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https://www.readbyqxmd.com/read/29665350/pxr-structure-specific-activation-by-hepatotoxic-pyrrolizidine-alkaloids
#1
Claudia Luckert, Albert Braeuning, Alfonso Lampen, Stefanie Hessel-Pras
Pyrrolizidine alkaloids (PAs) comprise a large group of more than 660 secondary metabolites found in more than 6000 plant species worldwide. Acute PA intoxication induces severe liver damage. Chronic exposure to sub-lethal doses may cause cumulative damage or cancer. Nuclear receptor activation often constitutes a molecular event for xenobiotic-induced toxicity. However, so far nothing is known about potential interactions of PAs with nuclear receptors as a toxicological mode of action. Thus, in the present study PA-dependent activation of a comprehensive panel of nuclear receptors (PPARs, LXRα, RARα, RXRα, FXR, CAR, PXR, ERα/β) was investigated using GAL4/UAS-based transactivation reporter gene assays...
April 14, 2018: Chemico-biological Interactions
https://www.readbyqxmd.com/read/29608908/cinpa1-binds-directly-to-constitutive-androstane-receptor-and-inhibits-its-activity
#2
Milu T Cherian, Sergio C Chai, William C Wright, Aman Singh, Morgan Alexandra Casal, Jie Zheng, Jing Wu, Richard E Lee, Patrick R Griffin, Taosheng Chen
The constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are xenobiotic sensors that regulate the expression of drug-metabolizing enzymes and efflux transporters. CAR activation promotes drug elimination, thereby reducing therapeutic effectiveness, or causes adverse drug effects via toxic metabolites. CAR inhibitors could be used to attenuate these adverse drug effects. CAR and PXR share ligands and target genes, confounding the understanding of the regulation of receptor-specific activity. We previously identified a small-molecule inhibitor, CINPA1, that inhibits CAR (without activating PXR at lower concentrations) by altering CAR-coregulator interactions and reducing CAR recruitment to DNA response elements of regulated genes...
March 30, 2018: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29569723/cytochrome-p450-3a-induction-predicts-p-glycoprotein-induction-1-establishing-induction-relationships-using-ascending-dose-rifampin
#3
Justin D Lutz, Brian J Kirby, Lu Wang, Qinghua Song, John Ling, Benedetta Massetto, Angela Worth, Brian P Kearney, Anita Mathias
Drug transporter and cytochrome P450 expression is regulated by shared nuclear receptors and hence, an inducer should induce both, though magnitude may differ. The objective of this study was to establish relative induction relationships between CYP3A and drug transporters (P-gp, OATP and BCRP) or other P450s (CYP2C9 and CYP1A2) using ascending doses of the prototypical PXR agonist, rifampin, to elicit weak, moderate and strong PXR agonism. Healthy subjects received dabigatran etexilate, pravastatin, rosuvastatin and a midazolam/tolbutamide/caffeine cocktail before and after rifampin 2, 10, 75, or 600 mg qd...
March 23, 2018: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29569712/cytochrome-p450-3a-induction-predicts-p-glycoprotein-induction-2-prediction-of-decreased-substrate-exposure-after-rifabutin-or-carbamazepine
#4
Justin D Lutz, Brian J Kirby, Lu Wang, Qinghua Song, John Ling, Benedetta Massetto, Angela Worth, Brian P Kearney, Anita Mathias
Rifampin demonstrated dose-dependent relative induction between CYP3A and P-gp, OATP or CYP2C9; P-gp, OATP and CYP2C9 induction was one DDI category lower than observed for CYP3A across a wide range of PXR agonism. The objective of this study was to determine if these relationships could be utilized to predict transporter induction by other CYP3A inducers (rifabutin and carbamazepine) and of another P-gp substrate, sofosbuvir. Healthy subjects received sofosbuvir and a six probe drug cassette before and after 300 mg qd rifabutin or 300 mg bid carbamazepine...
