subject:(Pregnane X Receptor)

Texas A&M University

1. Eagleton, Navada Lorraine. Novel Functions for the Pregnane X Receptor include Regulation of mRNA Turnover and Involvement in Colon Cancer Progression.

Degree: MS, Toxicology, 2011, Texas A&M University

URL: http://hdl.handle.net/1969.1/ETD-TAMU-2010-08-8029

► To understand the mechanisms of transcriptional regulation of PXR, we performed yeast two-hybrid screenings to search for PXR-interacting proteins in a human liver cDNA library… (more)

▼ To understand the mechanisms of transcriptional regulation of PXR, we performed yeast two-hybrid screenings to search for PXR-interacting proteins in a human liver cDNA library using the PXR ligand binding domain as the bait. More than one million independent clones were screened. One positive clone was a partial cDNA of CNOT2 (amino acid 183-540). CNOT2 is a component of CCR4-NOT that is a multi-subunit protein complex highly conserved from yeast to humans. Using a mammalian two-hybrid system in CV-1 cells and GST-pull down assays, we confirmed the direct interaction between PXR and CNOT2 and mapped the specific domains of association. In HepG2 cells, over expression of CNOT2 suppressed the PXR-regulated luciferase reporter gene activity. siRNA knockdown of CNOT2 potentiated PXR-transcriptional activity. These results strongly suggest that the CCR4-NOT complex is significantly involved in transcriptional regulation of PXR. The immuno-precipitated CNOT2 complex contained deadenylase activity as determined by an in vitro RNA decay assay. The presence of transfected PXR inhibited the cNOT2-associated deadenylase activity, as demonstrated by poly(A) tail PCR. Cellular localization of PXR and cNOT2 by immuno-fluorescence microscopy indicates that the interaction might occur within Cajal Bodies. Taken together, these results suggest that PXR regulates the mRNA turnover through direct interaction with the NOT2 component of the CCR4-NOT complex. PXR is also involved in colon cancer progression. Our results indicate that the evolutionarily conserved PXR protects organisms from carcinogenesis by inhibiting tumor growth as well as eliminating carcinogenic substances. Our laboratory proposes that pregnane X receptor has an important role in maintaining the balance of cells progressing through the cell cycle. In vitro and in vivo experiments demonstrate expression of PXR in colon cancer cells slows the progression of tumor formation. Colony growth of the PXR-transfected HT29 cells was suppressed in soft agar assay. In the xenograft assay, the tumor size formed in nude mice was significantly suppressed in HT29 cells stably transfected with PXR (310 mg /- 6.2 vs. 120 mg±6, p<0.01). The number of Ki-67 positive cells were significantly decreased in PXR-transfected HT29 xenograft tumor tissue compared vector-transfected HT29 controls (p<0.01) as determined by immuno-histochemistry suggesting that PXR inhibits proliferation of colon cancer cells. Results of flow cytometry analysis indicated that PXR-transfection in HT29 cells caused G0/G1 arrest. The growth inhibitory effects of PXR are likely mediated through the E2F/Rb-regulated check point since E2F1 nuclear expression was significantly inhibited by PXR over expression. Advisors/Committee Members: Tian, Yanan (advisor), Safe, Stephen (committee member), Porter, Weston (committee member), Villalobos, Alice (committee member).

Subjects/Keywords: pregnane X receptor; PXR; CNOT2; colon cancer

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APA (6^th Edition):

Eagleton, N. L. (2011). Novel Functions for the Pregnane X Receptor include Regulation of mRNA Turnover and Involvement in Colon Cancer Progression. (Masters Thesis). Texas A&M University. Retrieved from http://hdl.handle.net/1969.1/ETD-TAMU-2010-08-8029

Chicago Manual of Style (16^th Edition):

Eagleton, Navada Lorraine. “Novel Functions for the Pregnane X Receptor include Regulation of mRNA Turnover and Involvement in Colon Cancer Progression.” 2011. Masters Thesis, Texas A&M University. Accessed January 23, 2021. http://hdl.handle.net/1969.1/ETD-TAMU-2010-08-8029.

MLA Handbook (7^th Edition):

Eagleton, Navada Lorraine. “Novel Functions for the Pregnane X Receptor include Regulation of mRNA Turnover and Involvement in Colon Cancer Progression.” 2011. Web. 23 Jan 2021.

Vancouver:

Eagleton NL. Novel Functions for the Pregnane X Receptor include Regulation of mRNA Turnover and Involvement in Colon Cancer Progression. [Internet] [Masters thesis]. Texas A&M University; 2011. [cited 2021 Jan 23]. Available from: http://hdl.handle.net/1969.1/ETD-TAMU-2010-08-8029.

Council of Science Editors:

Eagleton NL. Novel Functions for the Pregnane X Receptor include Regulation of mRNA Turnover and Involvement in Colon Cancer Progression. [Masters Thesis]. Texas A&M University; 2011. Available from: http://hdl.handle.net/1969.1/ETD-TAMU-2010-08-8029

2. Barretto, Sharon Ann. Etude des interactions bidirectionnelles entre le microbiote intestinal et les récepteurs aux xénobiotiques CAR et PXR : Insights into the bidirectional interactions between the gut microbiota and the xenobiotic receptors CAR and PXR.

Degree: Docteur es, Maladies métaboliques et cardiovasculaires, 2019, Université Toulouse III – Paul Sabatier

URL: http://www.theses.fr/2019TOU30233

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Le pregnane X receptor (PXR, NR1I2) et le récepteur constitutif aux androstanes (CAR, NR1I3) sont deux récepteurs nucléaires hépatiques et intestinaux qui régulent la transcription… (more)

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Le pregnane X receptor (PXR, NR1I2) et le récepteur constitutif aux androstanes (CAR, NR1I3) sont deux récepteurs nucléaires hépatiques et intestinaux qui régulent la transcription d'enzymes de détoxification des xénobiotiques. Des travaux antérieurs ont montré que l'expression des gènes cibles de CAR et PXR est significativement réduite dans le foie des souris axéniques. Dans ce projet de thèse, nous avions pour objectif de mieux comprendre les interactions bidirectionnelles entre le microbiote intestinal et ces xénosenseurs. Nous avons d'abord utilisé une approche pharmacologique chez les souris mâles WT vs Pxr-/- et comparé la signature transcriptomique des gènes régulés par PXR dans le foie lors de l'activation via le PCN. L'activation de PXR a augmenté l'accumulation de triglycérides hépatiques. Nous avons observé un chevauchement significatif entre les gènes régulés négativement lors de l'activation de PXR et une liste de gènes cibles de PPARδ induits par le jeûne. Parmi ceux-ci, nous avons identifié le facteur de croissance de fibroblastes 21 (Fgf21) comme un nouveau gène régulé par PXR. L'activation de PXR a aboli les taux plasmatiques de FGF21. Ces premiers résultats ont fourni une signature complète de l'activation de PXR dans le foie et ont identifié de nouveaux gènes cibles potentiellement impliqués dans les effets stéatogènes et pléiotropes de PXR. Ensuite, nous avons comparé la signature hépatique à la signature intestinale de l'activation pharmacologique de PXR, ce qui nous a permis d'identifier les gènes cibles communs de PXR dans ces 2 organes. Enfin, nous avons utilisé des souris Pxr+/+ et Pxr-/- littermate et supprimé le microbiote intestinal au moyen d'antibiotiques (ATB). En utilisant les gènes cibles de PXR identifiés précédemment, nous avons confirmé que les ATB réduisaient de manière significative l'activité de PXR dans le foie et l'iléon. Des analyses transcriptomiques hépatiques ont montré que les ATB diminuaient un nombre beaucoup plus élevé de gènes PXR-dépendants dans le foie des souris mâles que chez les femelles. Chez les mâles, l'axe microbiote intestinal-PXR contrôlait le métabolisme des xénobiotiques et le remodelage des lipides hépatiques. À l'inverse, le séquençage 16S et la métabolomique par RMN du contenu caecal ont révélé des différences subtiles mais significatives dans la composition du microbiote intestinal des souris Pxr-/- par rapport aux souris Pxr+/+, uniquement chez les mâles. Nos résultats démontrent donc que, dans le foie, PXR est un senseur majeur du microbiote intestinal qui contrôle les capacités de détoxication de l'hôte et le métabolisme des lipides de manière sexuellement dimorphique. [...]

The pregnane X receptor (PXR, NR1I2) and the constitutive androstane receptor (CAR, NR1I3) are two liver and intestine-enriched nuclear receptors that act as transcriptional regulators of enzymes critical for the detoxification of xenobiotics and endogenous metabolites. Previous works have shown that the expression of CAR and PXR target genes is significantly reduced in the…

Advisors/Committee Members: Payrastre, Laurence (thesis director), Ellero, Sandrine (thesis director).

Subjects/Keywords: Antibiotiques; Xénobiotiques; Microbiote intestinal; Constitutive androstane receptor; Pregnane X receptor; Antibiotics; Xenobiotics; Gut microbiota; Constitutive androstane receptor; Pregnane X receptor

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Barretto, S. A. (2019). Etude des interactions bidirectionnelles entre le microbiote intestinal et les récepteurs aux xénobiotiques CAR et PXR : Insights into the bidirectional interactions between the gut microbiota and the xenobiotic receptors CAR and PXR. (Doctoral Dissertation). Université Toulouse III – Paul Sabatier. Retrieved from http://www.theses.fr/2019TOU30233

Chicago Manual of Style (16^th Edition):

Barretto, Sharon Ann. “Etude des interactions bidirectionnelles entre le microbiote intestinal et les récepteurs aux xénobiotiques CAR et PXR : Insights into the bidirectional interactions between the gut microbiota and the xenobiotic receptors CAR and PXR.” 2019. Doctoral Dissertation, Université Toulouse III – Paul Sabatier. Accessed January 23, 2021. http://www.theses.fr/2019TOU30233.

MLA Handbook (7^th Edition):

Barretto, Sharon Ann. “Etude des interactions bidirectionnelles entre le microbiote intestinal et les récepteurs aux xénobiotiques CAR et PXR : Insights into the bidirectional interactions between the gut microbiota and the xenobiotic receptors CAR and PXR.” 2019. Web. 23 Jan 2021.

Vancouver:

Barretto SA. Etude des interactions bidirectionnelles entre le microbiote intestinal et les récepteurs aux xénobiotiques CAR et PXR : Insights into the bidirectional interactions between the gut microbiota and the xenobiotic receptors CAR and PXR. [Internet] [Doctoral dissertation]. Université Toulouse III – Paul Sabatier; 2019. [cited 2021 Jan 23]. Available from: http://www.theses.fr/2019TOU30233.

Council of Science Editors:

Barretto SA. Etude des interactions bidirectionnelles entre le microbiote intestinal et les récepteurs aux xénobiotiques CAR et PXR : Insights into the bidirectional interactions between the gut microbiota and the xenobiotic receptors CAR and PXR. [Doctoral Dissertation]. Université Toulouse III – Paul Sabatier; 2019. Available from: http://www.theses.fr/2019TOU30233

3. Xu, Chenshu. REGULATION OF DRUG METABOLISM AND INFLAMMATION BY PREGNANE X RECEPTOR.

Degree: PhD, Pharmacology & Toxicology, 2011, University of Kansas

URL: http://hdl.handle.net/1808/9708

► Liver-enriched nuclear receptor (NR) proteins regulate the expression and activity of several pivotal hepatic biochemical pathways including the uptake, metabolism and excretion of cholesterol, bile… (more)

▼ Liver-enriched nuclear receptor (NR) proteins regulate the expression and activity of several pivotal hepatic biochemical pathways including the uptake, metabolism and excretion of cholesterol, bile acids, glucose, and xenobiotic compounds from the body. The pregnane x receptor (PXR, NR1I2) was first identified in 1998 as a member of the NR superfamily. Over the past decade, it has been well established that PXR functions as a master-regulator of xenobiotic- and drug-inducible expression and activity of numerous genes that encode key members of the phase I and phase II metabolic enzymes, as well as several membrane transporter proteins. In this way, activation of PXR serves as the principal defense mechanism defending the body from toxic insult. Similarly, the PXR protein also forms the molecular basis of an important class of drug-drug interactions in the clinical setting. Moreover, ligand-activated PXR negatively regulates inflammatory processes in both liver and intestine. An integrated model is emerging to reveal a key role for the post-translational modification of PXR in the selective suppression of gene expression, and is opening the door to the study of completely new modes of PXR-mediated gene regulation. This dissertation contributes mainly to two key areas of PXR research: (1) Identification a novel PXR target gene- carboxylesterase 6 (Ces6); (2) a study of the SUMOylation and ubiquitination of PXR protein. The results presented in this dissertation were primarily obtained from mouse and cell-culture systems. Data presented here reveal that activation of the inflammatory response modulates the SUMOylation and ubiquitination status of ligand-bound PXR protein. The SUMOylation and ubiquitination of the PXR protein functions to feedback-repress the inflammatory and xenobiotic responses, respectively. Taken together, the data represent a likely mechanism and provides initial molecular details for the connection between the PXR signaling pathway and inflammation. Studies on post-translational modification of PXR indicate how this protein is converted from a positive regulator in drug metabolism into a transcriptional repressor in inflammatory response. Finally, detailed protocols for purification of mammalian proteins necessary to perform in vitro SUMOylation reactions are presented. Taken together, the work presented in this dissertation contributes to understanding the interface between PXR, drug metabolism, and inflammation, which is expected to produce new opportunities for the development of novel therapeutic strategies. Advisors/Committee Members: Staudinger, Jeff L. (advisor), Dobrowsky, Rick T (cmtemember), Shi, Honglian (cmtemember), Moise, Alex (cmtemember), Lundquist, Erik A. (cmtemember).

Subjects/Keywords: Pharmacology; Toxicology; Carboxylesterase; Constitutive androstane receptor; Inflammation; Pregnane x receptor; Sumoylation

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Xu, C. (2011). REGULATION OF DRUG METABOLISM AND INFLAMMATION BY PREGNANE X RECEPTOR. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/9708

Chicago Manual of Style (16^th Edition):

Xu, Chenshu. “REGULATION OF DRUG METABOLISM AND INFLAMMATION BY PREGNANE X RECEPTOR.” 2011. Doctoral Dissertation, University of Kansas. Accessed January 23, 2021. http://hdl.handle.net/1808/9708.

MLA Handbook (7^th Edition):

Xu, Chenshu. “REGULATION OF DRUG METABOLISM AND INFLAMMATION BY PREGNANE X RECEPTOR.” 2011. Web. 23 Jan 2021.

