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https://www.readbyqxmd.com/read/28716828/creation-and-preliminary-characterization-of-pregnane-x-receptor-and-constitutive-androstane-receptor-knockout-rats
#1
Kevin P Forbes, Evguenia Kouranova, Daniel Tinker, Karen Janowski, Doug Cortner, Aaron McCoy, Xiaoxia Cui
The nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are closely related transcription factors that regulate the expression of Phase I (Cytochrome P450s), Phase II metabolizing enzymes and transporter genes in response to stimulation from xenobiotics, including prescription drugs. PXR and CAR are also involved in other endogenous processes, such as in inflammation, glucose homeostasis and lipid metabolism, and are thus potential drug targets themselves. PXR and CAR knockout and humanized mouse models have proven useful...
July 17, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28699014/predictive-models-for-identifying-the-binding-activity-of-structurally-diverse-chemicals-to-human-pregnane-x-receptor
#2
Cen Yin, Xianhai Yang, Mengbi Wei, Huihui Liu
Toxic chemicals entered into human body would undergo a series of metabolism, transport and excretion, and the key roles played in there processes were metabolizing enzymes, which was regulated by the pregnane X receptor (PXR). However, some chemicals in environment could activate or antagonize human pregnane X receptor, thereby leading to a disturbance of normal physiological systems. In this study, based on a larger number of 2724 structurally diverse chemicals, we developed qualitative classification models by the k-nearest neighbor method...
July 12, 2017: Environmental Science and Pollution Research International
https://www.readbyqxmd.com/read/28698304/prediction-of-clinically-relevant-herb-drug-clearance-interactions-using-a-whole-cell-approach-schisandra-sphenanthera-case-study
#3
Jonathan P Jackson, Kimberly M Freeman, Weslyn W Friley, Ashley G Herman, Christopher B Black, Kenneth R Brouwer, Amy L Roe
The Schisandraceae family is reported to have a range of pharmacological activities, including anti-inflammatory effects. As with all herbal preparations, extracts of Schisandra species are mixtures composed of >50 lignans including schizandrins and deoxyschizandrins. In China, Schisandra sphenanthera extract (SSE) is often co-administered with immunosuppressant treatment of transplant recipients. In cases of co-administration, the potential for herb-drug interactions (HDI) increases. Clinical studies have been employed to assess HDI of extracts including SSE...
July 11, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28685622/induction-of-human-cytochrome-p450-3a4-by-the-irreversible-myeloperoxidase-inactivator-pf-06282999-is-mediated-by-the-pregnane-x-receptor
#4
Jamie E Moscovitz, Zhiwu Lin, Nathaniel Johnson, Meihua Tu, Theunis Goosen, Yan Weng, Amit S Kalgutkar
1. 2-(6-(5-Chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl) acetamide (PF-06282999) is a member of the thiouracil class of irreversible inactivators of human myeloperoxidase enzyme and a candidate for the treatment of cardiovascular disease. PF-06282999 is an inducer of CYP3A4 mRNA and midazolam-1'-hydroxylase activity in human hepatocytes, which is consistent with PF-06282999-dose dependent decreases in mean maximal plasma concentrations (Cmax) and area under the plasma concentration time curve (AUC) of midazolam in humans following 14-day treatment with PF-06282999...
July 7, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28682217/simvastatin-modulates-gene-expression-of-key-receptors-in-zebrafish-embryos
#5
V Cunha, M M Santos, P Moradas-Ferreira, L F C Castro, M Ferreira
Nuclear receptors (NR) are involved in the regulation of several metabolic processes and it is well known that these constituents may be modulated by different chemicals classes, including pharmaceuticals that may activate or antagonize NR. In mammals, some pharmaceuticals modulate the transcription of pregnane X receptor, Pxr, peroxisome proliferator activated receptor, Ppars, and aryl hydrocarbon receptor, Ahr, affecting mRNA expression of genes belonging to various regulatory pathways, including lipid metabolism and detoxification mechanisms...
July 6, 2017: Journal of Toxicology and Environmental Health. Part A
https://www.readbyqxmd.com/read/28678150/metabolism-of-the-marine-phycotoxin-ptx-2-and-its-effects-on-hepatic-xenobiotic-metabolism-activation-of-nuclear-receptors-and-modulation-of-the-phase-i-cytochrome-p450
#6
Jimmy Alarcan, Estelle Dubreil, Antoine Huguet, Dominique Hurtaud-Pessel, Stefanie Hessel-Pras, Alfonso Lampen, Valérie Fessard, Ludovic Le Hegarat
PTX-2 is a marine biotoxin frequently found in shellfish that can lead to food intoxication in humans. Information regarding PTX-2 metabolism is scarce, and little is known of its effect on xenobiotic-metabolizing enzymes (XME) or its molecular pathways. The aim of this study was consequently to examine PTX-2 Phase I metabolism using rat and human liver S9 fractions, and also to assess the capability of PTX-2: (i) to modulate the gene expression of a panel of Phase I (CYP450) and II (UGT, SULT, NAT, and GST) enzymes, as well as the Phase III or 0 (ABC and SLCO) transporters in the human hepatic HepaRG cell line using qPCR; (ii) to induce specific CYP450 in HepaRG cells measured by immunolabeling detection and the measurement of the cells' activities; and (iii) to activate nuclear receptors and induce CYP promoter activities in HEK-T and HepG2 transfected cell lines using transactivation and reporter gene assay, respectively...