March 23, 2018: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29569377/immune-regulation-by-microbiome-metabolites
#5
REVIEW
Chang H Kim
Commensal microbes and the host immune system have been co-evolved for mutual regulation. Microbes regulate the host immune system, in part, by producing metabolites. A mounting body of evidence indicates that diverse microbial metabolites profoundly regulate the immune system via host receptors and other target molecules. Immune cells express metabolite-specific receptors such as P2X7 , GPR41, GPR43, GPR109A, aryl hydrocarbon receptor precursor (AhR), pregnane X receptor (PXR), farnesoid X receptor (FXR), TGR5 and other molecular targets...
March 22, 2018: Immunology
https://www.readbyqxmd.com/read/29554630/effects-of-pyrethroid-pesticide-cis-bifenthrin-on-lipogenesis-in-hepatic-cell-line
#6
Dandan Xiang, Tianyi Chu, Meng Li, Qiangwei Wang, Guonian Zhu
Mounting evidence suggests there is a link between exposure to synthetic pyrethroids (SPs) and the development of obesity. The information presented in this study suggests that cis-bifenthrin (cis-BF) could activate pregnane X receptor (PXR) mediated pathway and lead to the lipid accumulation of human hepatoma (HepG2) cells. Cells were incubated in the control or different concentrations of cis-BF for 24 h. The 1 × 10-7  M and 1 × 10-6  M cis-BF exposure were found to induce cellular triglyceride (TG) accumulation significantly...
March 3, 2018: Chemosphere
https://www.readbyqxmd.com/read/29548889/comparison-of-the-hepatic-and-thyroid-gland-effects-of-sodium-phenobarbital-in-wild-type-and-constitutive-androstane-receptor-car-knockout-rats-and-pregnenolone-16%C3%AE-carbonitrile-in-wild-type-and-pregnane-x-receptor-pxr-knockout-rats
#7
Corinne Haines, Lynsey R Chatham, Audrey Vardy, Clifford R Elcombe, John R Foster, Brian G Lake
A number of chemicals produce liver and thyroid gland tumours in rodents by nongenotoxic modes of action (MOAs). In this study the hepatic and thyroid gland effects of the constitutive androstane receptor (CAR) activator sodium phenobarbital (NaPB) were examined in male Sprague-Dawley wild type (WT) rats and in CAR knockout (CAR KO) rats and the effects of the pregnane X receptor (PXR) activator pregnenolone-16α-carbonitrile (PCN) were examined in WT and PXR knockout (PXR KO) rats. Rats were either fed diets containing 0 (control) or 500 ppm NaPB or were dosed with 0 (control) or 100 mg/kg/day PCN orally for 7 days...
March 13, 2018: Toxicology
https://www.readbyqxmd.com/read/29527807/cyp-induction-and-xeno-sensing-receptors-pxr-car-ahr-and-ppar%C3%AE-at-the-crossroads-of-toxicokinetics-and-toxicodynamics
#8
Jukka Hakkola, Camilla Bernasconi, Sandra Coecke, Lysiane Richert, Tommy B Andersson, Olavi Pelkonen
Pregnane X receptor (PXR), constitutive androstane receptor (CAR), aryl hydrocarbon receptor (AHR) and peroxisome proliferator-activated receptor α (PPARα) are ligand-activated transcription factors that regulate expression of many xenobiotic metabolizing enzymes including several cytochrome P450 (CYP) enzymes. Many xenobiotics induce CYP enzymes through these intracellular receptors and consequently affect toxicokinetics and possible metabolic activation of the receptor ligands and other xenobiotics utilizing similar metabolic pathways...
March 12, 2018: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/29518658/in-vitro-profiling-of-toxic-effects-of-prominent-environmental-lower-chlorinated-pcb-congeners-linked-with-endocrine-disruption-and-tumor-promotion
#9
Kateřina Pěnčíková, Lucie Svržková, Simona Strapáčová, Jiří Neča, Iveta Bartoňková, Zdeněk Dvořák, Martina Hýžďalová, Jakub Pivnička, Lenka Pálková, Hans-Joachim Lehmler, Xueshu Li, Jan Vondráček, Miroslav Machala
The mechanisms contributing to toxic effects of airborne lower-chlorinated PCB congeners (LC-PCBs) remain poorly characterized. We evaluated in vitro toxicities of environmental LC-PCBs found in both indoor and outdoor air (PCB 4, 8, 11, 18, 28 and 31), and selected hydroxylated metabolites of PCB 8, 11 and 18, using reporter gene assays, as well as other functional cellular bioassays. We focused on processes linked with endocrine disruption, tumor promotion and/or regulation of transcription factors controlling metabolism of both endogenous compounds and xenobiotics...
