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https://www.readbyqxmd.com/read/27918128/mulberroside-a-suppresses-pxr-mediated-transactivation-and-gene-expression-of-p-gp-in-ls174t-cells
#1
Yuhua Li, Ling Huang, Jiahong Sun, Xiaohua Wei, Jinhua Wen, Guoping Zhong, Min Huang, Huichang Bi
Mulberroside A (Mul A) is the main bioactive constituents of Sangbaipi, which is officially listed in the Chinese Pharmacopoeia. The pregnane X receptor (PXR) has been recognized as the critical mediator of human P-glycoprotein (P-gp) gene transactivation. In this study, the effect of Mul A on PXR-mediated transactivation and gene expression of P-gp was investigated. It was found that Mul A significantly suppressed PXR-mediated P-gp luciferase activity induced by rifampicin (Rif). Furthermore, Rif induced an elevation of P-gp expression and transport activity, which was apparently suppressed by Mul A...
December 5, 2016: Journal of Biochemical and Molecular Toxicology
https://www.readbyqxmd.com/read/27899892/age-dependent-hepatic-udp-glucuronosyltransferase-gene-expression-and-activity-in-children
#2
Elizabeth Neumann, Huma Mehboob, Jacqueline Ramírez, Snezana Mirkov, Min Zhang, Wanqing Liu
UDP-glucuronosyltransferases (UGTs) are important phase II drug metabolism enzymes. The aim of this study was to explore the relationship between age and changes in mRNA expression and activity of major human hepatic UGTs, as well as to understand the potential regulatory mechanism underlying this relationship. Using previously generated data, we investigated age-dependent mRNA expression levels of 11 hepatic UGTs (UGT1A1, UGT1A3, UGT1A4, UGT1A5, UGT1A6, UGT1A9, UGT2B4, UGT2B7, UGT2B10, UGT2B15, and UGT2B17) and 16 transcription factors (AHR, AR, CAR, ESR2, FXR, GCCR, HNF1a, HNF3a, HNF3b, HNF4a, PPARA, PPARG, PPARGC, PXR, SP1, and STAT3) in liver tissue of donors (n = 38) ranging from 0 to 25 years of age...
2016: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/27878971/pregnane-x-receptors-regulate-cyp2c8-and-p-glycoprotein-to-impact-on-the-resistance-of-nsclc-cells-to-taxol
#3
Yan Chen, Wandan Huang, Feiyu Chen, Guoping Hu, Fenglei Li, Jianhua Li, Aiguo Xuan
Cytochrome P450 2C8 (CYP2C8) is one of the enzymes that primarily participate in producing metabolisms of medications and P-glycoprotein (P-gp) has been regarded as one of the important molecules in chemotherapeutically induced multidrug resistance (MDR). In addition, the pregnane X receptor (PXR) is involved in regulating both CYP2C8 and P-gp. We aim to research the effect of PXR on Taxol-resistant non-small-cell lung cancer (NSCLC cells) via regulating CYP2C8 and P-gp. NSCLC cells were treated with SR12813, LY335979, or PXR siRNA...
November 22, 2016: Cancer Medicine
https://www.readbyqxmd.com/read/27876007/effect-of-pregnane-x-receptor-1b-genetic-polymorphisms-on-postoperative-analgesia-with-fentanyl-in-chinese-patients-undergoing-gynecological-surgery
#4
Jing-Jing Yuan, Xiao-Jing Ma, Zhi-Song Li, Yan-Zi Chang, Wei Zhang, Quan-Cheng Kan, Jun-Kai Hou, Li-Rong Zhang
BACKGROUND: The purpose of the study was to investigate the effects of the pregnane X receptor (PXR)*1B polymorphisms on CYP3A4 enzyme activity and postoperative fentanyl consumption in Chinese patients undergoing gynecological surgery. METHODS: A total of 287 females of Han ethnicity, aged 20 to 50 years old, ASA I or II, scheduled to abdominal total hysterectomy or myomectomy under general anesthesia were enrolled. The analgesic model used was fentanyl consumption via patient-controlled intravenous analgesia (PCIA) in the post-operative period...