July 5, 2017: Toxins
https://www.readbyqxmd.com/read/28676933/association-of-nr1i2-cyp3a5-and-abcb1-genetic-polymorphisms-with-variability-of-temsirolimus-pharmacokinetics-and-toxicity-in-patients-with-metastatic-bladder-cancer
#7
Litaty C Mbatchi, Matthieu Gassiot, Philippe Pourquier, Alejando Goberna, Hakim Mahammedi, Loic Mourey, Florence Joly, Serge Lumbroso, Alexandre Evrard, Nadine Houede
PURPOSE: Temsirolimus is a mammalian target of rapamycin (mTOR) inhibitor that exhibits antitumor activity in renal cell carcinoma and mantle cell lymphoma. The metabolism of temsirolimus and its active metabolite sirolimus mainly depends on cytochrome P450 3A4/5 (CYP3A4/A5) and the ABCB1 transporter. Differently from sirolimus, no pharmacogenetic study on temsirolimus has been conducted. Therefore, the aim of this pilot study was to identify genetic determinants of the inter-individual variability in temsirolimus pharmacokinetics and toxicity...
July 4, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28674261/preliminary-evaluation-of-three-dimensional-primary-human-hepatocyte-culture-system-for-assay-of-drug-metabolizing-enzyme-inducing-potential
#8
Hiroshi Arakawa, Hiroki Kamioka, Tomoko Jomura, Satoshi Koyama, Yoko Idota, Kentaro Yano, Hajime Kojima, Takuo Ogihara
Drug-induced liver injury (DILI) is a common reason for withdrawal of candidate drugs from clinical trials, or of approved drugs from the market. DILI may be induced not only by intact parental drugs, but also by metabolites or intermediates, and therefore should be evaluated in the enzyme-induced state. Here, we present a protocol for assay of drug-metabolizing enzyme-inducing potential using three-dimensional (3D) primary cultures of human hepatocytes (hepatocyte spheroids). Hepatocyte spheroids could be used up to 21 d after seeding (pre-culture for 7 d and exposure to inducer for up to 14 d), based on preliminary evaluation of basal activities of CYP subtypes and mRNA expression of the corresponding transcription factor and xenobiotic receptors (aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR) and pregnane X receptor (PXR))...
2017: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/28673560/down-regulation-of-the-expression-of-alcohol-dehydrogenase-4-and-cyp2e1-by-the-combination-of-%C3%AE-endosulfan-and-dioxin-in-heparg-human-cells
#9
Eléonore A Attignon, Emilie Distel, Béatrice Le-Grand, Alix F Leblanc, Robert Barouki, Eliandre de Oliveira, Martine Aggerbeck, Etienne B Blanc
Pesticides and other persistent organic pollutants are considered as risk factors for liver diseases. We treated the human hepatic cell line HepaRG with both 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) and the organochlorine pesticide, α-endosulfan, to evaluate their combined impact on the expression of hepatic genes involved in alcohol metabolism. We show that the combination of the two pollutants (25nM TCDD and 10μM α-endosulfan) led to marked decreases in the amounts of both the mRNA (up to 90%) and protein (up to 60%) of ADH4 and CYP2E1...
June 30, 2017: Toxicology in Vitro: An International Journal Published in Association with BIBRA
https://www.readbyqxmd.com/read/28639323/molecular-interactions-of-dioxins-and-dlcs-with-the-xenosensors-pxr-and-car-an-in-silico-risk-assessment-approach
#10
Garima Verma, Mohemmed Faraz Khan, Mohammad Shaquiquzzaman, Wasim Akhtar, Mymoona Akhter, Syed Misbahul Hasan, Mohammad Mumtaz Alam
Dioxins and dioxin-like compounds (DLCs) are known to cause endocrine disruption in humans and animals. Being lipophilic xenobiotic chemicals, they can be easily absorbed into the biological system from the surrounding environments, thereby causing various health dysfunctions. In the present study, a total of 100 dioxins and DLCs were taken, and their binding pattern was assessed with the xenosensors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) in comparison with the corresponding known inhibitors and a well-studied endocrine disrupting xenobiotic, bisphenol A (BPA)...