March 5, 2018: Environmental Pollution
https://www.readbyqxmd.com/read/29493154/-transcriptional-regulation-effect-of-thsg-and-anthraquinones-in-tubers-of-polygonum-multiflorum-based-on-human-progesterone-x-receptor-pxr-mediated-cyp3a4-rapid-screening-system
#10
Zhao-Yan Zhang, Liang Yang, Xiao-Yan Huang, Mei-Xi Wang, Zeng-Chun Ma, Xiang-Lin Tang, Yu-Guang Wang, Yue Gao
The rapid screening technology was used to investigate the transcriptional regulation effect of main chemical constituents in tubers of Polygonum multiflorum, including 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucopyranoside(THSG) and anthraquinones (such as rhein, chrysophanol, aloe-emodin, emodin) on CYP3A4 drug inducers induced by human pregnancy X receptor (PXR).The effect of chemical composition on the cell activity was detected by MTS cell viability assay. IC₅₀ was calculated. The expression vector and the reporter vector were co-transfected into HepG2 cells, with 10 μmol•L⁻¹ rifampicin (RIF) as a positive control, and 10 μmol•L⁻¹ ketoconazole (TKZ) as a negative control...
December 2017: Zhongguo Zhong Yao za Zhi, Zhongguo Zhongyao Zazhi, China Journal of Chinese Materia Medica
https://www.readbyqxmd.com/read/29476972/response-of-pxr-signaling-pathway-to-simvastatin-exposure-in-mosquitofish-gambusia-affinis-and-its-histological-changes
#11
Shuang Bao, Xiangping Nie, Yang Liu, Chao Wang, Sijia Liu
As a widely used lipid lowering agent, simvastatin recently has been frequently detected in aquatic environment and the potential adverse effects from simvastatin exposure to non-target organisms such as fish is worthy of more attention. The aim of this study was to reveal the responses of detoxification system in fish to simvastatin exposure. In this investigation a ubiquitous small freshwater fish, mosquito fish (Gambusia affinis), was employed as test organism, and the transcriptional expression of nucleus transcriptional factor pregnane X receptor (PXR) and its downstream genes, including P-glycoprotein (P-gp), cytochrome 3A (CYP3A), multidrug resistance protein 2 (MRP2), UDP-glucuronosyl transferase (UGT) in mosquito fish were investigated by qRT-PCR methods under the exposure of concentrations of simvastatin (0...
February 21, 2018: Ecotoxicology and Environmental Safety
https://www.readbyqxmd.com/read/29476044/antiretroviral-drug-metabolism-in-humanized-pxr-car-cyp3a-nog-mice
#12
JoEllen M McMillan, Denise A Cobb, Zhiyi Lin, Mary G Banoub, Raghubendra S Dagur, Amanda A Branch Woods, Weimin Wang, Edward Makarov, Ted Kocher, Poonam S Joshi, Rolen M Quadros, Donald W Harms, Samuel M Cohen, Howard E Gendelman, Channabasavaiah B Gurumurthy, Santhi Gorantla, Larisa Y Poluektova
Antiretroviral drug (ARV) metabolism is linked largely to hepatic cytochrome P450 (CYP) activity. One ARV drug class known to be metabolized by intestinal and hepatic CYP3A are the protease inhibitors (PI). Plasma drug concentrations in are boosted by CYP3A inhibitors such as cobisistat and ritonavir (RTV). Studies of such drug-drug interactions are limited as the enzyme pathways are human specific. While immune-deficient mice reconstituted with human cells are an excellent model to study ARVs during human immunodeficiency virus type 1 (HIV-1) infection, they cannot reflect human drug metabolism...