Vancouver:

Xu C. REGULATION OF DRUG METABOLISM AND INFLAMMATION BY PREGNANE X RECEPTOR. [Internet] [Doctoral dissertation]. University of Kansas; 2011. [cited 2021 Jan 23]. Available from: http://hdl.handle.net/1808/9708.

Council of Science Editors:

Xu C. REGULATION OF DRUG METABOLISM AND INFLAMMATION BY PREGNANE X RECEPTOR. [Doctoral Dissertation]. University of Kansas; 2011. Available from: http://hdl.handle.net/1808/9708

University of Toronto

4. Hunter, Sarah Rachel. Induction of the Rat Hepatic Aryl Hydrocarbon Receptor Nuclear Translocator by Glucocorticoids.

Degree: 2014, University of Toronto

URL: http://hdl.handle.net/1807/73165

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The aryl hydrocarbon receptor (AHR) nuclear translocator (ARNT), a partner in the hypoxia and AHR signaling pathways, is induced in rat liver by dexamethasone (DEX),… (more)

Subjects/Keywords: aryl hydrocarbon receptor nuclear translocator; glucocorticoid receptor; glucocorticoids; pregnane X receptor; rat; signaling pathway; 0419

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Hunter, S. R. (2014). Induction of the Rat Hepatic Aryl Hydrocarbon Receptor Nuclear Translocator by Glucocorticoids. (Masters Thesis). University of Toronto. Retrieved from http://hdl.handle.net/1807/73165

Chicago Manual of Style (16^th Edition):

Hunter, Sarah Rachel. “Induction of the Rat Hepatic Aryl Hydrocarbon Receptor Nuclear Translocator by Glucocorticoids.” 2014. Masters Thesis, University of Toronto. Accessed January 23, 2021. http://hdl.handle.net/1807/73165.

MLA Handbook (7^th Edition):

Hunter, Sarah Rachel. “Induction of the Rat Hepatic Aryl Hydrocarbon Receptor Nuclear Translocator by Glucocorticoids.” 2014. Web. 23 Jan 2021.

Vancouver:

Hunter SR. Induction of the Rat Hepatic Aryl Hydrocarbon Receptor Nuclear Translocator by Glucocorticoids. [Internet] [Masters thesis]. University of Toronto; 2014. [cited 2021 Jan 23]. Available from: http://hdl.handle.net/1807/73165.

Council of Science Editors:

Hunter SR. Induction of the Rat Hepatic Aryl Hydrocarbon Receptor Nuclear Translocator by Glucocorticoids. [Masters Thesis]. University of Toronto; 2014. Available from: http://hdl.handle.net/1807/73165

5. Breuker, Cyril. Etude des xénorécepteurs CAR (NR1I3) et PXR (NR1I2) : identification d’un nouveau gène cible de CAR (SPOT14) et d’une nouvelle isoforme de PXR (PXR-small) dans l'hépatocyte humain : Study of the CAR (NR1I3) and PXR (NR1I2) : identification of a new CAR target gene (SPOT14) and a new PXR isoform (PXR-small) in human hepatocyte.

Degree: Docteur es, Sciences du médicament, 2010, Université Montpellier I

URL: http://www.theses.fr/2010MON13522

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CAR (Constitutive Androstane Receptor, NR1I3) et PXR (Pregnane X Receptor, NR1I2) sont deux récepteurs nucléaires dédiés à la reconna issance et à l'élimination de molécules… (more)

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CAR (Constitutive Androstane Receptor, NR1I3) et PXR (Pregnane X Receptor, NR1I2) sont deux récepteurs nucléaires dédiés à la reconna issance et à l'élimination de molécules lipophiles potentiellement toxiques pour l'organisme. Ces facteurs de transcription peuvent être activés par des ligands d'origines et de structures diverses (médicaments, polluants environnementaux, produits de l'alimentation et de phytothérapies). L'activation de ces récepteurs entraîne l'expression des gènes majeurs de la fonction de détoxication entéro-hépatique (CYP450, transférases, transporteurs) permettant l'élimination de ces toxiques. Dans ce travail, nous avons dans un premier temps 1) montré que CAR contrôle l'expression de Spot14, une protéine pro-lipogénique, et 2) nous avons identifié une nouvelle isoforme de PXR (PXR-small) codant uniquement pour le domaine de liaison des ligands de PXR. Nous avons pu déterminer les origines de transcription par 5'-RACE PCR et montrer que PXR-small représente environ 10% de l'ensemble des transcrits de PXR dans le tissu hépatique sain par une approche de PCR qua ntitative. Nous avons pu détecter sa présence par western-blot sur des extraits de protéines nucléaires issus de tissus hépatiques et de lignées cellulaires hépatiques. Par des expériences de gel retard, nous avons observé que cette nouvelle isoforme tronquée, qui ne code que pour le LBD de PXR, ne peut pas se lier à l'ADN. Des expériences de gènes rapporteurs suggèrent que cette isoforme se comporte comme un dominant négatif de PXR. Enfin, la présence d'un ilot CpG situé juste en amont de PXR-small suggère que cette nouvelle isoforme pourrait être régulée épigénétiquement par méthylation, notamment dans les cellules tumorales.

CAR (Constitutive Androstane Receptor, NR1I3) and PXR (Pregnane X Receptor, NR1I2) are two nuclear receptors devoted to the recognition and elimination of lipohilic molecules potentially toxic to the body.These transcription factors can be activated by ligands of different origins and structures (drugs, environmental pollutants, food products and herbal medicine...). The activation of these receptors leads to the expression of major genes of the detoxification process (CYP450, transferases, transporters) leading to the elimination of these toxics. In this work, we 1) showed that Spot14, a pro-lipogenic protein, is a target gene of CAR, then 2) we identified a novel isoform of PXR (PXR-small), coding only the ligand binding domain of PXR. By using 5'-RACE PXR, we established the origins of transcription of PXR-small and by quantitative PCR we observed that PXR-small represents about 10% of all PXR transcripts in human liver. By using western blo t, we detect its presence on nuclear protein extracts from liver tissues and hepatic cell lines. In Electromobility shift essays experiments, we observed that PXR-small cannot bind to DNA, while reporter essay experiments suggest that this isoform acts as a dominant negative of PXR. Finally, the presence of a CpG island just upstream of PXR-small suggests that this novel…

Advisors/Committee Members: Pascussi, Jean-Marc (thesis director), Lumbroso, Serge (thesis director).

Subjects/Keywords: Récepteur nucléaire; Pregnane X Receptor; Constitutive Androstane Receptor; Métabolisme des médicaments; Perturbateur métabolique; Nuclear receptor; Pregnane X Receptor; Constitutive Androstane Receptor; Drugs metabolism; Metabolic disruptive

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Breuker, C. (2010). Etude des xénorécepteurs CAR (NR1I3) et PXR (NR1I2) : identification d’un nouveau gène cible de CAR (SPOT14) et d’une nouvelle isoforme de PXR (PXR-small) dans l'hépatocyte humain : Study of the CAR (NR1I3) and PXR (NR1I2) : identification of a new CAR target gene (SPOT14) and a new PXR isoform (PXR-small) in human hepatocyte. (Doctoral Dissertation). Université Montpellier I. Retrieved from http://www.theses.fr/2010MON13522

Chicago Manual of Style (16^th Edition):

Breuker, Cyril. “Etude des xénorécepteurs CAR (NR1I3) et PXR (NR1I2) : identification d’un nouveau gène cible de CAR (SPOT14) et d’une nouvelle isoforme de PXR (PXR-small) dans l'hépatocyte humain : Study of the CAR (NR1I3) and PXR (NR1I2) : identification of a new CAR target gene (SPOT14) and a new PXR isoform (PXR-small) in human hepatocyte.” 2010. Doctoral Dissertation, Université Montpellier I. Accessed January 23, 2021. http://www.theses.fr/2010MON13522.

MLA Handbook (7^th Edition):

Breuker, Cyril. “Etude des xénorécepteurs CAR (NR1I3) et PXR (NR1I2) : identification d’un nouveau gène cible de CAR (SPOT14) et d’une nouvelle isoforme de PXR (PXR-small) dans l'hépatocyte humain : Study of the CAR (NR1I3) and PXR (NR1I2) : identification of a new CAR target gene (SPOT14) and a new PXR isoform (PXR-small) in human hepatocyte.” 2010. Web. 23 Jan 2021.

Vancouver:

Breuker C. Etude des xénorécepteurs CAR (NR1I3) et PXR (NR1I2) : identification d’un nouveau gène cible de CAR (SPOT14) et d’une nouvelle isoforme de PXR (PXR-small) dans l'hépatocyte humain : Study of the CAR (NR1I3) and PXR (NR1I2) : identification of a new CAR target gene (SPOT14) and a new PXR isoform (PXR-small) in human hepatocyte. [Internet] [Doctoral dissertation]. Université Montpellier I; 2010. [cited 2021 Jan 23]. Available from: http://www.theses.fr/2010MON13522.

Council of Science Editors:

Breuker C. Etude des xénorécepteurs CAR (NR1I3) et PXR (NR1I2) : identification d’un nouveau gène cible de CAR (SPOT14) et d’une nouvelle isoforme de PXR (PXR-small) dans l'hépatocyte humain : Study of the CAR (NR1I3) and PXR (NR1I2) : identification of a new CAR target gene (SPOT14) and a new PXR isoform (PXR-small) in human hepatocyte. [Doctoral Dissertation]. Université Montpellier I; 2010. Available from: http://www.theses.fr/2010MON13522

6. Leguelinel, Géraldine. Rôle des récepteurs des xénobiotiques CAR (Constitutive Androstane Receptor, NR1I3) et PXR (Pregnane X receptor, NR1I2) dans le métabolisme des chimiothérapies conventionnelles du cancer colorectal : Role of xenoreceptors CAR (Constitutive Androstane Receptor, NR1I3) and PXR (Pregnane X Receptor, NR1I2) in the metabolism of conventionnal chemotherapy in colorectal cancer.

Degree: Docteur es, Biologie Santé, 2011, Université Montpellier I

URL: http://www.theses.fr/2011MON13512

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Le cancer colorectal est marqué par une importante mortalité dans les stades avancés du fait du fort taux de récidives tumorales après chimiothérapie. La prédiction… (more)

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Le cancer colorectal est marqué par une importante mortalité dans les stades avancés du fait du fort taux de récidives tumorales après chimiothérapie. La prédiction de l'efficacité et de la toxicité des cytotoxiques s'impose comme un des enjeux majeurs de ces prochaines années. Parce que la majorité des anticancéreux sont pris en charge par les enzymes et transporteurs dont l'expression est contrôlée par le niveau d'expression et d'activation des xénosenseurs CAR et PXR, il est fort probable que ces xénosenseurs puissent représenter des facteurs prédictifs à prendre en compte dans la prise en charge des cancers. Notre équipe a récemment montré que les récepteurs des xénobiotiques PXR (NR1I2) (Raynal et al, 2010) et CAR (NR1I3) sont exprimés dans des lignées cellulaires et des tissus coliques humains. Leur surexpression dans les lignées coliques LS174T et T84 entraine leur résistance à l'irinotécan et à son métabolite actif le SN38 alors que leur inhibition antagonise cette résistance. Des dosages intra- et extra-cellulaires du SN38 et du SN38-G, ainsi que la quantification des ARNm des l'UGT1As et du transporteur MDR1, montrent que CAR et PXR augmentent le métabolisme détoxifiant et l'efflux du SN38. L'impact de la surexpression de ces xénosenseurs sur la viabilité des cellules LS174T à différentes classes de cytotoxiques (anti-métabolites, intercalants, inhibiteurs de topoisomérases, poisons du fuseau) a ensuite été évaluée. Nous avons observé que l'expression de CAR ou PXR conduit à une forte chimiorésistance au paclitaxel, au docétaxel et au 4-hydroxy-cyclophosphamide alors que PXR entraîne une sensibilisation marquée au cisplatine et au carboplatine en augmentant la quantité d'adduits de platine sur l'ADN. Les études du transcriptome de nos modèles cellulaires nous ont permis d'identifier les gènes cibles impliqués dans ces variations de cytotoxicité. Des études de confirmation par modulation pharmacologique ou ARNs interférents de ces gènes cibles sont en cours et nous permettront de préciser les mécanismes mis en jeu dans les variations de chimiosensibilité. Ces travaux devraient permettent de mieux appréhender le rôle des xénosenseurs CAR et PXR sur le métabolisme intra-tumoral des cytotoxiques et potentiellement sur la réponse à des chimiothérapies variées.

Colorectal cancer is characterized by high mortality in advanced stages due to the high rate of tumor recurrence after chemotherapy. The prediction of the efficacy and toxicity of cytotoxic drugs represents a major challenge in the coming years. Because the majority of cancer drugs are supported by the enzymes and transporters whose expression is controlled by the level of expression and activation of the xenosensors CAR (NR1I3) and PXR (NR1I2), it is likely that they may represent predictive factors in the management of cancer. Our team has recently shown that xenobiotic receptors PXR (Raynal et al, 2010) and CAR are expressed in cell lines and human colon tissues. Their overexpression in colon cancer cell lines LS174T and T84 leads to resistance to…

Advisors/Committee Members: Pascussi, Jean-Marc (thesis director), Evrard, Alexandre (thesis director).

Subjects/Keywords: Xénorécepteurs; Métabolisme intratumoral; Cancer colorectal; Chimiosensibilité; Constitutive Androstane Receptor; Pregnane X Receptor; Xenoreceptors; Intratumoral metabolism; Colorectal cancer; Chemosensibility; Constitutive Androstane Receptor; Pregnane X Receptor

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Leguelinel, G. (2011). Rôle des récepteurs des xénobiotiques CAR (Constitutive Androstane Receptor, NR1I3) et PXR (Pregnane X receptor, NR1I2) dans le métabolisme des chimiothérapies conventionnelles du cancer colorectal : Role of xenoreceptors CAR (Constitutive Androstane Receptor, NR1I3) and PXR (Pregnane X Receptor, NR1I2) in the metabolism of conventionnal chemotherapy in colorectal cancer. (Doctoral Dissertation). Université Montpellier I. Retrieved from http://www.theses.fr/2011MON13512

Chicago Manual of Style (16^th Edition):

Leguelinel, Géraldine. “Rôle des récepteurs des xénobiotiques CAR (Constitutive Androstane Receptor, NR1I3) et PXR (Pregnane X receptor, NR1I2) dans le métabolisme des chimiothérapies conventionnelles du cancer colorectal : Role of xenoreceptors CAR (Constitutive Androstane Receptor, NR1I3) and PXR (Pregnane X Receptor, NR1I2) in the metabolism of conventionnal chemotherapy in colorectal cancer.” 2011. Doctoral Dissertation, Université Montpellier I. Accessed January 23, 2021. http://www.theses.fr/2011MON13512.