June 22, 2017: Journal of Molecular Recognition: JMR
https://www.readbyqxmd.com/read/28633424/three-dimensional-3d-heparg-spheroid-model-with-physiologically-relevant-xenobiotic-metabolism-competence-and-hepatocyte-functionality-for-liver-toxicity-screening
#11
Sreenivasa C Ramaiahgari, Suramya Waidyanatha, Darlene Dixon, Michael J DeVito, Richard S Paules, Stephen S Ferguson
Effective prediction of human responses to chemical and drug exposure is of critical importance in environmental toxicology research and drug development. While significant progress has been made to address this challenge using in vitro liver models, these approaches often fail due to inadequate tissue model functionality. Herein, we describe the development, optimization, and characterization of a novel three-dimensional (3D) spheroid model using differentiated HepaRG cells that achieve and maintain physiologically-relevant levels of xenobiotic metabolism (CYP1A2, CYP2B6, and CYP3A4/5)...
June 15, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28624525/regulation-of-hepatic-abcb4-and-cyp3a65-gene-expression-and-multidrug-multixenobiotic-resistance-mdr-mxr-functional-activity-in-the-model-teleost-danio-rerio-zebrafish
#12
Jeremy S Jackson, Christopher J Kennedy
Multidrug/multixenobiotic resistance (MDR/MXR) confers resistance to a diverse range of potentially toxic pharmaceuticals and environmental contaminants through a cellular response that involves the coordinated induction and activity of the ATP-binding cassette (ABC) transporter P-glycoprotein (P-gp) and the Phase I metabolizing enzyme cytochrome P450 3A (CYP3A). In mammals, ligand-mediated pregnane X receptor (PXR) transcriptional activity regulates the induction of P-gp and CYP3A; however, this mechanism has not been well-characterized in fish...
June 14, 2017: Comparative Biochemistry and Physiology. Toxicology & Pharmacology: CBP
https://www.readbyqxmd.com/read/28623334/novel-complex-of-hat-protein-tip60-and-nuclear-receptor-pxr-promotes-cell-migration-and-adhesion
#13
Karishma Bakshi, B Ranjitha, Shraddha Dubey, Jaisri Jagannadham, Bharti Jaiswal, Ashish Gupta
PXR is a member of nuclear receptor superfamily and a well-characterized mediator of xenobiotic metabolism. The classical mode of PXR activation involves its binding to appropriate ligand and subsequent heterodimerization with its partner RXR. However, various factors such as post-translational modifications and crosstalk with different cellular factors may also regulate the functional dynamics and behavior of PXR. In the present study, we have identified that TIP60, an essential lysine acetyltransferase protein interacts with unliganded PXR and together this complex promotes cell migration & adhesion...
June 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28599754/the-effects-of-sex-protein-receptors-and-sex-steroid-hormone-gene-polymorphisms-on-breast-cancer-risk
#14
REVIEW
Somayeh Jahandoost, Pourandokht Farhanghian, Sakineh Abbasi
Breast cancer is a common disease and a major cause of death among women throughout the world. Various genes are believed to be involved in the initiation and progression of the disease. Some polymorphisms of these genes increase susceptibility to breast cancer in particular ethnicities. This study used electronic literature search to review the effects of different sex steroid hormone gene polymorphisms on breast cancer risk. Our findings indicated that some polymorphisms in estrogen receptor alpha (ER-α), ER-β, progesterone receptor (PGR), pregnane X receptor (PXR), and cytochrome P450 enzymes (CYPs) affected breast cancer susceptibility, especially in African American women...
July 2017: Journal of the National Medical Association
https://www.readbyqxmd.com/read/28594304/role-of-vitamin-d-pathway-gene-polymorphisms-on-rifampicin-plasma-and-intracellular-pharmacokinetics
#15
Sarah Allegra, Giovanna Fatiguso, Andrea Calcagno, Lorena Baietto, Ilaria Motta, Fabio Favata, Jessica Cusato, Stefano Bonora, Giovanni Di Perri, Antonio D'Avolio
AIM: We retrospectively evaluate the pharmacogenetic role of single nucleotide polymorphisms involved in rifampicin transport (SLCO1B1, MDR1 and PXR genes) and vitamin D (VDR, CYP24A1 and CYP27B1 genes) metabolism and activity on drug plasma and intracellular concentrations. PATIENTS & METHODS: Rifampicin Cmax and Ctrough were measured at weeks 2 and 4 using Ultra-Performance Liquid Chromatography-tandem mass spectroscopy methods. Allelic discrimination was performed by real-time polymerase chain reaction...