February 23, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29470550/the-pregnane-x-receptor-pxr-and-the-nuclear-receptor-corepressor-2-ncor2-modulate-cell-growth-in-head-and-neck-squamous-cell-carcinoma
#13
Juan Pablo Rigalli, Matthias Reichel, Tasmin Reuter, Guillermo Nicolás Tocchetti, Gerhard Dyckhoff, Christel Herold-Mende, Dirk Theile, Johanna Weiss
Head and neck squamous cell carcinoma (HNSCC) is the sixth most frequent cancer worldwide. The pregnane X receptor (PXR) is a nuclear receptor regulating several target genes associated with cancer malignancy. We here demonstrated a significant effect of PXR on HNSCC cell growth, as evidenced in PXR knock-down experiments. PXR transcriptional activity is more importantly regulated by the presence of coactivators and corepressors than by PXR protein expression. To date, there is scarce information on the regulation of PXR in HNSCC and on its role in the pathogenesis of this disease...
2018: PloS One
https://www.readbyqxmd.com/read/29440451/establishing-transcriptional-signatures-to-differentiate-pxr-car-and-ahr-mediated-regulation-of-drug-metabolism-and-transport-genes-in-cryopreserved-human-hepatocytes
#14
Jamie E Moscovitz, Amit S Kalgutkar, Kelly Nulick, Nathaniel Johnson, Zhiwu Lin, Theunis C Goosen, Yan Weng
The potential for drug-drug interactions (DDIs) arising from transcriptional regulation of drug disposition genes via activation of nuclear receptors (NRs) such as pregnane X receptor (PXR), constitutive androstane receptor (CAR), and/or aryl hydrocarbon receptor (AhR) remains largely unexplored, as highlighted in a recent guidance document from the European Medicines Agency. The goal of this research was to establish PXR/CAR/AhR-specific drug metabolizing enzyme (DME) and transporter gene expression signatures in sandwich-cultured cryopreserved human hepatocytes using selective activators of PXR (rifampin), CAR (CITCO) and AhR (omeprazole)...
February 12, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29440179/role-of-c-jun-n-terminal-kinase-in-pregnane-x-receptor-mediated-induction-of-human-cytochrome-p4503a4-in-vitro
#15
Guncha Taneja, Chun Chu, Paramahamsa Maturu, Bhagavatula Moorthy, Romi Ghose
Cytochrome P450 (CYP) 3A4 is the most abundant drug metabolizing enzyme and is responsible for the metabolism of ~50% of clinically available drugs. Induction of CYP3A4 impacts the disposition of its substrates and leads to harmful clinical consequences such as failure of therapy. In order to prevent such undesirable consequences, molecular mechanisms of regulation of CYP3A4 need to be fully understood. CYP3A4 induction is primarily regulated by the xenobiotic nuclear receptor, pregnane-X-receptor (PXR). After ligand binding, PXR is transported to the nucleus, where it binds to the CYP3A4 promoter and induces its gene expression...
February 12, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29438418/bile-acid-detoxifying-enzymes-limit-susceptibility-to-liver-fibrosis-in-female-shrsp5-dmcr-rats-fed-with-a-high-fat-cholesterol-diet
#16
Husna Yetti, Hisao Naito, Yuan Yuan, Xiaofang Jia, Yumi Hayashi, Hazuki Tamada, Kazuya Kitamori, Katsumi Ikeda, Yukio Yamori, Tamie Nakajima
During middle age, women are less susceptible to nonalcoholic steatohepatitis (NASH) than men. Thus, we investigated the underlying molecular mechanisms behind these sexual differences using an established rat model of NASH. Mature female and male stroke-prone spontaneously hypertensive 5/Dmcr rats were fed control or high-fat-cholesterol (HFC) diets for 2, 8, and 14 weeks. Although HFC-induced hepatic fibrosis was markedly less severe in females than in males, only minor gender differences were observed in expression levels of cytochrome P450 enzymes (CYP)7A1, CYP8B1 CYP27A1, and CYP7B1, and multidrug resistance-associated protein 3, and bile salt export pump, which are involved in fibrosis-related bile acid (BA) kinetics...
