response to TCDD in F442A cells could be an alteration in aryl hydrocarbon receptor (AhR) functionality. This hypothesis was tested first, but no differences were found in the levels or functions of AhR. To find an alternate explanation for such a differential effect of TCDD, we tested the action of several diagnostic agents on the process of adipocyte differentiation of these two cells. No differences were found between these two lines of cells in the susceptibility to the antiadipogenic action of 12-0-tetradecanoylphorbol-13-acetate (TPA), or to TNF,, indicating that the basic biochemical components engaged in the antiadipogenic actions of these agents in these two cell lines are similar. In contrast, F442A cells were found to be more resistant to the antiadipogenic action of EGF or TGF, than L1 cells which were tested side by side. Based on the knowledge that TNF, preferentially affects C/EBP, and that TGF, specifically controls C/EBP, and , in their antiadipogenic action, we hypothesized that the major cause for the differential response of these two similar cell lines could be the insensitivity of C/EBP, and/or , of F442A cells to the action of TCDD. We could obtain supporting data for this hypothesis, showing that in F442A cells, the level of C/EBP, is already high even before the addition of adipocyte differentiation factors and that TCDD did not cause any significant changes in the titer of C/EBP,. © 2002 Wiley Periodicals, Inc. J Biochem Mol Toxicol 16:70,83, 2002; Published online in Wiley Interscience (www.interscience.wiley.com). DOI 10.1002/jbt.10020 [source] Environmental Toxicants May Modulate Osteoblast Differentiation by a Mechanism Involving the Aryl Hydrocarbon Receptor,,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 10 2007Elizabeth P Ryan Abstract The AHR mediates many of the toxicological effects of aromatic hydrocarbons. We show that AHR expression in osteoblasts parallels the induction of early bone-specific genes involved in maturation. The AHR may not only mediate the effects of toxicants, but with an as yet unidentified ligand, be involved in the differentiation pathways of osteoblasts. Introduction: Metabolic bone diseases arise as a result of an imbalance in bone cell activities. Recent evidence suggests that environmental toxicants may be contributing factors altering these activities. One candidate molecule implicated in mediating the toxic effects of exogenous compounds is the aryl hydrocarbon receptor (AHR). Materials and Methods: Osteoblasts isolated from neonatal rat calvaria were analyzed for AHR expression by quantitative PCR, Western blot, and immunohistochemistry. In addition, AHR activation was evaluated by electromobility gel shift assay and fluorescence microscopy. Results: Our findings showed AHR expression in mature osteoblasts in vivo. The pattern of AHR expression peaks after alkaline phosphatase and before induction of osteocalcin. We first show that AHR functions as a transactivating receptor in osteoblasts, as evidenced by its ligand-dependent migration to the nucleus and its association with known dioxin response elements. AHR activation by 2,3,7,8-tetrachlorodibenzo -p -dioxin (TCDD) mediated the induction of cytochrome p450 1A1 and cycloxygenase-2 protein levels. This effect could be inhibited by the potent AHR antagonist, 3,4 methoxynitroflavone. Furthermore, lead treatment of osteoblasts upregulates the expression of AHR mRNA and protein levels, supporting a novel mechanism whereby lead in the skeleton may increase the sensitivity of bone cells to toxicant exposure. Conclusions: These data imply that the AHR mediates the effects of aromatic toxicants on bone and that AHR expression is regulated during osteoblast differentiation. [source] Structural basis for preferential binding of non- ortho -substituted polychlorinated biphenyls by the monoclonal antibody S2B1JOURNAL OF MOLECULAR RECOGNITION, Issue 4 2005Jean-Luc Pellequer Abstract Polychlorinated biphenyls (PCBs) are a family of 209 isomers (congeners) with a wide range of toxic effects. In structural terms, they are of two types: those with and those without chlorines at the ortho positions (2, 2,, 6 and 6,). Only 20 congeners have no ortho chlorines. Three of these are bound by the aryl hydrocarbon receptor and are one to four orders of magnitude more toxic than all others. A monoclonal antibody, S2B1, and its recombinant Fab have high selectivity and nanomolar binding affinities for two of the most toxic non- ortho -chlorinated PCBs, 3,4,3,,4,-tetrachlorobiphenyl and 