November 23, 2016: BMC Medical Genetics
https://www.readbyqxmd.com/read/27871908/acetylated-deoxycholic-dca-and-cholic-ca-acids-are-potent-ligands-of-pregnane-x-pxr-receptor
#5
Alejandro Carazo, Lucie Hyrsova, Jan Dusek, Hana Chodounska, Alzbeta Horvatova, Karel Berka, Vaclav Bazgier, Hongying Gan-Schreier, Waleé Chamulitrat, Eva Kudova, Petr Pavek
The Pregnane X (PXR), Vitamin D (VDR) and Farnesoid X (FXR) nuclear receptors have been shown to be receptors of bile acids controlling their detoxification or synthesis. Chenodeoxycholic (CDCA) and lithocholic (LCA) acids are ligands of FXR and VDR, respectively, whereas 3-keto and acetylated derivates of LCA have been described as ligands for all three receptors. In this study, we hypothesized that oxidation or acetylation at position 3, 7 and 12 of bile acids DCA (deoxycholic acid), LCA, CA (cholic acid), and CDCA by detoxification enzymes or microbiome may have an effect on the interactions with bile acid nuclear receptors...
November 18, 2016: Toxicology Letters
https://www.readbyqxmd.com/read/27871799/molecular-mechanisms-of-pfoa-induced-toxicity-in-animals-and-humans-implications-for-health-risks
#6
REVIEW
Kan Li, Peng Gao, Ping Xiang, Xuxiang Zhang, Xinyi Cui, Lena Q Ma
As an emerging persistent organic pollutant (POP), perfluorooctanoate (PFOA) is one of the most abundant perfluorinated compounds (PFCs) in the environment. This review summarized the molecular mechanisms and signaling pathways of PFOA-induced toxicity in animals and humans as well as their implications for health risks in humans. Traditional PFOA-induced signal pathways such as peroxisome proliferating receptor alpha (PPARα), constitutive androstane receptor (CAR), farnesoid X receptor (FXR), and pregnane-X receptor (PXR) may not be important for PFOA-induced health effects on humans...
November 18, 2016: Environment International
https://www.readbyqxmd.com/read/27856527/role-of-glucocorticoid-receptor-and-pregnane-x-receptor-in-dexamethasone-induction-of-rat-hepatic-aryl-hydrocarbon-receptor-nuclear-translocator-and-nadph-cytochrome-p450-oxidoreductase
#7
Sarah R Hunter, Alex Vonk, Anne K Mullen Grey, David S Riddick
The aryl hydrocarbon receptor (AHR) nuclear translocator (ARNT), as the AHR's heterodimerization partner, and NADPH-cytochrome P450 oxidoreductase (POR), as the key electron donor for all microsomal P450s, are independent and indispensable components in the adaptive and toxic responses to polycyclic aromatic hydrocarbons. Expression of both ARNT and POR in rat liver is induced by dexamethasone (DEX), a synthetic glucocorticoid known to activate both the glucocorticoid receptor (GR) and the pregnane X receptor (PXR)...
November 16, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27852458/treatment-of-estrogen-dependent-diseases-design-synthesis-and-profiling-of-a-selective-17%C3%AE-hsd1-inhibitor-with-sub-nanomolar-ic50-for-a-proof-of-principle-study
#8
Ahmed S Abdelsamie, Chris J van Koppen, Emmanuel Bey, Mohamed Salah, Carsten Börger, Lorenz Siebenbürger, Matthias W Laschke, Michael D Menger, Martin Frotscher
Current endocrine therapeutics for the estrogen-dependent disease endometriosis often lead to considerable side-effects as they act by reducing estrogen action systemically. A more recent approach takes advantage of the fact that the weak estrogen estrone (E1) which is abundant in the plasma, is activated in the target cell to the highly estrogenic estradiol (E2) by 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1). 17β-HSD1 is overexpressed in endometriosis and thus a promising target for the treatment of this disease, with the prospect of less target-associated side-effects...
November 4, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27806127/rifampicin-induced-hepatic-lipid-accumulation-association-with-up-regulation-of-peroxisome-proliferator-activated-receptor-%C3%AE-in-mouse-liver
#9
Jia-Hui Huang, Cheng Zhang, Da-Gang Zhang, Lu Li, Xi Chen, De-Xiang Xu
Previous study found that rifampicin caused intrahepatic cholestasis. This study investigated the effects of rifampicin on hepatic lipid metabolism. Mice were orally administered with rifampicin (200 mg/kg) daily for different periods. Results showed that serum TG level was progressively reduced after a short elevation. By contrast, hepatic TG content was markedly increased in rifampicin-treated mice. An obvious hepatic lipid accumulation, as determined by Oil Red O staining, was observed in mice treated with rifampicin for more than one week...