2018: PloS One
https://www.readbyqxmd.com/read/29432831/pxr-polymorphisms-have-impact-on-the-clinical-efficacy-of-clopidogrel-in-patients-undergoing-percutaneous-coronary-intervention
#17
Yan Wu, Hua Yu, Hai-Qin Tang, Yong Su, Tian-Lu Shi, Sheng Liu, Quan Xia, Du-Juan Xu
BACKGROUNDS: Clopidogrel is widely used in Coronary Heart Disease (CHD) patients undergoing percutaneous coronary intervention (PCI) to prevent thrombotic events. However, clopidogrel response variability (CRV) may affect the patients' clinical outcomes. The current data have shown that genetic factors play an important role in CRV. The aim of this research is to investigate the association of pregnane X receptor (PXR, also called NR1I2) genetic polymorphisms with the clinical efficacy of clopidogrel in patients undergoing PCI...
February 9, 2018: Gene
https://www.readbyqxmd.com/read/29431616/role-of-the-pregnane-x-receptor-in-binge-ethanol-induced-steatosis-and-hepatotoxicity
#18
Sora Choi, Afua A Gyamfi, Prince Neequaye, Samuel Addo, Frank J Gonzalez, Maxwell A Gyamfi
The pregnane X receptor (PXR, NR1I2) is a xenobiotic-sensing nuclear receptor that defends against toxic agents. We have shown that PXR promotes chronic ethanol (EtOH)-induced steatosis. Therefore, we examined the role of PXR in binge EtOH-induced hepatotoxicity. Male wild type (WT) and Pxr-null mice were orally administered three binge doses of EtOH (4.5 g/kg, every 12 hours) and euthanized four hours after the final dose. Pxr-null mice displayed higher basal mRNA levels of hepatic lipogenic transcription factor sterol regulatory element binding protein 1c (Srebp-1c) and its target stearoyl-CoA desaturase 1 (Scd1) and the lipid peroxide detoxifying aldo-keto reductase 1b7 (Akr1b7) and higher protein levels of EtOH-metabolizing alcohol dehydrogenase 1 (ADH1)...
February 5, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29430850/probing-ligand-structure-activity-relationships-in-pregnane-x-receptor-pxr-efavirenz-and-8-hydroxyefavirenz-exhibit-divergence-in-activation
#19
Bhargavi Narayanan, Julie Lade, Carley J S Heck, Kevin D Dietz, Herschel V Wade, Namandje N Bumpus
Efavirenz (EFV), an antiretroviral that interacts clinically with co-administered drugs via activation of the pregnane X receptor (PXR), is extensively metabolized by the cytochromes P450. We tested whether its primary metabolite, 8-hydroxyEFV (8-OHEFV) can activate PXR and potentially contribute to PXR-mediated drug-drug interactions attributed to EFV. Luciferase reporter assays revealed that despite only differing from EFV by an oxygen atom, 8-OHEFV did not activate PXR. Corroborating this, treatment with EFV for 72 h elevated the mRNA abundance of the PXR target gene, Cyp3a11, an approximate 28-fold in primary hepatocytes isolated from PXR-humanized mice while treatment with 8-OHEFV did not result in a change in Cyp3a11 mRNA levels...
February 11, 2018: ChemMedChem
https://www.readbyqxmd.com/read/29425889/comparison-of-the-effects-of-sodium-phenobarbital-in-wild-type-and-humanized-constitutive-androstane-receptor-car-pregnane-x-receptor-pxr-mice-and-in-cultured-mouse-rat-and-human-hepatocytes
#20
Corinne Haines, Barbara M Elcombe, Lynsey R Chatham, Audrey Vardy, Larry G Higgins, Clifford R Elcombe, Brian G Lake
Phenobarbital (PB), a constitutive androstane receptor (CAR) activator, produces liver tumours in rodents by a mitogenic mode of action involving CAR activation. In this study, the hepatic effects of sodium phenobarbital (NaPB) were compared in male C57BL/6J wild type (WT) mice and in humanized mice, where both the mouse CAR and pregnane X receptor (PXR) have been replaced by their human counterparts (hCAR/hPXR mice). Investigations were also performed in cultured male C57BL/6J and CD-1 mouse, male Sprague-Dawley rat and male and female human hepatocytes...
February 6, 2018: Toxicology
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