3,4,3,,4,,5,-pentachlorobiphenyl. To investigate the basis for these properties, we built a three-dimensional structure model of the S2B1 variable fragment (Fv) based on the high-resolution crystallographic structures of antibodies 48G7 and N1G9. Two plausible conformations for the complementarity-determining region (CDR) H3 loop led to two putative PCB-binding pockets with very different shapes (models A and B). Docking studies using molecular mechanics and potentials of mean force (PMF) indicated that model B was most consistent with the selectivity observed for S2B1 in competition ELISAs. The binding site in model B had a deep, narrow pocket between VL and VH, with a slight constriction at the top that opened into a wider pocket between CDRs H1 and H3 on the antibody surface. This binding site resembles those of esterolytic antibodies that bind haptens with phenyl rings. One phenyl ring of the PCB fits into the deep pocket, and the other ring is bound in the shallower one. The bound PCB is surrounded by the side chains of TyrL91, TyrL96 and TrpH98, and it has a ,-cation interaction with ArgL46. The tight fit of the binding pocket around the ortho positions of the bound PCBs indicates that steric hindrance of ortho chlorines in the binding site, rather than induced conformational change of the PCBs, is responsible for the selectivity of S2B1. Copyright © 2005 John Wiley & Sons, Ltd. [source] Xenobiotic response element binding enriched in both nuclear and microsomal fractions of rat cerebellumJOURNAL OF NEUROCHEMISTRY, Issue 1 2003Nobuyuki Kuramoto Abstract Xenobiotic response element (XRE) is a core nucleotide sequence at the upstream of inducible target genes for the transcription factor aryl hydrocarbon receptor (AhR) that is responsible for signal transduction of exogenous environmental pollutants in eukaryotic cells. Immunoblotting analysis revealed the constitutive expression of AhR-related proteins in rat liver and brain, while specific binding of a radiolabelled probe containing XRE was detected in nuclear preparations of both liver and brain on gel retardation electrophoresis. Among discrete rat brain structures examined, cerebellum exhibited the highest XRE binding with less potent binding in hypothalamus, midbrain, medulla-oblongata, hippocampus, cerebral cortex and striatum. In contrast to liver and hippocampus, cerebellum also contained unusually higher XRE binding in microsomal fractions than that in either nuclear or mitochondrial fractions. Limited proteolysis by V8 protease did not markedly affect XRE binding in cerebellar nuclear extracts, with concomitant diminution of that in hepatic and hippocampal nuclear extracts. In primary cultured cerebellar neurons, indigo was effective in significantly increasing XRE binding only when determined immediately after sustained exposure for 120 min in the presence of high potassium chloride. These results suggest the abundance of as-yet unidentified proteins with high affinity for XRE and responsiveness to indigo in both nuclear and microsomal fractions of rat cerebellum. [source] Role of nitric oxide in downregulation of cytochrome P450 1a1 and NADPH: Quinone oxidoreductase 1 by tumor necrosis factor-, and lipopolysaccharideJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 10 2007Negar Gharavi Abstract We previously demonstrated that tumor necrosis factor alpha (TNF-,) and lipopolysaccharide (LPS) downregulate aryl hydrocarbon receptor (AhR)-regulated genes, such as cytochrome P450 1a1 (Cyp1a1) and NADPH: quinone oxidoreductase 1 (Nqo1) gene expression, yet the mechanisms involved remain unknown. The correlation between the inflammation-mediated suppression of AhR-regulated genes and the TNF-, or LPS-induced nitric oxide (NO) production especially in murine hepatoma Hepa 1c1c7 cells has been questioned; therefore we investigated whether NO is involved in the modulation of Cyp1a1 and Nqo1 by TNF-, or LPS in Hepa 1c1c7 cells. A significant dose-dependent increase in the inducible nitric oxide synthase (NOS2) expression and NO production were observed by various concentrations of TNF-, (1, 5, and 10 ng/mL) and LPS (1 and 5 µg/mL) which was completely inhibited by a NOS2 inhibitor, L-N6-(1-iminoethyl) lysine (L-NIL) (1 mM). Furthermore, TNF-, and LPS significantly induced NOS2 expression. Both TNF-, and LPS repressed the ,-naphthoflavone (,NF)-mediated induction of Cyp1a1 and Nqo1 at mRNA and activity levels. The downregulation of Cyp1a1, but not Nqo1, was significantly prevented by L-NIL. However, proxynitrite decomposer, iron tetrakis (N -methyl-4,-pyridyl) porphyrinato (FeTMPyP) (5 µM) did not affect TNF-,- and LPS-mediated downregulation of Cyp1a1 and Nqo1 at mRNA and activity levels. These results show that NO, but not peroxynitrite, may be involved in TNF-,- and LPS-mediated downregulation of Cyp1a1 without affecting the downregulation of Nqo1. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 2795,2807, 2007 [source] Nuclear receptors and drug disposition gene regulationJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 6 2005Rommel G. Tirona Abstract In this minireview, the role of various nuclear receptors and transcription factors in the expression of drug disposition genes is summarized. Specifically, the molecular aspects and functional impact of the aryl hydrocarbon receptor (AhR), nuclear factor-E2 p45-related factor 2 (Nrf2), hepatocyte nuclear factor 1, (HNF1,), constitutive androstane receptor (LAR), pregnane X receptor (PXR), farnesoid X receptor (FXR), peroxisome proliferator-activated receptor , (PPAR,), hepatocyte nuclear factor 4, (HNF4,), vitamin D receptor (VDR), liver receptor homolog 1 (LRH1), liver X receptor (LXR,), small heterodimer partner-1 (SHP-1), and glucocorticoid receptor (GR) on gene expression are detailed. Finally, we discuss some current topics and themes in nuclear receptor-mediated regulation of drug metabolizing enzymes and drug transporters. © 2005 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:1169,1186, 2005 [source] Suppressive effects of flavonoids on dioxin toxicityBIOFACTORS, Issue 1-4 2000Hitoshi Ashida Abstract Dioxin type chemicals such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) cause a variety of toxicity. Most of the toxicity of TCDD has been attributed to a mechanism by which TCDD is bound to aryl hydrocarbon receptor (AhR) and transforms the receptor. Thus, suppression of the AhR transformation by food factors can suppress the dioxin toxicity. In this study, flavonoids at various concentrations were treated to a rat cytosolic fraction containing AhR before adding 1 nM TCDD. The transformed AhR was detected by an electrophoretic mobility shift assay with a DNA oligonucleotide consensus to dioxin response element. As the results, flavones and flavonols at dietary levels act as the antagonists for AhR and suppress the transformation. The antagonistic IC50 values were in a range between 0.14 and 10 ,M, which are close to the physiological levels in human. These results suggest that a plant-based diet can prevent the dioxin toxicity. [source] Selective Adsorption of Polychlorinated Dibenzo- p -dioxins and Dibenzofurans by the Zeosils UTD-1, SSZ-24, and ITQ-4CHEMISTRY - A EUROPEAN JOURNAL, Issue 1 2004Ralph Jäger Dr. Abstract Zeosils are microporous solids with a pure silica framework. Due to their hydrophobic properties, zeosils are ideal host materials for the adsorption of hydrophobic guest molecules. We tested zeosils with different pore diameters (UTD-1, SSZ-24 and ITQ-4 as well as CIT-5) for the selective adsorption of the polychlorinated dibenzo- p -dioxins and dibenzofurans. This group of highly toxic substances contains 210 congeners that possess similar chemical properties, but differ in their size and shape. In the experiment, polychlorinated dibenzo- p -dioxins and dibenzofurans were extracted from fly ash of a waste incinerator, adsorbed on amorphous silica, then thermally desorbed and flushed over a sequential arrangement of the zeosils at elevated temperature by a stream of nitrogen. ITQ-4 with the smallest pore diameter was placed first, followed by SSZ-24 and, finally, by UTD-1 with the largest pore diameter. After the experiment, the zeosils were analysed for their contents of the different congeners. The results show that the sorption of the congeners occurs selectively and that it is governed by the size and the shape of the dioxin molecules, which in turn depend on the number of chlorine atoms and the pattern of chlorine substitution (regioisomers). Geometrical reasoning as well as molecular dynamics calculations on the zeosil structures and on the dioxin molecules were helpful in rationalising the results. This work represents an especially complex case of the molecular sieving effect and may lead to a selective on-line monitoring of the concentrations of dioxin molecules in waste gases of industrial combustion processes. The size- and shape-selective sorption of dioxin molecules may also bear some resemblance to the molecular recognition process that occurs in nature at the aryl hydrocarbon receptor. [source] | ||||||||||||||||