MLA Handbook (7^th Edition):

Leguelinel, Géraldine. “Rôle des récepteurs des xénobiotiques CAR (Constitutive Androstane Receptor, NR1I3) et PXR (Pregnane X receptor, NR1I2) dans le métabolisme des chimiothérapies conventionnelles du cancer colorectal : Role of xenoreceptors CAR (Constitutive Androstane Receptor, NR1I3) and PXR (Pregnane X Receptor, NR1I2) in the metabolism of conventionnal chemotherapy in colorectal cancer.” 2011. Web. 23 Jan 2021.

Vancouver:

Leguelinel G. Rôle des récepteurs des xénobiotiques CAR (Constitutive Androstane Receptor, NR1I3) et PXR (Pregnane X receptor, NR1I2) dans le métabolisme des chimiothérapies conventionnelles du cancer colorectal : Role of xenoreceptors CAR (Constitutive Androstane Receptor, NR1I3) and PXR (Pregnane X Receptor, NR1I2) in the metabolism of conventionnal chemotherapy in colorectal cancer. [Internet] [Doctoral dissertation]. Université Montpellier I; 2011. [cited 2021 Jan 23]. Available from: http://www.theses.fr/2011MON13512.

Council of Science Editors:

Leguelinel G. Rôle des récepteurs des xénobiotiques CAR (Constitutive Androstane Receptor, NR1I3) et PXR (Pregnane X receptor, NR1I2) dans le métabolisme des chimiothérapies conventionnelles du cancer colorectal : Role of xenoreceptors CAR (Constitutive Androstane Receptor, NR1I3) and PXR (Pregnane X Receptor, NR1I2) in the metabolism of conventionnal chemotherapy in colorectal cancer. [Doctoral Dissertation]. Université Montpellier I; 2011. Available from: http://www.theses.fr/2011MON13512

7. Iannelli, Antonio. Lésions hépatiques induites par l'ischémie reperfusion et la NAFLD : mécanismes et protection : Liver injuries due to ischemia reperfusion and NAFLD : mechanisms and protection.

Degree: Docteur es, Sciences de l'environnement terrestre, 2010, Aix-Marseille 2

URL: http://www.theses.fr/2010AIX20659

► Le pregnane X receptor (PXR) est un récepteur nucléaire associé à la réponse au stresscellulaire. Des travaux in vitro de notre groupe ont démontré que… (more)

▼ Le pregnane X receptor (PXR) est un récepteur nucléaire associé à la réponse au stresscellulaire. Des travaux in vitro de notre groupe ont démontré que les activateurs de cerécepteur (spironolactone (SPIR), clotrimazole (CTZ)) inhibent significativement l’apoptosespontanée ou induite, dans des primo-cultures d’hépatocytes de rat ou d’origine humaine.Les données in vitro sont en faveur d’un rôle clé du PXR dans la protection hépatique contreles xénobiotiques et endobiotiques en régulant de façon concertée leur détoxication(transport, métabolisme) et en augmentant leur résistance à l’apoptose. D’autres travauxrécents ont démontré le rôle majeur de ce récepteur dans la régulation de l’homéostasielipidique et glucidique, d’une part en favorisant la lipogenèse, d’autre part inhibant la lipolyseet la néoglucogenèse. L’induction du PXR peut être responsable de l’accumulation de lipidesdans le foie (NAFLD non alcoholic fatty liver disease). La NAFLD est fortement associée àl’obésité. La chirurgie bariatrique est à ce jour le seul traitement efficace à long terme pourl’obésité morbide. L’évolution des lésions hépatiques de la NAFLD après chirurgiebariatrique n’est pas complètement élucidée. L’objectif de ce travail de thèse, a été d’analyser si, in vivo, les agonistes du PXR tels que le CTZ et la SPIR, présentaient chez l’animal les mêmes effets que ceux décrits in vitro, et s’ilspouvaient conduire à une protection similaire du foie, lors d’atteintes pathologiques commeles lésions hépatiques induites par l’ischémie reperfusion. Dans un autre chapitre les effetsde deux procédures bariatriques, le court circuit gastrique (gastric bypass- GBP) et lagastrectomie en gouttière (sleeve gastrectomy- SG), sur le comorbiditées liées à la obésitéont été analysés. Le modèle d’ischémie reperfusion normothermique partielle et totale du foie chez le rongeur(rat et souris) a été utilisé pour étudier le rôle protecteur du PXR contre les lésionsapoptotiques. Les effets du court circuit gastrique sur les comorbiditées associées à l’obésitéont été étudiés dans deux groupes de patients obèses (index de masse corporelle > 50Kg/m2 et < 50 Kg/m2). Les résultats du GBP et de la SG ont été étudiés dans deux groupescomparables de sujets super obèses (IMC > 50 Kg/m2).Résultats 1/ Le traitement par les activateurs du PXR (CTZ et SPIR), chez le rat et chezla souris, provoque l’induction d’expression du CYP 3A1, enzyme sous le contrôle du PXR. Ilest associé à une réduction significative du nombre d’hépatocytes apoptotiques, du niveaudes transaminases, de la caspases activée et de son substrat PARP (poly-ADP-ribosepolymérase).Les mécanismes impliqués comprennent l’induction d’expression de la protéineantiapoptotique Bcl-xL, l’activation de la voie MAP kinase ERK ½, l’inhibition de l’activationde JNK et la sous-expression des heat schock proteins 27, 70, et 90, dans le cas del’ischémie complète du foie. 2/ Un an après l’intervention bariatique, le GBP a montré uneefficacité comparable sur la réversibilité du syndrome métabolique, de l’inflammationsystémique… Advisors/Committee Members: Rahmani, Roger (thesis director), Sousa, Georges de (thesis director).

Subjects/Keywords: Pregnane X receptor; Ischémie reperfusion; Foie; Bcl-xL; Stéatose; Stéatohépatite; Obésité; Syndrome métabolique; Bariatrique; Pregnane X receptor; Ischemia reperfusion; Liver; Bcl-xL; Steatosis; Steatohepatitis; Obesity; Metabolic syndrome; Bariatric

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Iannelli, A. (2010). Lésions hépatiques induites par l'ischémie reperfusion et la NAFLD : mécanismes et protection : Liver injuries due to ischemia reperfusion and NAFLD : mechanisms and protection. (Doctoral Dissertation). Aix-Marseille 2. Retrieved from http://www.theses.fr/2010AIX20659

Chicago Manual of Style (16^th Edition):

Iannelli, Antonio. “Lésions hépatiques induites par l'ischémie reperfusion et la NAFLD : mécanismes et protection : Liver injuries due to ischemia reperfusion and NAFLD : mechanisms and protection.” 2010. Doctoral Dissertation, Aix-Marseille 2. Accessed January 23, 2021. http://www.theses.fr/2010AIX20659.

MLA Handbook (7^th Edition):

Iannelli, Antonio. “Lésions hépatiques induites par l'ischémie reperfusion et la NAFLD : mécanismes et protection : Liver injuries due to ischemia reperfusion and NAFLD : mechanisms and protection.” 2010. Web. 23 Jan 2021.

Vancouver:

Iannelli A. Lésions hépatiques induites par l'ischémie reperfusion et la NAFLD : mécanismes et protection : Liver injuries due to ischemia reperfusion and NAFLD : mechanisms and protection. [Internet] [Doctoral dissertation]. Aix-Marseille 2; 2010. [cited 2021 Jan 23]. Available from: http://www.theses.fr/2010AIX20659.

Council of Science Editors:

Iannelli A. Lésions hépatiques induites par l'ischémie reperfusion et la NAFLD : mécanismes et protection : Liver injuries due to ischemia reperfusion and NAFLD : mechanisms and protection. [Doctoral Dissertation]. Aix-Marseille 2; 2010. Available from: http://www.theses.fr/2010AIX20659

Texas A&M University

8. Gu, Xinsheng. Regulation of cytochrome P450 3A4 gene expression through modulating pregnane X receptor transcriptional activity by NF-ꢬ aryl hydrocarbon receptor and xenobiotics.

Degree: PhD, Toxicology, 2009, Texas A&M University

URL: http://hdl.handle.net/1969.1/ETD-TAMU-1630

► Cytochrome P450 3A4 (CYP3A4) is a key enzyme responsible for the metabolism of drugs and endogenous compounds in human liver and intestine. CYP3A4 gene expression… (more)

▼ Cytochrome P450 3A4 (CYP3A4) is a key enzyme responsible for the metabolism of drugs and endogenous compounds in human liver and intestine. CYP3A4 gene expression is mainly regulated by Pregnane X receptor (PXR) which is a ligand-dependent nuclear receptor. It is a long-standing observation that inflammatory responses and infections decrease drug metabolism capacity in human and experimental animals. In this study, I reported that NF-κB activation by LPS and TNF-α plays a pivotal role in the suppression of CYP3A4 through interactions of NF-κB with PXR/RXR complex. Inhibition of NF-κB by NF-κB specific suppressor SRIκBα reversed the suppressive effects of LPS and TNF-α. Furthermore, I showed that NF-κB p65 disrupted the association of PXR/RXRα complex with DNA sequences as determined by EMSA and chromatin immunoprecipitation assays. NF-κB p65 directly interacted with DNA binding domain of RXRα and DNA binding domain, hinge domain and ligand-binding domain of PXR and may prevent its binding to the consensus DNA sequences, thus inhibiting the transactivation by PXR/RXRα complex. This mechanism of suppression by NF-κB activation may be extended to other nuclear receptor-regulated systems where RXRα is a dimerization partner. Many genes regulated by PXR and AhR are important for phase I, II and III drug metabolism. In this study I reported a crosstalk between PXR and AhR pathways. AhR physically and functionally interacted with PXR and enhanced the PXR transcriptional activity, and the interaction repressed the AhR transcriptional activity. AhR also physically interacted with RXRα. The synergistic induction of Gsta1 in the liver of mice by PCN and TCDD might assume a different mechanism. The results suggested the metabolism kinetics of mixture drugs was different from and more complicated than that of single compound. Using a HepG2 cell-based PXR-driven CYP3A4-Luciferase assay, I reported that E/F domain of PXR was responsible for ligand-dependant activation. A/B domain was necessary for co-activating the ligand-dependent activation and D domain was suppressive. High doses of Valerian Root extraction were PXR-dependent CYP3A4 inducers. Green tea polyphenols, aflatoxin B1, CuSO4 and MnCl2 enhanced the PXR transcription activity activated by rifampicin. The results suggested PXR-mediated drug metabolism kinetics altered on xenobiotic exposure. Advisors/Committee Members: Tian, Yanan (advisor), Donnelly, Kirby C. (committee member), Porter, Weston W. (committee member), Safe, Stephen H. (committee member).

Subjects/Keywords: cytochrome P450 3A4; Pregnane X Receptor

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Gu, X. (2009). Regulation of cytochrome P450 3A4 gene expression through modulating pregnane X receptor transcriptional activity by NF-ꢬ aryl hydrocarbon receptor and xenobiotics. (Doctoral Dissertation). Texas A&M University. Retrieved from http://hdl.handle.net/1969.1/ETD-TAMU-1630

Chicago Manual of Style (16^th Edition):

Gu, Xinsheng. “Regulation of cytochrome P450 3A4 gene expression through modulating pregnane X receptor transcriptional activity by NF-ꢬ aryl hydrocarbon receptor and xenobiotics.” 2009. Doctoral Dissertation, Texas A&M University. Accessed January 23, 2021. http://hdl.handle.net/1969.1/ETD-TAMU-1630.

MLA Handbook (7^th Edition):

Gu, Xinsheng. “Regulation of cytochrome P450 3A4 gene expression through modulating pregnane X receptor transcriptional activity by NF-ꢬ aryl hydrocarbon receptor and xenobiotics.” 2009. Web. 23 Jan 2021.

Vancouver:

Gu X. Regulation of cytochrome P450 3A4 gene expression through modulating pregnane X receptor transcriptional activity by NF-ꢬ aryl hydrocarbon receptor and xenobiotics. [Internet] [Doctoral dissertation]. Texas A&M University; 2009. [cited 2021 Jan 23]. Available from: http://hdl.handle.net/1969.1/ETD-TAMU-1630.

Council of Science Editors:

Gu X. Regulation of cytochrome P450 3A4 gene expression through modulating pregnane X receptor transcriptional activity by NF-ꢬ aryl hydrocarbon receptor and xenobiotics. [Doctoral Dissertation]. Texas A&M University; 2009. Available from: http://hdl.handle.net/1969.1/ETD-TAMU-1630

University of British Columbia

9. Yeung, Eugene Y. H. Activation of pregnane X receptor by Ginkgo biloba extract.

Degree: MS- MSc, Pharmaceutical Sciences, 2008, University of British Columbia

URL: http://hdl.handle.net/2429/2688

► Pregnane X receptor (PXR) is a ligand-activated transcription factor that plays a role in a broad array of biological processes, including drug metabolism and transport.… (more)

▼ Pregnane X receptor (PXR) is a ligand-activated transcription factor that plays a role in a broad array of biological processes, including drug metabolism and transport. Ginkgo biloba is an herb commonly used to improve cognitive function. In primary cultures of rat hepatocytes, Ginkgo biloba induces the mRNA expression of CYP3A23, a target gene for rat PXR. The present study tested the hypothesis that Ginkgo biloba activates PXR. Cultured HepG2 human hepatoma cells were transfected with the full-length human PXR (pCR3-hPXR), the full-length mouse PXR (pCR3-mPXR), or an empty vector (pCR3) in addition to a reporter plasmid (XREM-CYP3A4-LUC; firefly luciferase) and an internal control plasmid (phRL-TK; Renilla luciferase). At 24 h after transfection, cells were treated for 24 h with Ginkgo biloba extract and luciferase activity was measured. The extract at 200 µg/ml increased mouse and human PXR activity by 3.0-fold and 9.5-fold, respectively, indicating that Ginkgo biloba more effectively activates human PXR. Dose-response experiments showed that the extract produced a log-linear increase over the range of 200–800 µg/ml. To determine whether Ginkgo biloba extract induces human PXR target gene expression, cultured LS180 human colon adenocarcinoma cells were treated for 72 h with the extract. Total cellular RNA was isolated and reverse transcribed. CYP3A4, CYP3A5, and ABCB1 cDNAs were amplified by real-time PCR. Ginkgo biloba extract at 200, 400, and 800 µg/ml increased CYP3A4 mRNA expression by 1.7-, 2.4-, and 2.5-fold, respectively. The extract at the same concentrations increased the mRNA expression of CYP3A5 (1.3 to 3.6-fold) and ABCB1 (2.7 to 6.4-fold). To determine whether the increased expression involved PXR activation, cells were treated with a PXR antagonist, L-sulforaphane, and Ginkgo biloba extract. L-sulforaphane at 5, 10, and 20 µM decreased CYP3A4 mRNA expression by 54%, 78%, and 93%, respectively, in cells co-treated with the extract. A similar pattern of response was obtained with CYP3A5 and ABCB1. In cells co-treated with the extract, L-sulforaphane (5 and 10 µM) was not cytotoxic and did not decrease PXR mRNA expression. Our data from cell culture experiments indicate that Ginkgo biloba activates PXR and increases CYP3A4, CYP3A5, and ABCB1 mRNA expression.