2016: PloS One
https://www.readbyqxmd.com/read/27803452/mechanism-for-increased-expression-of-ugt2b-in-the-liver-of-mice-with-neuropathic-pain
#10
Mitsumasa Kaneta, Wataru Ochiai, Marina Nagae, Wataru Suto, Mika Hanagata, Haruka Suzuki, Satoshi Kitaoka, Jo Hatogai, Nobutomo Ikarashi, Kiyoshi Sugiyama
Approximately 30% of patients with cancer pain experience concurrent neuropathic pain. Since these patients are not sufficiently responsive to morphine, the development of an effective method of pain relief is urgently needed. Decreased function of the μ opioid receptor, which binds to the active metabolite of morphine M-6-G in the brain, has been proposed as a mechanism for morphine resistance. Previously, we pharmacokinetically examined morphine resistance in mice with neuropathic pain, and demonstrated that the brain morphine concentration was decreased, expression level of P-glycoprotein (P-gp) in the small intestine was increased, and expression level and activity of uridine diphosphate glucuronosyltransferase (UGT)2B in the liver were increased...
2016: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/27799961/heterozygous-inactivation-of-the-nuclear-receptor-pxr-nr1i2-in-a-patient-with-anabolic-steroid-induced-intrahepatic-cholestasis
#11
Roman Liebe, Marcin Krawczyk, Joanna Raszeja-Wyszomirska, Beata Kruk, Rebecca Preis, Jocelyn Trottier, Olivier Barbier, Piotr Milkiewicz, Frank Lammert
INTRODUCTION: The incidence of liver damage due to steroid consumption is increasing due to the omnipresence of the idealized body image and the widespread availability of drugs via the Internet. The genetic factors underlying individual susceptibility are not presently known. CASE PRESENTATION: A male patient developed cholestatic liver injury two weeks after a two-month course of anabolic steroids. Next-generation sequencing (NGS) of 24 cholestasis-related genes revealed a heterozygous two-basepair deletion in exon 1 of the pregnane X receptor gene (PXR)...
August 2016: Hepatitis Monthly
https://www.readbyqxmd.com/read/27798827/discovery-of-2-r-4-2-fluoro-4-methylsulfonyl-phenyl-2-methylpiperazin-1-yl-n-1r-2s-3s-5s-7s-5-hydroxyadamantan-2-yl-pyrimidine-4-carboxamide-ski2852-a-highly-potent-selective-and-orally-bioavailable-inhibitor-of-11%C3%AE-hydroxysteroid-dehydrogenase-type-1-11%C3%AE-hsd1
#12
Je Ho Ryu, Jung A Lee, Shinae Kim, Young Ah Shin, Jewon Yang, Hye Young Han, Hyun Joo Son, Yong Hyuk Kim, Joon Ho Sa, Jae-Sun Kim, Jungeun Lee, Jeeyeon Lee, Hyeung-Geun Park
A series of picolinamide- and pyrimidine-4-carboxamide-based inhibitors of 11β-hydroxysteroid dehydrogenase type 1 was synthesized and evaluated to optimize the lead compound 9. The combination of the replacement of a pyridine ring of 9 with a pyrimidine ring and the introduction of an additional fluorine substituent at the 2-position of the phenyl ring resulted in the discovery of a potent, selective, and orally bioavailable inhibitor, 18a (SKI2852), which demonstrated no CYP and PXR liabilities, excellent PK profiles across species, and highly potent and sustainable PD activity...
October 31, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27795941/a-molecular-aspect-in-the-regulation-of-drug-metabolism-does-pxr-induced-enzyme-expression-always-lead-to-functional-changes-in-drug-metabolism
#13
Yuan Wei, Chenxiao Tang, Vinayak Sant, Song Li, Samuel M Poloyac, Wen Xie
Pregnane X receptor (PXR, NR112) is a xenobiotic receptor whose primary function is to regulate the expression of drug-metabolizing enzymes (DMEs) and drug transporters. Drug-induced PXR activation and subsequent enzyme and transporter induction has been proposed to be an important mechanism for the drug-drug interactions. In addition to activating PXR, many pharmaceutical chemicals can also function as reversible or irreversible inhibitors of DMEs, which may also impact the pharmacokinetics and pharmacodynamics (PK/PD) of drugs...