June 8, 2017: Pharmacogenomics
https://www.readbyqxmd.com/read/28575098/mir-148a-mediated-estrogen-induced-cholestasis-in-intrahepatic-cholestasis-of-pregnancy-role-of-pxr-mrp3
#16
Zhou-Zhou Rao, Xiao-Wen Zhang, Yi-Ling Ding, Meng-Yuan Yang
Intrahepatic cholestasis of pregnancy (ICP) is an idiopathic liver disease while the biochemical characteristic is the elevated level of total bile acid (TBA). The present study investigated whether miR-148a mediates the induced effect of estrogen on the development of ICP and the proper mechanism: PXR/MRP3 signal pathway. mRNA expression was detected by qPCR, protein expression was detected by western blotting, the concentration of estrogen and TBA were detected by reagent kit respectively. In the cinical research, it was found that miR-148a expression was positive related with the concentration of TBA in the serum of ICP patients...
2017: PloS One
https://www.readbyqxmd.com/read/28574832/impact-of-chronic-unpredicted-mild-stress-induced-depression-on-repaglinide-fate-via-glucocorticoid-signaling-pathway
#17
Hongyan Wei, Ting Zhou, Boyu Tan, Lei Zhang, Mingming Li, Zhijun Xiao, Feng Xu
Chronic unpredicted mild stress (CUMS)-induced depression could alter the pharmacokinetics of many drugs in rats, however, the underlying mechanism is not clear. In this work we studied the pharmacokinetics of repaglinide, and explored the role of glucocorticoid and adrenergic signaling pathway in regulating drug metabolizing enzymes (DMEs) in GK rats and BRL 3A cells. The plasma cortisol and epinephrine levels were increased, meanwhile the pharmacokinetics of repaglinide were altered significantly in depression model rats...
July 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28571685/activation-of-the-aryl-hydrocarbon-receptor-decreases-rifampicin-induced-cyp3a4-expression-in-primary-human-hepatocytes-and-heparg
#18
Martin Krøyer Rasmussen, Martine Daujat-Chavanieu, Sabine Gerbal-Chaloin
The role of the cross-talk between nuclear receptors in the regulation of Cytochrome P450 expression in the liver is well-documented. Most studies have focused on the cross-talk between the pregnane X receptor (PXR) and other receptors, such as the constitutive androstane receptor. However, cross-talk between PXRs and aryl hydrocarbon receptors (AhRs) has also been suggested, but reports regarding this cross-talk are conflicting. In the present study, we treated HepaRG and primary human hepatocytes (PHHs) with both a strong (TCDD) and weak (3-methylindole; 3MI) AhR activator to investigate their impact on PXR-regulated expression of CYP3A4...
May 29, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/28546421/statins-attenuate-activation-of-the-nlrp3-inflammasome-by-oxidized-ldl-or-tnf-%C3%AE-in-vascular-endothelial-cells-through-a-pxr-dependent-mechanism
#19
Shaolan Wang, Xinya Xie, Ting Lei, Kang Zhang, Baochang Lai, Zihui Zhang, Youfei Guan, Guangmei Mao, Lei Xiao, Nanping Wang
Excessive activation of the NLRP3 inflammasome is implicated in cardiovascular diseases. Statins exert an anti-inflammatory effect independent of their cholesterol lowering effect. This study investigated the potential role of statins in the activation of the NLRP3 inflammasome in endothelial cells (ECs). Western blotting and qRT-PCR showed that oxidized-LDL (oxLDL) or tumor necrosis factor alpha (TNFα) activated the NLRP3 inflammasome in ECs. Simvastatin or mevastatin significantly suppressed the effects of oxLDL or TNFα...
May 25, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28546420/alterations-of-histone-modifications-contribute-to-pregnane-x-receptor-mediated-induction-of-cyp3a4-by-rifampicin
#20
Liang Yan, Yiting Wang, Jingyang Liu, Yali Nie, Xiaobo Zhong, Quancheng Kan, Lirong Zhang
Cytochrome P450 3A4 (CYP3A4) is one of the major drug-metabolizing enzymes in human and is responsible for the metabolism of 60% of the clinically used drugs. Many drugs are able to induce the expression of CYP3A4, which usually causes drug-drug interactions and adverse drug reactions. This study aims to explore the role of histone modifications in rifampicin-induced expression of CYP3A4 in LS174T cells. We found that the induction of CYP3A4 mRNA by rifampicin in LS174T cells was associated with increased levels of histone H3 lysine 4 trimethylation (H3K4me3) and H3 acetylation and a decreased level of histone H3 lysine 27 trimethylation (H3K27me3) in the CYP3A4 promoter...
May 25, 2017: Molecular Pharmacology
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