Subjects/Keywords: Pregnane X receptor; Ginkgo biloba extract

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Yeung, E. Y. H. (2008). Activation of pregnane X receptor by Ginkgo biloba extract. (Masters Thesis). University of British Columbia. Retrieved from http://hdl.handle.net/2429/2688

Chicago Manual of Style (16^th Edition):

Yeung, Eugene Y H. “Activation of pregnane X receptor by Ginkgo biloba extract.” 2008. Masters Thesis, University of British Columbia. Accessed January 23, 2021. http://hdl.handle.net/2429/2688.

MLA Handbook (7^th Edition):

Yeung, Eugene Y H. “Activation of pregnane X receptor by Ginkgo biloba extract.” 2008. Web. 23 Jan 2021.

Vancouver:

Yeung EYH. Activation of pregnane X receptor by Ginkgo biloba extract. [Internet] [Masters thesis]. University of British Columbia; 2008. [cited 2021 Jan 23]. Available from: http://hdl.handle.net/2429/2688.

Council of Science Editors:

Yeung EYH. Activation of pregnane X receptor by Ginkgo biloba extract. [Masters Thesis]. University of British Columbia; 2008. Available from: http://hdl.handle.net/2429/2688

10. Roques, Beatrice. Bases mécanistiques des effets d'un insecticide agrovétérinaire, le fiproni, et/ou de ses métabolites sur la fonction thyroïdienne chez le rat : Mechanistic basis of the effects of an agroveterinary insecticide, the fipronil, and/or its metabolites on the thyroid function in rat.

Degree: Docteur es, Pathologie, Toxicologie, Génétique et Nutrition, 2012, Toulouse, INSA

URL: http://www.theses.fr/2012ISAT0029

►

Le fipronil, insecticide largement utilisé, est un perturbateur thyroïdien chez le rat modulant le catabolisme hépatique des hormones thyroïdiennes. Ses effets chez le mouton, considéré… (more)

▼

Le fipronil, insecticide largement utilisé, est un perturbateur thyroïdien chez le rat modulant le catabolisme hépatique des hormones thyroïdiennes. Ses effets chez le mouton, considéré comme un modèle plus pertinent que le rat pour étudier une régulation de la fonction thyroïdienne chez l'Homme, sont plus limités. Le but de cette thèse était de caractériser au niveau hépatique le mode d'action du fipronil sur la fonction thyroïdienne en s'intéressant 1) au rôle potentiel du principal métabolite du fipronil formé in vivo, le fipronil sulfone, et 2) aux différences interspécifiques de métabolisme du fipronil et/ou de sensibilité à la perturbation thyroïdienne qui peuvent préjuger de la pertinence des différents modèles animaux pour l'analyse du risque du fipronil pour la santé humaine. L'efficacité du fipronil sulfone à induire l'expression et/ou l'activité d'enzymes responsables du métabolisme hépatique des hormones thyroïdiennes ou du fipronil était la même que celle du fipronil autant in vivo chez le rat que in vitro sur hépatocytes. L'utilisation d'un modèle de souris déficientes pour des récepteurs nucléaires xénosenseurs suggérait fortement une implication des récepteurs nucléaires Constitutive Androstane Receptor et/ou Pregnane X Receptor dans la perturbation thyroïdienne induite par le fipronil

The widely used insecticide fipronil is a thyroid disruptor in rat acting on thyroid hormone hepatic metabolism. In sheep, a more relevant species for the human thyroid regulation, fipronil-induced thyroid-disruption is much more limited. The goal of this thesis was to characterize the mode of action of fipronil on thyroid function at the hepatic level focusing on 1) the potential role of fipronil sulfone, the main fipronil metabolite formed in vivo, and on 2) interspecific differences in terms of fipronil metabolism and/or sensitivity to thyroid disruption that can prejudge of the relevance of the different animal models for the risk assessment of fipronil for human health. Fipronil sulfone was as efficient as fipronil to induce the expression and/or activity of enzymes involved in thyroid hormone or fipronil hepatic metabolism both in vivo in rat and in vitro on hepatocytes. The use of knock-out mice for xenosensors nuclear receptors strongly suggested an implication of the nuclear receptor Constitutive Androstane Receptor and/or Pregnane X Receptor on fipronil-induced thyroid disruption

Advisors/Committee Members: Viguié, Catherine (thesis director), Martin, Pascal Guy Pierre (thesis director).

Subjects/Keywords: Perturbateur endocrinien; Fipronil; Fipronil sulfone; Fonction thyroïdienne; Métabolisme hépatique; Rat; Souris transgéniques; Hépatocytes; Constitutive Androstane Receptor; Pregnane X Receptor; Endocrine disruptor; Fipronil; Fipronil sulfone; Thyroid function; Hepatic metabolism; Rat; Transgenic mice; Hepatocytes; Constitutive Androstane Receptor; Pregnane X Receptor; 613

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Roques, B. (2012). Bases mécanistiques des effets d'un insecticide agrovétérinaire, le fiproni, et/ou de ses métabolites sur la fonction thyroïdienne chez le rat : Mechanistic basis of the effects of an agroveterinary insecticide, the fipronil, and/or its metabolites on the thyroid function in rat. (Doctoral Dissertation). Toulouse, INSA. Retrieved from http://www.theses.fr/2012ISAT0029

Chicago Manual of Style (16^th Edition):

Roques, Beatrice. “Bases mécanistiques des effets d'un insecticide agrovétérinaire, le fiproni, et/ou de ses métabolites sur la fonction thyroïdienne chez le rat : Mechanistic basis of the effects of an agroveterinary insecticide, the fipronil, and/or its metabolites on the thyroid function in rat.” 2012. Doctoral Dissertation, Toulouse, INSA. Accessed January 23, 2021. http://www.theses.fr/2012ISAT0029.

MLA Handbook (7^th Edition):

Roques, Beatrice. “Bases mécanistiques des effets d'un insecticide agrovétérinaire, le fiproni, et/ou de ses métabolites sur la fonction thyroïdienne chez le rat : Mechanistic basis of the effects of an agroveterinary insecticide, the fipronil, and/or its metabolites on the thyroid function in rat.” 2012. Web. 23 Jan 2021.

Vancouver:

Roques B. Bases mécanistiques des effets d'un insecticide agrovétérinaire, le fiproni, et/ou de ses métabolites sur la fonction thyroïdienne chez le rat : Mechanistic basis of the effects of an agroveterinary insecticide, the fipronil, and/or its metabolites on the thyroid function in rat. [Internet] [Doctoral dissertation]. Toulouse, INSA; 2012. [cited 2021 Jan 23]. Available from: http://www.theses.fr/2012ISAT0029.

Council of Science Editors:

Roques B. Bases mécanistiques des effets d'un insecticide agrovétérinaire, le fiproni, et/ou de ses métabolites sur la fonction thyroïdienne chez le rat : Mechanistic basis of the effects of an agroveterinary insecticide, the fipronil, and/or its metabolites on the thyroid function in rat. [Doctoral Dissertation]. Toulouse, INSA; 2012. Available from: http://www.theses.fr/2012ISAT0029

University of Western Ontario

11. Woolsey, Sarah J. Cytochrome P450 3A4 Expression and Regulation in Non-Alcoholic Fatty Liver Disease.

Degree: 2015, University of Western Ontario

URL: https://ir.lib.uwo.ca/etd/3355

► Non-alcoholic fatty liver disease (NAFLD) is defined as lipid accumulation within hepatocytes (steatosis) in the absence of excess alcohol consumption. It is the most common… (more)

▼ Non-alcoholic fatty liver disease (NAFLD) is defined as lipid accumulation within hepatocytes (steatosis) in the absence of excess alcohol consumption. It is the most common liver disease in the western world, affecting one third of the general adult population with particularly high prevalence in obesity and type 2 diabetes. NAFLD is a disease continuum originating with simple hepatic steatosis that can progress to non-alcoholic steatohepatitis (NASH) with fibrosis and potentially cirrhosis, which places patients at risk for hepatocellular carcinoma. Unfortunately, there are not yet specific pharmacologic agents to treat NAFLD and so its management involves treatment of comorbidities, but there are significant efforts to develop new drugs to reverse disease course and prevent progression. While the liver is the major organ of drug elimination, little is known regarding the effect of NAFLD on hepatic drug metabolism in humans. The most important drug metabolizing enzyme is cytochrome P450 (CYP) 3A4, which metabolizes medications widely prescribed in NAFLD patients including those to treat hypertension, type 2 diabetes and dyslipidemia. We tested the hypothesis that CYP3A4 expression and activity are altered in NAFLD. In the first study, we evaluated the use of predictive endogenous plasma biomarkers of drug metabolic function against the gold-standard midazolam pharmacokinetic phenotyping approach for the assessment of constitutive CYP3A activity in healthy subjects. There was a lack of association between levels of the CYP3A derived metabolites 4β-hydroxycholesterol and 6β-hydroxycortisol with midazolam pharmacokinetics indicating that these biomarkers have limited utility within the context of relatively narrow enzyme activity variability in healthy individuals. CYP3A activity was next examined in patients with biopsy-proven NAFLD in comparison to healthy control subjects using midazolam pharmacokinetic phenotyping and biomarker approaches. We demonstrated, for the first time, that in vivo CYP3A activity is reduced in patients with simple steatosis or NASH and that fibrosis was also associated with lower enzyme function. Likewise, experimental NAFLD in mice and cultured hepatoma cells was associated with lower CYP3A4 expression. In the third study, mouse and cell models of NAFLD were used to define a novel regulatory pathway involved in the observed reduction of CYP3A4 expression and activity. We found that NAFLD causes hepatic upregulation of the metabolic hormone, fibroblast growth factor 21 (FGF21), stimulating a canonical cellular phospho-signaling pathway. FGF21 acted on the liver to decrease the nuclear localization and activity of the pregnane X receptor, a key transcriptional regulator of CYP3A4 gene expression. These findings provide novel insights to altered drug metabolism in NAFLD and a mechanistic basis for studies aimed to optimize pharmacotherapy and drug development for this common liver disease.

Subjects/Keywords: Non-alcoholic fatty liver disease; Cytochrome P450 3A4; Drug metabolism; Gene regulation; Fibroblast growth factor 21; Pregnane x receptor; Diseases; Pharmacology

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Woolsey, S. J. (2015). Cytochrome P450 3A4 Expression and Regulation in Non-Alcoholic Fatty Liver Disease. (Thesis). University of Western Ontario. Retrieved from https://ir.lib.uwo.ca/etd/3355

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Woolsey, Sarah J. “Cytochrome P450 3A4 Expression and Regulation in Non-Alcoholic Fatty Liver Disease.” 2015. Thesis, University of Western Ontario. Accessed January 23, 2021. https://ir.lib.uwo.ca/etd/3355.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Woolsey, Sarah J. “Cytochrome P450 3A4 Expression and Regulation in Non-Alcoholic Fatty Liver Disease.” 2015. Web. 23 Jan 2021.

Vancouver:

Woolsey SJ. Cytochrome P450 3A4 Expression and Regulation in Non-Alcoholic Fatty Liver Disease. [Internet] [Thesis]. University of Western Ontario; 2015. [cited 2021 Jan 23]. Available from: https://ir.lib.uwo.ca/etd/3355.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Woolsey SJ. Cytochrome P450 3A4 Expression and Regulation in Non-Alcoholic Fatty Liver Disease. [Thesis]. University of Western Ontario; 2015. Available from: https://ir.lib.uwo.ca/etd/3355

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Western Ontario

12. Wilson, Aze. Drug Response And Metabolism In Crohn's Disease.

Degree: 2018, University of Western Ontario

URL: https://ir.lib.uwo.ca/etd/5557

► Inflammatory bowel disease (IBD) is an illness of chronic intestinal inflammation comprised of Crohn's disease (CD) and ulcerative colitis (UC). Specialists rely heavily on drugs… (more)

▼ Inflammatory bowel disease (IBD) is an illness of chronic intestinal inflammation comprised of Crohn's disease (CD) and ulcerative colitis (UC). Specialists rely heavily on drugs that target a dysregulated immune system. There is a staggering degree of variation in drug response in CD. Our understanding of drug metabolism and response in IBD is limited. Gaining new insights into IBD-specific modifications of drug metabolism may allow for improved drug efficacy and reduced toxicity. Cytochrome P450 (CYP) 3A4 is the most relevant determinant of drug metabolism and exposure for medications prescribed today. CYP3A4 is highly expressed in the liver, but is also important to intestinal drug metabolism. Little is known about CYP3A4 activity in disease states. We tested the hypothesis that CD affects the activity, expression and regulation of CYP3A4. Acute, non-hepatic inflammatory states are reported to reduce hepatic CYP3A4 activity. Using midazolam pharmacokinetics and the cholesterol metabolite, 4β- hydroxycholesterol as in vivo probes of CYP3A4 activity, we were able to demonstrate and confirm that CYP3A4 activity is lower in CD. Conversely, we were unable to show, using in vitro modeling, that differences in CYP3A4 activity were due to differential nuclear receptor-signaling in CD. CYP3A4 plays a key role in hepatic and intestinal first-pass metabolism, likely in concert with the xenobiotic exporter, P-glycoprotein (P-gp). The intestinal and colonic ii expression of CYP3A4 in CD has not been well characterized. Using an immunobloting technique, we were able to demonstrate that the intestinal and colonic expression of CYP3A4 are reduced in CD. Lastly, nuclear receptors such as FXR and PXR are important regulators of CYP3A4. Both are down-regulated in IBD. This may have important consequences for drug response in IBD. We confirm that a novel single nucleotide polymorphism in FXR results in a reduction in its downstream products in vivo and reveal a link between genetic variation in FXR and outcomes of CD severity, such as risk and time to surgery, particularly relevant to women affected by CD. Ultimately, these studies demonstrate the impact of CD on drug metabolism pathways and offer insight into the overlap between CD pathogenesis and drug metabolism.

Subjects/Keywords: Crohn's disease; drug metabolism; farnesoid X receptor; pregnane X receptor; cytochrome P450 3A4; pharmacokinetics; Digestive System Diseases; Gastroenterology; Medical Pharmacology; Medicine and Health Sciences; Translational Medical Research

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Wilson, A. (2018). Drug Response And Metabolism In Crohn's Disease. (Thesis). University of Western Ontario. Retrieved from https://ir.lib.uwo.ca/etd/5557

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Wilson, Aze. “Drug Response And Metabolism In Crohn's Disease.” 2018. Thesis, University of Western Ontario. Accessed January 23, 2021. https://ir.lib.uwo.ca/etd/5557.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Wilson, Aze. “Drug Response And Metabolism In Crohn's Disease.” 2018. Web. 23 Jan 2021.

Vancouver:

Wilson A. Drug Response And Metabolism In Crohn's Disease. [Internet] [Thesis]. University of Western Ontario; 2018. [cited 2021 Jan 23]. Available from: https://ir.lib.uwo.ca/etd/5557.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Wilson A. Drug Response And Metabolism In Crohn's Disease. [Thesis]. University of Western Ontario; 2018. Available from: https://ir.lib.uwo.ca/etd/5557

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

13. Richter, Ingrid. Molecular evolution and functional characterisation of tunicate xenobiotic receptors.

Degree: 2015, Victoria University of Wellington

URL: http://hdl.handle.net/10063/4652

► Marine microorganisms generate a wide range of ’bioactive’ compounds that can have far-reaching effects on biological and ecological processes. Metazoans have developed specialised biochemical pathways… (more)

▼ Marine microorganisms generate a wide range of ’bioactive’ compounds that can have far-reaching effects on biological and ecological processes. Metazoans have developed specialised biochemical pathways that metabolise and eliminate potentially toxic chemicals (xenobiotics) from their bodies. The vertebrate xenobiotic receptor, pregnane X receptor (PXR), is a ligand-activated nuclear receptor transcription factor regulating expression of multiple detoxification genes. Ligand-binding domains (LBDs) of vertebrate PXR orthologues may have adaptively evolved to bind toxins typically encountered by these organisms. Marine invertebrate filter-feeders are exposed to relatively high concentrations of xenobiotics associated with their diet. Tunicates (phylum: Chordata) are of particular interest as they form the sister clade to the Vertebrata. Genomes of the solitary tunicate Ciona intestinalis and the colonial tunicate Botryllus schlosseri both encode at least two xenobiotic receptors that are orthologues to both the vertebrate vitamin D receptor (VDR) and PXR. Pursuing the idea that tunicate xenobiotic receptors (VDR/PXR) may adaptively evolve to bind toxic chemicals commonly present in an organism’s environment, this thesis aims to identify if: (i) adaptive evolution is acting on putative tunicate VDR/PXR orthologues to enhance binding of dietary xenobiotics; (ii) these receptors are activated by dietary xenobiotics (e.g. microalgal biotoxins) and; (iii) tunicate VDR/PXR LBDs can be used as sensor elements in yeast bioassays for the detection of both natural and synthetic bioactive compounds. To identify genetic variation and to search for evidence of positive selection, next-generation sequencing was performed on three tunicate VDR/PXR orthologues genes. Recombinant yeast (Saccharomyces cerevisiae) cell lines were developed for the functional characterisation of tunicate VDR/PXR LBDs. These tunicate VDR/PXR LBD-based yeast bioassays were utilised to detect known microalgal biotoxins, natural bioactive compounds, and environmental contaminants. Next-generation sequencing revealed both an unusually high genetic diversity and strong purifying selection in VDR/PXR orthologues from C. intestinalis and B. schlosseri. Single-base-deletion allelic variants were found in C. intestinalis VDR/PXR orthologues resulting in predicted proteins having a DNA-binding domain but lacking a LBD. The persistence of these variants may reflect constitutive expression of detoxification genes as a selective advantage in the marine environment. To assess the functional characteristics of tunicate VDR/PXR orthologues, recombinant yeast cell lines were developed that express VDR/PXRα LBDs from C. intestinalis and B. schlosseri. These chimeric proteins mediate liganddependent expression of a lacZ reporter gene which encodes an easily assayed enzyme (β-galactosidase). These yeast bioassays were highly sensitive towards both synthetic and natural toxins (coefficients of variance, CV <25%). Microalgal biotoxins (okadaic acid and portimine) were two… Advisors/Committee Members: McNatty, Ken, Fidler, Andrew.

Subjects/Keywords: Yeast bioassay; PXR; Pregnane X receptor; Molecular evolution

…tunicate orthologues of the pregnane X receptor (PXR): characterisation and natural… …11 Pectenotoxin-11 PXR Pregnane X receptor qPCR Quantitative polymerase chain reaction… …domains (DBDs) and ligand-binding domains (LBDs) from pregnane X receptor… …Appendix Four: 204 Amplification of Ciona intestinalis vitamin D receptor/pregnane X receptor α… …for the expression of Ciona intestinalis vitamin D receptor/pregnane X receptor α (…

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APA (6^th Edition):

Richter, I. (2015). Molecular evolution and functional characterisation of tunicate xenobiotic receptors. (Doctoral Dissertation). Victoria University of Wellington. Retrieved from http://hdl.handle.net/10063/4652

Chicago Manual of Style (16^th Edition):

Richter, Ingrid. “Molecular evolution and functional characterisation of tunicate xenobiotic receptors.” 2015. Doctoral Dissertation, Victoria University of Wellington. Accessed January 23, 2021. http://hdl.handle.net/10063/4652.

MLA Handbook (7^th Edition):

Richter, Ingrid. “Molecular evolution and functional characterisation of tunicate xenobiotic receptors.” 2015. Web. 23 Jan 2021.

Vancouver:

Richter I. Molecular evolution and functional characterisation of tunicate xenobiotic receptors. [Internet] [Doctoral dissertation]. Victoria University of Wellington; 2015. [cited 2021 Jan 23]. Available from: http://hdl.handle.net/10063/4652.

Council of Science Editors:

Richter I. Molecular evolution and functional characterisation of tunicate xenobiotic receptors. [Doctoral Dissertation]. Victoria University of Wellington; 2015. Available from: http://hdl.handle.net/10063/4652

University of Oslo

14. Tapia, German. Regulation of ABCA1 in hepatocytes by the nuclear receptor PXR.

Degree: 2005, University of Oslo

URL: http://urn.nb.no/URN:NBN:no-11209 ; https://www.duo.uio.no/handle/10852/11364 ; Fulltext https://www.duo.uio.no/bitstream/handle/10852/11364/2/Masteroppgave.pdf

► Abstract Nuclear receptors that work as heterodimers with RXR control several aspects of lipid metabolism. One such nuclear receptor, pregnane X receptor (PXR) is the… (more)

Subjects/Keywords: molekylærbiologi ABCA1 kolesterol lever PKR pregnane X-receptor atherosclerosis åreforkalkning; VDP::476

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Tapia, G. (2005). Regulation of ABCA1 in hepatocytes by the nuclear receptor PXR. (Thesis). University of Oslo. Retrieved from http://urn.nb.no/URN:NBN:no-11209 ; https://www.duo.uio.no/handle/10852/11364 ; Fulltext https://www.duo.uio.no/bitstream/handle/10852/11364/2/Masteroppgave.pdf

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Tapia, German. “Regulation of ABCA1 in hepatocytes by the nuclear receptor PXR.” 2005. Thesis, University of Oslo. Accessed January 23, 2021. http://urn.nb.no/URN:NBN:no-11209 ; https://www.duo.uio.no/handle/10852/11364 ; Fulltext https://www.duo.uio.no/bitstream/handle/10852/11364/2/Masteroppgave.pdf.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Tapia, German. “Regulation of ABCA1 in hepatocytes by the nuclear receptor PXR.” 2005. Web. 23 Jan 2021.

Vancouver:

Tapia G. Regulation of ABCA1 in hepatocytes by the nuclear receptor PXR. [Internet] [Thesis]. University of Oslo; 2005. [cited 2021 Jan 23]. Available from: http://urn.nb.no/URN:NBN:no-11209 ; https://www.duo.uio.no/handle/10852/11364 ; Fulltext https://www.duo.uio.no/bitstream/handle/10852/11364/2/Masteroppgave.pdf.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Tapia G. Regulation of ABCA1 in hepatocytes by the nuclear receptor PXR. [Thesis]. University of Oslo; 2005. Available from: http://urn.nb.no/URN:NBN:no-11209 ; https://www.duo.uio.no/handle/10852/11364 ; Fulltext https://www.duo.uio.no/bitstream/handle/10852/11364/2/Masteroppgave.pdf

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

15. Lichti-Kaiser, Kristin Nicole. Regulation of the Pregnane X Receptor Signaling Pathway.

Degree: PhD, Pharmacology & Toxicology, 2009, University of Kansas

URL: http://hdl.handle.net/1808/6188

► Liver-enriched nuclear receptors (NRs) collectively function as metabolic and toxicological `sensors' that mediate liver-specific gene-activation in mammals. NR-mediated gene-environment interaction regulates important steps in the… (more)

▼ Liver-enriched nuclear receptors (NRs) collectively function as metabolic and toxicological `sensors' that mediate liver-specific gene-activation in mammals. NR-mediated gene-environment interaction regulates important steps in the hepatic uptake, metabolism and excretion of glucose, fatty acids, lipoproteins, cholesterol, bile acids, and xenobiotics. While it is well-recognized that ligand-binding is the primary mechanism behind activation of NRs, recent research is revealing that multiple signal transduction pathways modulate NR-function in liver. The interface between specific signal transduction pathways and NRs helps to determine their overall responsiveness to various environmental and physiological stimuli. The pregnane x receptor (PXR, NR1I2) was identified in 1998 as a member of the NR superfamily of ligand-activated transcription factors. PXR is activated by a broad range of lipophilic compounds in a species-specific manner. The primary function ascribed to PXR is the homeostatic control of steroids, bile acids, and xenobiotics. This function is mediated through PXR's ability to coordinately activate gene expression and regulate the subsequent activity of phase I and phase II metabolic enzymes, as well as several membrane transporter proteins. While PXR likely evolved primarily to protect the liver from toxic assault, its activation also represents the molecular basis for an important class of drug-drug, herb-drug, and food-drug interactions. While ligand binding is the primary mode of PXR activation, several signal transduction pathways interface with the PXR protein to determine its overall responsiveness to environmental stimuli. Multiple signaling pathways modulate the activity of PXR, likely through direct alteration of the phosphorylation status of the receptor and its protein cofactors. Therefore, specific combinations of ligand binding and cell signaling pathways affect PXR-mediated gene activation and determine the overall biological response. This dissertation contributes to the molecular understanding of the regulation of PXR by novel agonists, cAMP-dependent protein kinase (PKA) signaling, and phosphorylation. The results presented here were primarily obtained from mouse and tissue culture systems. This dissertation identifies Tian Xian, a traditional Chinese herbal anti-cancer remedy, as a novel PXR activator. This evidence suggests that Tian Xian should be used cautiously by cancer patients taking chemotherapy due to its potential to increase the metabolism of co-administered medications. In addition, data presented here show that activation of PKA signaling modulates PXR activity in a species-specific manner. It is further revealed that PXR exists as phospho-protein in vivo and that the activation of PKA signaling modulates the phospho-threonine status of PXR. Finally, the potential phosphorylation sites within the PXR protein are identified. These phosphorylation sites are characterized, using a phosphomimetic and phospho-deficient site-directed mutagenesis based approach, based on their… Advisors/Committee Members: Staudinger, Jeff L. (advisor), Muma, Nancy (cmtemember), Dobrowsky, Rick T (cmtemember), Timmons, Lisa (cmtemember), Carrasco, Gonzalo A. (cmtemember).

Subjects/Keywords: Health sciences; Pharmacology; Cell signaling; Gene expression; Pregnane x receptor

…Pregnane X Receptor PXR-KO: Pregnane X Receptor Knockout RAR: Retinoic Acid Receptor RIF… …and may affect the function of PPARα as a drug target. 1.2.3 NR1I2, PXR Pregnane x receptor… …LPS: Lipopolysaccharide LRH-1: Liver Receptor Homolog 1 LXR: Liver X Receptor MAPK: Mitogen… …Rifampicin ROS: Reactive Oxygen Species RXR: Retinoid X Receptor ix SCD1: Stearoyl-CoA… …Glucuronosyltransferase VDR: Vitamin D Receptor XREM: Xenobiotic Responsive Enhancer Module x Table of…

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Lichti-Kaiser, K. N. (2009). Regulation of the Pregnane X Receptor Signaling Pathway. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/6188

Chicago Manual of Style (16^th Edition):

Lichti-Kaiser, Kristin Nicole. “Regulation of the Pregnane X Receptor Signaling Pathway.” 2009. Doctoral Dissertation, University of Kansas. Accessed January 23, 2021. http://hdl.handle.net/1808/6188.

MLA Handbook (7^th Edition):

Lichti-Kaiser, Kristin Nicole. “Regulation of the Pregnane X Receptor Signaling Pathway.” 2009. Web. 23 Jan 2021.

Vancouver:

Lichti-Kaiser KN. Regulation of the Pregnane X Receptor Signaling Pathway. [Internet] [Doctoral dissertation]. University of Kansas; 2009. [cited 2021 Jan 23]. Available from: http://hdl.handle.net/1808/6188.

Council of Science Editors:

Lichti-Kaiser KN. Regulation of the Pregnane X Receptor Signaling Pathway. [Doctoral Dissertation]. University of Kansas; 2009. Available from: http://hdl.handle.net/1808/6188

RMIT University

16. Liu, Y. A bioinformatic and cell-based study on the mutation and regulation of human nuclear receptors and their target genes.

Degree: 2010, RMIT University

URL: http://researchbank.rmit.edu.au/view/rmit:160620

► Human nuclear receptor (NR) superfamily represents an important group of regulating factors of a large number of physiologically important target genes. In this project, we… (more)

▼ Human nuclear receptor (NR) superfamily represents an important group of regulating factors of a large number of physiologically important target genes. In this project, we hypothesized that the phenotype of non-synonymous single nucleotide polymorphisms (nsSNPs) of NRs and their target genes could be predicted using computational approaches and that herbal compounds regulated CYP3A4 via pregnane X receptor (PXR) mediated pathway. To test this hypothesis: Firstly, we employed SIFT and PolyPhen to predict the impact of 442 nsSNPs in 48 human NR genes on NR activities and disease susceptibility. Of 442 nsSNPs, 289 (65.38%) were classified as â€œintolerantâ€ by SIFT and 269 (60.86%) were classified as â€œprobably damagingâ€ or â€œpossibly damagingâ€ by PolyPhen respectively. The results from the two algorithms were in concordance. Among the 442 mutations, 229 of them have been functionally characterized. SIFT gave a correct prediction rate of 83.84%, while PolyPhen gave a prediction rate of 76.86%. These results indicate that both SIFT and PolyPhen are useful and efficient tools to predict the functional effects of nsSNPs of human NR genes. Secondly, we predict the phenotypical impact of 1632 nsSNPs from human ABC transporter genes. Using the PolyPhen and SIFT, 41.8-53.6% of nsSNPs in ABC transporter genes were predicted to have an impact on protein function. The prediction accuracy was up to 63-85% when compared with known phenotypical data. Of nsSNPs predicted as deleterious, the prediction scores by SIFT and PolyPhen were significantly related to the number of nsSNPs with known phenotypes confirmed by experimental and human studies. Finally, we investigated the effect of an array of compounds isolated from commonly used Chinese herbal medicines on the activity of PXR in transiently transfected HepG2 and Huh7 cells and on the expression of PXR and CYP3A4 in human intestinal LS174T cells. The study found that praeruptorin A and C, salvianolic acid B, sodium danshensu, and protocatechuic aldehyde, cryptotanshinone, emodin, morin, and tanshinone IIA significantly transactivated the CYP3A4 reporter gene construct in HepG2 cells or Huh7 cells. The PXR mRNA expression in LS174T cells was significantly induced by physcion, protocatechuic aldehyde, salvianolic acid B, and sodium danshensu. However, epifriedelanol, morin, praeruptorin D, mulberroside A, tanshinone I, and tanshinone IIA significantly down-regulated the expression of PXR mRNA in LS174T cells. Furthermore, emodin, physcion, praeruptorin C and E, protocatechuic aldehyde, rhein, salvianolic acid B, and sodium danshensu significantly induced CYP3A4 mRNA expression in human intestinal LS174T cells. These findings suggest that: a) predicting the phenotypic consequence of nsSNPs in human NRs and their target genes ABC transporters using computational algorithms may provide further understanding of genetic differences in susceptibility to diseases and drug response and would be useful hints for further genotype-phenotype studies; and b) herbal…

Subjects/Keywords: Fields of Research; Nuclear Receptor; Pregnane X Receptor (PXR); Cytochrome P450 3A4 (CYP3A4); Single Nucleotide Polymorphism (SNP); non-synonymous SNP; ATP-Binding Cassette (ABC) Transporters; Sorting Intolerant from Tolerant (SIFT); Polymorphism Phenotyping (PolyPhen); Target Gene; Chinese Herbal Medicine; Herb-Drug Interaction

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APA (6^th Edition):

Liu, Y. (2010). A bioinformatic and cell-based study on the mutation and regulation of human nuclear receptors and their target genes. (Thesis). RMIT University. Retrieved from http://researchbank.rmit.edu.au/view/rmit:160620

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Liu, Y. “A bioinformatic and cell-based study on the mutation and regulation of human nuclear receptors and their target genes.” 2010. Thesis, RMIT University. Accessed January 23, 2021. http://researchbank.rmit.edu.au/view/rmit:160620.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Liu, Y. “A bioinformatic and cell-based study on the mutation and regulation of human nuclear receptors and their target genes.” 2010. Web. 23 Jan 2021.

Vancouver:

Liu Y. A bioinformatic and cell-based study on the mutation and regulation of human nuclear receptors and their target genes. [Internet] [Thesis]. RMIT University; 2010. [cited 2021 Jan 23]. Available from: http://researchbank.rmit.edu.au/view/rmit:160620.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Liu Y. A bioinformatic and cell-based study on the mutation and regulation of human nuclear receptors and their target genes. [Thesis]. RMIT University; 2010. Available from: http://researchbank.rmit.edu.au/view/rmit:160620

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

North Carolina State University

17. Jackson, Jonathan Patrick. The Role of the Nuclear Receptors CAR and PXR in the Drug Induced Transcriptional Regulation of the Murine CYP2C Subfamily of Cytochrome P450 Monooxygenases.

Degree: PhD, Toxicology, 2007, North Carolina State University

URL: http://www.lib.ncsu.edu/resolver/1840.16/4828

► The CYP2C subfamily of cytochrome P450 monoxygenases (P450) is responsible for the metabolism of approximately 20% of therapeutic drugs. Recently, phenytoin has been reported to… (more)

▼ The CYP2C subfamily of cytochrome P450 monoxygenases (P450) is responsible for the metabolism of approximately 20% of therapeutic drugs. Recently, phenytoin has been reported to induce the expression of the human genes CYP2B6, CYP3A4, and CYP2C8. Cytochrome P450 expression is often induced by prior exposure to xenobiotics often resulting in drug-drug interactions. Induction of the human CYP2C enzymes by xenobiotics occurs at the transcriptional level and is reported to involve the constitutive androstane receptor (CAR) and/or the pregnane X receptor (PXR). However, the molecular mechanisms regulating drug induction of the murine CYP2C enzymes remain unclear. The mouse is an excellent model system to investigate CYP2C drug induced transcription due to the availability of nuclear receptor knockout mice. Herein, we report the identification of two phenobarbital and phenytoin inducible murine CYP2C genes, Cyp2c29 and Cyp2c37. Quantitative RT-PCR demonstrates that hepatic CYP2C29 and CYP2C37 mRNA is induced by phenobarbital and phenytoin. Additionally, immunoblots indicated that phenytoin induced hepatic CYP2C29 and CYP2C37 protein. We utilized in vivo gene reporter assays of the Cyp2c29 promoter to delineate the phenytoin-response activity to a phenytoin responsive module (PHREM) located -1371 bp upstream of the Cyp2c29 translation start site. Similarly, using in vitro gene reporter assays of the Cyp2c37 promoter, we identified a single functional CAR-RE located -2791 bp upstream of translation start site of Cyp2c37. Mutagenesis studies demonstrated that these sites are essential for CAR transactivation of their respective gene promoters in HepG2 cells. Using quantitative RT-PCR, we demonstrated that induction of CYP2B10 mRNA by phenytoin was completely abolished in CAR-null mice, but only moderately reduced in PXR-null mice. Similarly, phenytoin induction of CYP2C29 and CYP2C37 mRNA was severely reduced in CAR-null mice and only modestly reduced in PXR-null mice. Taken together, these results indicate that the induction of Cyp2b10, Cyp2c29, and Cyp2c37 by phenytoin is predominately regulated by mCAR. However, induction of CYP3A11 mRNA was only partially decreased in either null mice strain. Studies have demonstrated that CYP3A11 mRNA is induced by CAR and PXR agonists, thus our results also indicate that phenytoin acts as an agonist of both CAR and PXR. Advisors/Committee Members: Joyce A Goldstein, Ph.D., Committee Co-Chair (advisor), Randy Rose, Ph.D., Committee Co-Chair (advisor), Masahiko Negishi, Ph.D., Committee Member (advisor), Andrew Wallace, Ph.D., Committee Member (advisor), Ernest Hodgson, Ph.D., Committee Member (advisor).

Subjects/Keywords: Cyp2c37; Cyp2c29; Nuclear Receptors; Pregnane X Receptor; Constitutive Androstane Receptor; Phenytoin; Phenobarbital; Drug Induction

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APA (6^th Edition):

Jackson, J. P. (2007). The Role of the Nuclear Receptors CAR and PXR in the Drug Induced Transcriptional Regulation of the Murine CYP2C Subfamily of Cytochrome P450 Monooxygenases. (Doctoral Dissertation). North Carolina State University. Retrieved from http://www.lib.ncsu.edu/resolver/1840.16/4828

Chicago Manual of Style (16^th Edition):

Jackson, Jonathan Patrick. “The Role of the Nuclear Receptors CAR and PXR in the Drug Induced Transcriptional Regulation of the Murine CYP2C Subfamily of Cytochrome P450 Monooxygenases.” 2007. Doctoral Dissertation, North Carolina State University. Accessed January 23, 2021. http://www.lib.ncsu.edu/resolver/1840.16/4828.

MLA Handbook (7^th Edition):

Jackson, Jonathan Patrick. “The Role of the Nuclear Receptors CAR and PXR in the Drug Induced Transcriptional Regulation of the Murine CYP2C Subfamily of Cytochrome P450 Monooxygenases.” 2007. Web. 23 Jan 2021.

Vancouver:

Jackson JP. The Role of the Nuclear Receptors CAR and PXR in the Drug Induced Transcriptional Regulation of the Murine CYP2C Subfamily of Cytochrome P450 Monooxygenases. [Internet] [Doctoral dissertation]. North Carolina State University; 2007. [cited 2021 Jan 23]. Available from: http://www.lib.ncsu.edu/resolver/1840.16/4828.

Council of Science Editors:

Jackson JP. The Role of the Nuclear Receptors CAR and PXR in the Drug Induced Transcriptional Regulation of the Murine CYP2C Subfamily of Cytochrome P450 Monooxygenases. [Doctoral Dissertation]. North Carolina State University; 2007. Available from: http://www.lib.ncsu.edu/resolver/1840.16/4828

Indian Institute of Science

18. Dighe, Anasuya. Studies on Dynamic Plasticity of Ligand Binding Sites in Proteins.

Degree: PhD, Faculty of Science, 2019, Indian Institute of Science

URL: http://etd.iisc.ac.in/handle/2005/4236

► Molecular recognition between proteins and their associated ligands constitutes ligand-induced protein rewiring thereby enabling the formation of a stable protein-ligand complex. The studies presented in… (more)

▼ Molecular recognition between proteins and their associated ligands constitutes ligand-induced protein rewiring thereby enabling the formation of a stable protein-ligand complex. The studies presented in this thesis address the conformational plasticity inherent to proteins by virtue of which they adapt to diverse ligands and orchestrate complex biological processes like signal transduction, transcription and protein-protein interaction. Adopting network theory based formalisms for understanding protein-ligand associations involve deconstructing the three-dimensional structure of a protein in terms of nodes and edges. With this view, Protein Structure Networks (PSNs) of ligand-bound complexes are studied by considering their side-chain non-covalent interactions. Agonist and antagonist-bound G-Protein Coupled Receptors (GPCRs) are investigated to gain mechanistic insights into allostery and its role in signal transduction. The degree of similarity between PSNs of these complexes is quantified by means of Network Similarity Score (NSS). The physical nature of these networks is inspected by subjecting them to perturbations and major players in maintaining the stability of such networks are identified. Residue-wise groupings (at backbone and side-chain level) are obtained by applying graph spectral methods. All-atom Molecular Dynamics (MD) simulations are carried out to gain a better understanding of protein-ligand binding by analysing conformational ensembles of these complexes. In this scenario, two members from a highly versatile ligand-inducible transcription factor superfamily, i.e., Nuclear Receptors (NR) are studied, that are known to exhibit extremes of ligand binding behavior ranging from promiscuity to specificity. Diverse ligands are known to bind to proteins and the overall nature of their binding site is investigated. In particular, similarities among binding sites of diverse proteins are analysed by using PocketMatch. Percolation of these similarities to regions surrounding the binding site is reported and examples depicting this extended similarity are discussed. Overall, studies presented in this thesis provide a structural perspective into the adaptability of proteins for recognizing diverse ligands and undergoing local or global re-organizations in their framework to regulate complex biological processes. Advisors/Committee Members: Vishveshwara, Saraswathi (advisor), Chandra, Nagasuma (advisor).

Subjects/Keywords: Protein-ligand Interactions; Protein Ligand Interactions; Protein Structure Networks (PSNs); Graph Theory; Protein Side-chain Networks (PScN); Muscarinic Acetylcholine Receptors; Muscarinic Receptor Cmplexes; Protein-Protein Interactions; Pregnane X Receptor; G-Protein Coupled Receptors (GPCRs); Network Similarity Score (NSS); Biochemistry

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Dighe, A. (2019). Studies on Dynamic Plasticity of Ligand Binding Sites in Proteins. (Doctoral Dissertation). Indian Institute of Science. Retrieved from http://etd.iisc.ac.in/handle/2005/4236

Chicago Manual of Style (16^th Edition):

Dighe, Anasuya. “Studies on Dynamic Plasticity of Ligand Binding Sites in Proteins.” 2019. Doctoral Dissertation, Indian Institute of Science. Accessed January 23, 2021. http://etd.iisc.ac.in/handle/2005/4236.

MLA Handbook (7^th Edition):

Dighe, Anasuya. “Studies on Dynamic Plasticity of Ligand Binding Sites in Proteins.” 2019. Web. 23 Jan 2021.

Vancouver:

Dighe A. Studies on Dynamic Plasticity of Ligand Binding Sites in Proteins. [Internet] [Doctoral dissertation]. Indian Institute of Science; 2019. [cited 2021 Jan 23]. Available from: http://etd.iisc.ac.in/handle/2005/4236.

Council of Science Editors:

Dighe A. Studies on Dynamic Plasticity of Ligand Binding Sites in Proteins. [Doctoral Dissertation]. Indian Institute of Science; 2019. Available from: http://etd.iisc.ac.in/handle/2005/4236

University of Kansas

19. Pacyniak, Erik Kristofer. Molecular Mechanism of Polybrominated Diphenyl Ether Disposition in the Liver.

Degree: PhD, Pharmacology, Toxicology & Therapeutics, 2010, University of Kansas

URL: http://hdl.handle.net/1808/7717

► Polybrominated diphenyl ethers (PBDEs) were introduced in the late 1970's as additive flame retardants incorporated into textiles, electronics, plastics and furniture. Although 2,2',3,3',4,4',5,5',6,6'-decabromodiphenyl ether (BDE209)… (more)

▼ Polybrominated diphenyl ethers (PBDEs) were introduced in the late 1970's as additive flame retardants incorporated into textiles, electronics, plastics and furniture. Although 2,2',3,3',4,4',5,5',6,6'-decabromodiphenyl ether (BDE209) is the only congener currently on the market, 2,2`,4,4`-tetrabromodiphenyl ether (BDE47), 2,2`,4,4`,5-pentabromodiphenyl ether (BDE99), and 2,2`,4,4`,5,5`-hexabromodiphenyl ether (BDE153) are the predominant congeners detected in human and wildlife samples. Upon exposure, PBDEs enter the liver where they are biotransformed to potentially toxic metabolites. Although the human liver burden of PBDEs is not clear, the presence of PBDEs in human liver is particularly alarming because it has been demonstrated in rodents that hydroxylated metabolites may play a pivotal role in PBDE-mediated toxicity. The mechanism by which PBDEs enter the liver was not known. However, due to their large molecular weights (MWs ~485 to 1000 Da), they were not likely to enter hepatocytes by simple diffusion. Organic anion transporting polypeptides (OATPs: human; Oatps: rodents) are responsible for hepatic uptake of a variety of amphipathic compounds of MWs larger than 350 Da. Therefore, I tested the hypothesis that OATPs/Oatps expressed in human and mouse hepatocytes are responsible for the uptake of PBDE congeners 47, 99, and 153 by using Chinese hamster ovary (CHO) cell lines expressing OATP1B1, OATP1B3, or OATP2B1 and Human Embryonic Kidney 293 (HEK293) cells transiently expressing Oatp1a1, Oatp1a4, Oatp1b2, or Oatp2b1. Direct uptake studies illustrated that PBDE congeners are substrates of human and mouse hepatic OATPs/Oatps, except for Oatp1a1. Detailed kinetic analysis revealed that OATP1B1, OATP1B3, Oatp1a4, and Oatp1b2 transport BDE47 with the highest affinity followed by BDE99 and BDE153. However, both OATP2B1 and Oatp2b1 transported all three congeners with similar affinities. The importance of hepatic Oatps for the accumulation of BDE47 in liver was confirmed using Oatp1a4- and Oatp1b2-null mice. These results clearly suggest that uptake of PBDEs via these OATPs/Oatps are responsible for liver-specific accumulation of PBDEs. In mouse liver, PBDEs induce drug metabolizing enzymes, namely cytochrome P450s (Cyps). However, the molecular mechanisms underlying this induction was unknown. Cyp2b10 and 3a11 are target genes of the xenobiotic nuclear receptors, the constitutive androstane receptor (CAR) and pregnane X receptor (PXR), both of which are responsible for mediating induction of Cyp2b10 and Cyp3a11, respectively. I hypothesized that PBDE congeners are CAR and/or PXR activators. Using reporter-gene luciferase assays I showed that BDE47, BDE99 and BDE209 activate human and mouse CAR and PXR in a concentration-dependent manner. Furthermore, induction of Cyp2b10 and Cyp3a11 was markedly suppressed in CAR- and PXR-null mice, respectively, indicating that PBDE congeners activate these receptors in vivo. BDE47 and BDE99, the primary congeners detected in humans in the United States, are capable of inducing… Advisors/Committee Members: Guo, Grace L. (advisor), Hagenbuch, Bruno (cmtemember), Klaassen, Curtis D. (cmtemember), Reed, Gregory A. (cmtemember), Petroff, Brian K. (cmtemember).

Subjects/Keywords: Toxicology; Constitutive androstane receptor; Nuclear receptors; Organic anion transporting polypeptide; Polybrominated diphenyl ethers; Pregnane x receptor

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Pacyniak, E. K. (2010). Molecular Mechanism of Polybrominated Diphenyl Ether Disposition in the Liver. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/7717

Chicago Manual of Style (16^th Edition):

Pacyniak, Erik Kristofer. “Molecular Mechanism of Polybrominated Diphenyl Ether Disposition in the Liver.” 2010. Doctoral Dissertation, University of Kansas. Accessed January 23, 2021. http://hdl.handle.net/1808/7717.

MLA Handbook (7^th Edition):

Pacyniak, Erik Kristofer. “Molecular Mechanism of Polybrominated Diphenyl Ether Disposition in the Liver.” 2010. Web. 23 Jan 2021.

Vancouver:

Pacyniak EK. Molecular Mechanism of Polybrominated Diphenyl Ether Disposition in the Liver. [Internet] [Doctoral dissertation]. University of Kansas; 2010. [cited 2021 Jan 23]. Available from: http://hdl.handle.net/1808/7717.

Council of Science Editors:

Pacyniak EK. Molecular Mechanism of Polybrominated Diphenyl Ether Disposition in the Liver. [Doctoral Dissertation]. University of Kansas; 2010. Available from: http://hdl.handle.net/1808/7717

University of Oulu

20. Käräjämäki, A. (Aki). Non-alcoholic fatty liver disease (NAFLD):perspectives to etiology, complications and lipid metabolism.

Degree: 2017, University of Oulu

URL: http://urn.fi/urn:isbn:9789526217376

►

Abstract Obesity, insulin resistance, type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) form a dangerous quartet which threatens human health all over the… (more)

▼

Abstract Obesity, insulin resistance, type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) form a dangerous quartet which threatens human health all over the world. About 25% of adults around the world have NAFLD, which poses risks for cardiovascular and metabolic well-being and may develop into liver cirrhosis and hepatocellular carcinoma. Apart from lifestyle modification, treatment options for NAFLD are scarce. This thesis presents atrial fibrillation (AF) as a new complication of NAFLD among general population of 958 individuals aged 40-60 years participating in the OPERA study. Even after multiple-adjustments for confounding factors, ultrasound-based NAFLD predicted the development of AF during about 16 years of follow-up. Moreover, the association between AF and liver fibrosis in 76 individuals aged 64-82 years in a cross-sectional setting is presented. The thesis also shows that individuals with metabolic syndrome (MetS), with or without NAFLD, are at increased risk of cardiovascular events, T2D and the increase of left ventricular mass index in a study population of 958 individuals aged 40-60 years during a 20-year follow-up. In other words, NAFLD without MetS does not seem to expose to these three cardiometabolic complications. The thesis also shows that rifampicin-activated pregnane X receptor (PXR), a member of the nuclear receptor superfamily of ligand-activated transcription factors with several endobiotic and xenobiotic activators, increases serum levels of cholesterol, phospholipids and certain fatty acids, assessed by nuclear magnetic resonance metabolomics technique, in a randomized, open, placebo-controlled trial among 34 young and healthy individuals. These serum lipids are considered toxic lipids and capable of transforming hepatosteatosis into steatohepatitis and even more severe forms of NAFLD. Moreover, rifampicin-activated PXR has no effect on serum triglycerides, that are non-toxic lipids, or triglyceride accumulation in the liver, assessed by magnetic resonance imaging, in 15 young and healthy individuals. In conclusion, this thesis advances the knowledge in the pathogenesis, lipid metabolism, complications and heterogeneous nature of NAFLD. These may have implications for patient care and follow-up.

Tiivistelmä Maailmanlaajuisesti noin 25% täysi-ikäisistä henkilöistä sairastaa alkoholinkäyttöön liittymätöntä rasvamaksaa. Sen tiedetään altistavan sydän- ja verisuonisairauksille, aineenvaihduntahäiriöille, maksakirroosille ja jopa maksasyövälle, mutta elämäntapahoitoa lukuun ottamatta hoitomahdollisuudet ovat toistaiseksi vähäisiä. Tässä väitöskirjassa osoitetaan ensimmäistä kertaa alkoholinkäyttöön liittymättömän rasvamaksan ennustavan itsenäisesti eteisvärinän ilmaantuvuutta noin 16 vuoden seurannan aikana 958 tavallisen keski-ikäisen ihmisen aineistossa osana OPERA-tutkimusta. Lisäksi väitöskirjassa osoitetaan maksan sidekudosmuodostuksen ja eteisvärinän välillä olevan yhteys poikkileikkausasetelmassa 76 iäkkään ihmisen muodostamassa aineistossa. Väitöstutkimuksessa…

Advisors/Committee Members: Ukkola, O. (Olavi), Hukkanen, J. (Janne).

Subjects/Keywords: atrial fibrillation; cardiovascular diseases; liver fibrosis; non-alcoholic fatty liver disease; pregnane X receptor; type 2 diabetes; alkoholin käyttöön liittymätön rasvamaksa; eteisvärinä; maksafibroosi; pregnaani X reseptori; sydän- ja verisuonisairaudet; tyypin 2 diabetes

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APA (6^th Edition):

Käräjämäki, A. (. (2017). Non-alcoholic fatty liver disease (NAFLD):perspectives to etiology, complications and lipid metabolism. (Doctoral Dissertation). University of Oulu. Retrieved from http://urn.fi/urn:isbn:9789526217376

Chicago Manual of Style (16^th Edition):

Käräjämäki, A (Aki). “Non-alcoholic fatty liver disease (NAFLD):perspectives to etiology, complications and lipid metabolism.” 2017. Doctoral Dissertation, University of Oulu. Accessed January 23, 2021. http://urn.fi/urn:isbn:9789526217376.

MLA Handbook (7^th Edition):

Käräjämäki, A (Aki). “Non-alcoholic fatty liver disease (NAFLD):perspectives to etiology, complications and lipid metabolism.” 2017. Web. 23 Jan 2021.

Vancouver:

Käräjämäki A(. Non-alcoholic fatty liver disease (NAFLD):perspectives to etiology, complications and lipid metabolism. [Internet] [Doctoral dissertation]. University of Oulu; 2017. [cited 2021 Jan 23]. Available from: http://urn.fi/urn:isbn:9789526217376.

Council of Science Editors:

Käräjämäki A(. Non-alcoholic fatty liver disease (NAFLD):perspectives to etiology, complications and lipid metabolism. [Doctoral Dissertation]. University of Oulu; 2017. Available from: http://urn.fi/urn:isbn:9789526217376

21. Shaffer, Hally A. Engineering the pregnane X receptor and estrogen receptor alpha to bind novel small molecules using negative chemical complementation.

Degree: PhD, Chemistry and Biochemistry, 2011, Georgia Tech

URL: http://hdl.handle.net/1853/39620

► Nuclear receptors are ligand-activated transcription factors that play significant roles in various biological processes within the body, such as cell development, hormone metabolism, reproduction, and… (more)

Subjects/Keywords: Nuclear receptors; Chemical complementation; Negative chemical complementation; Yeast-two hybrid selection; Pregnane X receptor; Estrogen receptor; Pregnane; Protein engineering; Nuclear receptors (Biochemistry); Transcription factors; Yeast Genetics

…ANTIBIOTICS: PREGNANE X RECEPTOR 27 2.1 Engineering Nuclear Receptors to Bind Antibiotics 27 2.2… …galactopyranoside ONPG PDB Protein Data Bank xvii PXR Pregnane X Receptor RE Response Element… …activate transcription in response to the β-lactam antibiotics was the pregnane X receptor (… …Ligand-binding Domain LXR Liver X Receptor MR Mineralocorticoid Receptor o-nitrophenyl β-D… …RNAP RNA Polymerase RXR Retinoid X Receptor SERM Selective Estrogen Receptor Modulator…

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APA (6^th Edition):

Shaffer, H. A. (2011). Engineering the pregnane X receptor and estrogen receptor alpha to bind novel small molecules using negative chemical complementation. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/39620

Chicago Manual of Style (16^th Edition):

Shaffer, Hally A. “Engineering the pregnane X receptor and estrogen receptor alpha to bind novel small molecules using negative chemical complementation.” 2011. Doctoral Dissertation, Georgia Tech. Accessed January 23, 2021. http://hdl.handle.net/1853/39620.

MLA Handbook (7^th Edition):

Shaffer, Hally A. “Engineering the pregnane X receptor and estrogen receptor alpha to bind novel small molecules using negative chemical complementation.” 2011. Web. 23 Jan 2021.

Vancouver:

Shaffer HA. Engineering the pregnane X receptor and estrogen receptor alpha to bind novel small molecules using negative chemical complementation. [Internet] [Doctoral dissertation]. Georgia Tech; 2011. [cited 2021 Jan 23]. Available from: http://hdl.handle.net/1853/39620.

Council of Science Editors:

Shaffer HA. Engineering the pregnane X receptor and estrogen receptor alpha to bind novel small molecules using negative chemical complementation. [Doctoral Dissertation]. Georgia Tech; 2011. Available from: http://hdl.handle.net/1853/39620

22. WOO SZE KWANG. VIRTUAL SCREENING FOR JNK INHIBITORS AND PREDICTION OF PXR ACTIVITY USING COMPUTATIONAL MODELS.

Degree: 2015, National University of Singapore

URL: http://scholarbank.nus.edu.sg/handle/10635/129129

Subjects/Keywords: Virtual screening; Molecular modeling; c-jun N-terminal kinase; Pregnane X receptor; Mitogen-activated protein kinase enzymes; Nuclear receptors

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APA (6^th Edition):

KWANG, W. S. (2015). VIRTUAL SCREENING FOR JNK INHIBITORS AND PREDICTION OF PXR ACTIVITY USING COMPUTATIONAL MODELS. (Thesis). National University of Singapore. Retrieved from http://scholarbank.nus.edu.sg/handle/10635/129129

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

KWANG, WOO SZE. “VIRTUAL SCREENING FOR JNK INHIBITORS AND PREDICTION OF PXR ACTIVITY USING COMPUTATIONAL MODELS.” 2015. Thesis, National University of Singapore. Accessed January 23, 2021. http://scholarbank.nus.edu.sg/handle/10635/129129.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

KWANG, WOO SZE. “VIRTUAL SCREENING FOR JNK INHIBITORS AND PREDICTION OF PXR ACTIVITY USING COMPUTATIONAL MODELS.” 2015. Web. 23 Jan 2021.

Vancouver:

KWANG WS. VIRTUAL SCREENING FOR JNK INHIBITORS AND PREDICTION OF PXR ACTIVITY USING COMPUTATIONAL MODELS. [Internet] [Thesis]. National University of Singapore; 2015. [cited 2021 Jan 23]. Available from: http://scholarbank.nus.edu.sg/handle/10635/129129.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

KWANG WS. VIRTUAL SCREENING FOR JNK INHIBITORS AND PREDICTION OF PXR ACTIVITY USING COMPUTATIONAL MODELS. [Thesis]. National University of Singapore; 2015. Available from: http://scholarbank.nus.edu.sg/handle/10635/129129

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

23. Helsley, Robert N. THE ROLE OF PXR AND IKKβ SIGNALING IN CARDIOMETABOLIC DISEASE.

Degree: 2016, University of Kentucky

URL: https://uknowledge.uky.edu/pharmacol_etds/14

► Cardiovascular disease (CVD) is the leading cause of death worldwide and is partially attributed to perturbations in lipid metabolism. Xenobiotics, such as pharmaceutical drugs and… (more)

▼ Cardiovascular disease (CVD) is the leading cause of death worldwide and is partially attributed to perturbations in lipid metabolism. Xenobiotics, such as pharmaceutical drugs and environmental chemicals, have been associated with increased risk of CVD in multiple large-scale human population studies, but the underlying mechanisms remain poorly defined. We and others have identified several xenobiotics as potent agonists for the pregnane X receptor (PXR), a nuclear receptor that can be activated by numerous drugs as well as environmental and dietary chemicals. However, the role of PXR in mediating the pathophysiological effects of xenobiotic exposure in humans and animals remains elusive. The work herein identified several widely used pharmaceutical agents and endocrine disrupting chemicals as PXR-selective agonists such as drugs involved in HIV therapy and phthalates/phthalate substitutes, respectively. We investigated the role of amprenavir, an HIV protease inhibitor, and tributyl citrate, a phthalate substitute, on PXR-dependent alterations in lipoprotein metabolism. Acute exposure with either xenobiotic in mice elicited increases in the proatherogenic LDL-cholesterol levels in a PXR-dependent manner. PXR activation significantly induced expression of genes involved in intestinal lipid metabolism. Further, we went on to identify the intestinal cholesterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), as a direct PXR-target gene. PXR activation also stimulated cholesterol uptake in both murine and human intestinal cells. Moreover, we provide evidence that the microsomal triglyceride transfer protein (MTP) may be a direct PXR-target gene. Taken together, these findings provide critical mechanistic insight into the role of xenobiotic-mediated PXR activation on lipid homeostasis and demonstrate a potential role of PXR in mediating adverse effects of xenobiotics on CVD risk in humans. In addition to PXR signaling, we investigated the role of IκB kinase β (IKKβ), a central coordinator of inflammation, in adipocyte progenitor cells. Targeting IKKβ in adipose progenitor cells resulted in decreased high fat diet (HFD)-elicited adipogenesis, while protecting mice from inflammation and associated insulin resistance. Consistently, we discovered that IKKβ inhibition by antisense oligonucleotides ablated HFD-induced adiposity, while protecting mice against associated metabolic disorders. In conclusion, targeting IKKβ with antisense therapy may present as a novel therapeutic approach to combat obesity and metabolic dysfunctions.

Subjects/Keywords: HIV drugs; Phthalates; Pregnane X Receptor; IκB Kinase β; Adipogenesis; Insulin Resistance; Cardiovascular Diseases; Hormones, Hormone Substitutes, and Hormone Antagonists; Lipids; Medical Molecular Biology; Medical Nutrition; Medical Pharmacology; Medical Sciences; Medical Toxicology; Molecular, Genetic, and Biochemical Nutrition; Nutritional and Metabolic Diseases; Other Pharmacology, Toxicology and Environmental Health

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APA (6^th Edition):

Helsley, R. N. (2016). THE ROLE OF PXR AND IKKβ SIGNALING IN CARDIOMETABOLIC DISEASE. (Doctoral Dissertation). University of Kentucky. Retrieved from https://uknowledge.uky.edu/pharmacol_etds/14

Chicago Manual of Style (16^th Edition):

Helsley, Robert N. “THE ROLE OF PXR AND IKKβ SIGNALING IN CARDIOMETABOLIC DISEASE.” 2016. Doctoral Dissertation, University of Kentucky. Accessed January 23, 2021. https://uknowledge.uky.edu/pharmacol_etds/14.

MLA Handbook (7^th Edition):

Helsley, Robert N. “THE ROLE OF PXR AND IKKβ SIGNALING IN CARDIOMETABOLIC DISEASE.” 2016. Web. 23 Jan 2021.

Vancouver:

Helsley RN. THE ROLE OF PXR AND IKKβ SIGNALING IN CARDIOMETABOLIC DISEASE. [Internet] [Doctoral dissertation]. University of Kentucky; 2016. [cited 2021 Jan 23]. Available from: https://uknowledge.uky.edu/pharmacol_etds/14.

Council of Science Editors:

Helsley RN. THE ROLE OF PXR AND IKKβ SIGNALING IN CARDIOMETABOLIC DISEASE. [Doctoral Dissertation]. University of Kentucky; 2016. Available from: https://uknowledge.uky.edu/pharmacol_etds/14

24. Touloupi, Katerina. Regulation of aldehyde dehydrogenases by nuclear receptors CAR and PXR in rats genetically predetermined in response to phenobarbital.

Degree: 2015, University of Ioannina; Πανεπιστήμιο Ιωαννίνων

URL: http://hdl.handle.net/10442/hedi/43024

►

The magnitude of the genes belonging to the ALDH superfamily in organism’s welfare andespecially their protection against xenobiotics, as well as the accumulating evidence that… (more)

▼

The magnitude of the genes belonging to the ALDH superfamily in organism’s welfare andespecially their protection against xenobiotics, as well as the accumulating evidence that indicateinvolvement of nuclear receptors in regulation of many genes including ALDHs, has excited our interestin unraveling the potential role of CAR and PXR in mediation/regulation of ALDH1As subfamily ofgenes, utilizing the unique experimental model of Wistar/Af/Han/Mol/Kuo/Io rats. Specifically, the tworat strains used in this study were either responsive (RR) or non-responsive (rr) to induction ofALDH1A genes after administration of PB (Phenobarbital) or other PB-type inducers.The apparent difference of ALDH1As induction between the two strains, both at basal levelsand after treatment with PB or PCN, which was detected with protein immunoprecipitation experiments,was further investigated at mRNA levels of expression. The results revealed that the remarkabledifference was attributed to the complete absence of ALDH1A7 expression in rr strain. Furthermore, astriking up-regulation of the gene was observed in RR rats in the presence the above drugs, which act as selective agonists for the nuclear receptors CAR and PXR. Concurrently, expression of ALDH1A1gene was only slightly higher in rr rats, compared to respective expression levels in RR animals.Supportive evidence to our findings was displayed in experiments of ontogenesis with liver samplesderived from neonates and corresponding in vitro studies in primary hepatocyte cultures.The nuclear translocation of CAR and PXR upon treatment with their selective agonists wasevident in both rat strains and also time- and dose-dependent, however their potential gene activationhad to be further tested by studying the induction of their well-studied target genes; CYP2B1 andCYP3A1, respectively.Focusing on the tremendous difference of ALDH1A7 expression between the strains and theuncontest effect of drugs in transcription regulation, we performed reporter gene assays with variousdeletion constructs of RR-ALDH1A7 and rr-ALDH1A7 promoters, as well as chromatinimmunoprecipitation assays on the same promoter regions. Interestingly, our results indicated RRALDH1A7as an active promoter highly-upregulated in response to PB administration, which is instrong contrast to the barely active rr-ALDH1A7. Although the proximal promoter is the essentialregion for turning on gene transcription, we nominated a region of the RR-ALDH1A7 promoter between-1566 to -452,which demonstrated highest activation potential.CAR was emerged as a substantial regulator of RR-ALDH1A7 gene activation, especially whenPB or other CAR-activators were administered. In RR-ALDH1A7, CAR was found to bind to the distalpromoter of the gene, serving as enhancer of gene expression, and presumably PXR may also be ableto bind, since the receptors are promiscuous to their binding to targets and cross-talk to each other.

H σπουδαιότητα των ενζύμων που ανήκουν στην υπερ-οικογένεια των αλδεϋδικών αφυδρογονασών (ALDHs) στην ευζωία των οργανισμών και…

Subjects/Keywords: Αλδεϋδικές αφυδρογονάσες 1Α1 και 1Α7; Πυρηνικοί υποδοχείς; Ιδιοσυστατικός υποδοχέας ανδροστενών; Υποδοχέας πρεγνανίου; φαινοβαρβιτάλη; Καρβονιτρίλιο της πρεγνενολόνης; Μετρήσεις γονιδίου αναφοράς; Δοκιμασίες ανοσοκαθίζησης χρωματίνης; Aldehyde dehydrogenases (ALDHs) 1A1 and 1A7; Nuclear receptors; Constitutive androstane receptor (CAR);

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APA (6^th Edition):

Touloupi, K. (2015). Regulation of aldehyde dehydrogenases by nuclear receptors CAR and PXR in rats genetically predetermined in response to phenobarbital. (Thesis). University of Ioannina; Πανεπιστήμιο Ιωαννίνων. Retrieved from http://hdl.handle.net/10442/hedi/43024

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Touloupi, Katerina. “Regulation of aldehyde dehydrogenases by nuclear receptors CAR and PXR in rats genetically predetermined in response to phenobarbital.” 2015. Thesis, University of Ioannina; Πανεπιστήμιο Ιωαννίνων. Accessed January 23, 2021. http://hdl.handle.net/10442/hedi/43024.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Touloupi, Katerina. “Regulation of aldehyde dehydrogenases by nuclear receptors CAR and PXR in rats genetically predetermined in response to phenobarbital.” 2015. Web. 23 Jan 2021.

Vancouver:

Touloupi K. Regulation of aldehyde dehydrogenases by nuclear receptors CAR and PXR in rats genetically predetermined in response to phenobarbital. [Internet] [Thesis]. University of Ioannina; Πανεπιστήμιο Ιωαννίνων; 2015. [cited 2021 Jan 23]. Available from: http://hdl.handle.net/10442/hedi/43024.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Touloupi K. Regulation of aldehyde dehydrogenases by nuclear receptors CAR and PXR in rats genetically predetermined in response to phenobarbital. [Thesis]. University of Ioannina; Πανεπιστήμιο Ιωαννίνων; 2015. Available from: http://hdl.handle.net/10442/hedi/43024

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Cincinnati

25. Sane, Rucha S. Differential Induction of Drug Metabolizing Enzymes and Drug Transporters by Tamoxifen: Molecular Mechanisms and Clinical Implications.

Degree: PhD, Pharmacy : Pharmaceutical Sciences, 2006, University of Cincinnati

URL: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1143410615

► Tamoxifen is a widely used antiestrogen in the treatment and prevention of breast cancer. Some of its unresolved problems include the occurrence of drug-drug interactions,… (more)

▼ Tamoxifen is a widely used antiestrogen in the treatment and prevention of breast cancer. Some of its unresolved problems include the occurrence of drug-drug interactions, acquired resistance and endometrial carcinogenesis. Here we hypothesized that tamoxifen and/or its metabolites induce drug metabolizing enzymes and transporters and these inductive effects entail activation of the human pregnane X receptor (hPXR). First, we evaluated the activity and expression of key phase I and II enzymes, Cytochrome P450 (CYP) 3A4 and UDP-Glucuronyltransferase and drug transporter, P-glycoprotein, in primary human hepatocytes and LS174T colon carcinoma cell line. Tamoxifen and 4-hydroxytamoxifen (4-OHT) exhibited significant induction of CYP3A4 and moderate induction of UGT1A1 and P-gp in hepatocytes. In LS174T cells tamoxifen/4OHT moderately induced UGT1A1 and P-gp but failed to induce CYP3A4. This apparent tissue-specific difference in CYP3A4 induction by tamoxifen may be related to the observed differences in the expression of transcription factors such as hPXR and glucocorticoid receptor in (GRá) these cells. Next, in promoter-reporter assays we observed that tamoxifen/4-OHT are efficient activators of hPXR. Attenuation of hPXR in human hepatocytes employing siRNA against hPXR caused a corresponding decrease in the extent of CYP3A4 induction indicating that induction by tamoxifen/4-OHT primarily results from their interactions with hPXR. Examination of the role of other receptors revealed that GRá potentiates hPXR mediated CYP3A4 promoter activation by the antiestrogens. However, activated estrogen receptor appeared to suppress the basal transcription of CYP3A4 in these assays. Based on our pre-clinical data, we initiated a clinical study to assess CYP3A4 induction in breast cancer patients who are prescribed the tamoxifen regimen (20 mg/day). Midazolam, a drug metabolized by CYP3A4, was employed as a probe for CYP3A4 activity. In four patients evaluated thus far, we have noted a distinct trend towards increased midazolam clearance, indicative of increased CYP3A4 activity, following steady state tamoxifen dosing (day 42) compared to basal CYP3A4 activity, evaluated prior to initiating tamoxifen therapy. Thus, our study suggests that tamoxifen/4-OHT upregulate CYP3A4, which has implications for optimizing the clinical use of tamoxifen and the development of new antiestrogens that do not carry the risk of drug interactions, acquired drug resistance and endometrial carcinogenesis. Advisors/Committee Members: Desai, Rucha (Advisor).

Subjects/Keywords: Health Sciences, General; Tamoxifen; CYP3A4; Cytochrome P450; Enzyme induction; drug metabolism; human hepatocytes; UDP-glucuronosyl transferase; P-glycoprotein; Pregnane X Receptor; PXR; LS174T

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APA (6^th Edition):

Sane, R. S. (2006). Differential Induction of Drug Metabolizing Enzymes and Drug Transporters by Tamoxifen: Molecular Mechanisms and Clinical Implications. (Doctoral Dissertation). University of Cincinnati. Retrieved from http://rave.ohiolink.edu/etdc/view?acc_num=ucin1143410615

Chicago Manual of Style (16^th Edition):

Sane, Rucha S. “Differential Induction of Drug Metabolizing Enzymes and Drug Transporters by Tamoxifen: Molecular Mechanisms and Clinical Implications.” 2006. Doctoral Dissertation, University of Cincinnati. Accessed January 23, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1143410615.

MLA Handbook (7^th Edition):

Sane, Rucha S. “Differential Induction of Drug Metabolizing Enzymes and Drug Transporters by Tamoxifen: Molecular Mechanisms and Clinical Implications.” 2006. Web. 23 Jan 2021.

Vancouver:

Sane RS. Differential Induction of Drug Metabolizing Enzymes and Drug Transporters by Tamoxifen: Molecular Mechanisms and Clinical Implications. [Internet] [Doctoral dissertation]. University of Cincinnati; 2006. [cited 2021 Jan 23]. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1143410615.

Council of Science Editors:

Sane RS. Differential Induction of Drug Metabolizing Enzymes and Drug Transporters by Tamoxifen: Molecular Mechanisms and Clinical Implications. [Doctoral Dissertation]. University of Cincinnati; 2006. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1143410615

Open Access Theses and Dissertations