August 2016: Current Pharmacology Reports
https://www.readbyqxmd.com/read/27777246/managing-the-risk-of-cyp3a-induction-in-drug-development-a-strategic-approach
#14
Barry C Jones, Helen Rollison, Susanne A Johansson, Kajsa P Kanebratt, Craig Lambert, Karthick Vishwanathan, Tommy B Andersson
Induction of cytochrome P450 (CYP) can impact the efficacy and safety of a drug molecule upon multiple dosing of co-administered drugs. This strategy is focused on CYP3A since the majority of clinically relevant cases of CYP induction are related to this enzyme. However, the in vitro evaluation of induction is applicable to other CYP enzymes but the in vivo relevance cannot be assessed because the scarcity of relevant clinical data. In the pre-clinical phase, compounds are screened using PXR reporter gene assay and, if necessary, structure-activity relationships (SAR) are developed...
October 24, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27773686/differential-modulation-of-fxr-activity-by-chlorophacinone-and-ivermectin-analogs
#15
Chia-Wen Hsu, Jui-Hua Hsieh, Ruili Huang, Dirk Pijnenburg, Thai Khuc, Jon Hamm, Jinghua Zhao, Caitlin Lynch, Rinie van Beuningen, Xiaoqing Chang, René Houtman, Menghang Xia
Chemicals that alter normal function of farnesoid X receptor (FXR) have been shown to affect the homeostasis of bile acids, glucose, and lipids. Several structural classes of environmental chemicals and drugs that modulated FXR transactivation were previously identified by quantitative high-throughput screening (qHTS) of the Tox21 10K chemical collection. In the present study, we validated the FXR antagonist activity of selected structural classes, including avermectin anthelmintics, dihydropyridine calcium channel blockers, 1,3-indandione rodenticides, and pyrethroid pesticides, using in vitro assay and quantitative structural-activity relationship (QSAR) analysis approaches...
December 15, 2016: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/27760163/role-of-pxr-in-hepatic-cancer-its-influences-on-liver-detoxification-capacity-and-cancer-progression
#16
Deepak Kotiya, Bharti Jaiswal, Sampa Ghose, Rachna Kaul, Kasturi Datta, Rakesh K Tyagi
The role of nuclear receptor PXR in detoxification and clearance of xenobiotics and endobiotics is well-established. However, its projected role in hepatic cancer is rather illusive where its expression is reported altered in different cancers depending on the tissue-type and microenvironment. The expression of PXR, its target genes and their biological or clinical significance have not been examined in hepatic cancer. In the present study, by generating DEN-induced hepatic cancer in mice, we report that the expression of PXR and its target genes CYP3A11 and GSTa2 are down-regulated implying impairment of hepatic detoxification capacity...
2016: PloS One
https://www.readbyqxmd.com/read/27732883/optical-isomers-of-dihydropyridine-calcium-channel-blockers-display-enantiospecific-effects-on-the-expression-and-enzyme-activities-of-human-xenobiotics-metabolizing-cytochromes-p450
#17
Martina Štěpánková, Kristýna Krasulová, Aneta Dořičáková, Ondřej Kurka, Pavel Anzenbacher, Zdeněk Dvořák
Dihydropyridine calcium channel blockers (CCBs) are used as anti-hypertensives and in the treatment of angina pectoris. Structurally, CCBs have at least one chiral center in the molecule, thereby existing in two or more different enantiomers. In the current paper we examined effects of benidipine, felodipine and isradipine enantiomers on the expression and enzyme activities of human xenobiotics-metabolizing cytochromes P450. All CCBs dose-dependently activated aryl hydrocarbon receptor (AhR) and pregnane X receptor (PXR), as revealed by gene reporter assays...
October 9, 2016: Toxicology Letters
https://www.readbyqxmd.com/read/27732639/transactivation-assays-to-assess-canine-and-rodent-pregnane-x-receptor-pxr-and-constitutive-androstane-receptor-car-activation
#18
Marija Pinne, Elsa Ponce, Judy L Raucy
The pregnane X receptor (PXR/SXR, NR1I2) and constitutive androstane receptor (CAR, NR1I3) are nuclear receptors (NRs) involved in the regulation of many genes including cytochrome P450 enzymes (CYPs) and transporters important in metabolism and uptake of both endogenous substrates and xenobiotics. Activation of these receptors can lead to adverse drug effects as well as drug-drug interactions. Depending on which nuclear receptor is activated will determine which adverse effect could occur, making identification important...
2016: PloS One
https://www.readbyqxmd.com/read/27723751/nuclear-receptors-control-pro-viral-and-antiviral-metabolic-responses-to-hepatitis-c-virus-infection
#19
Gahl Levy, Naomi Habib, Maria Angela Guzzardi, Daniel Kitsberg, David Bomze, Elishai Ezra, Basak E Uygun, Korkut Uygun, Martin Trippler, Joerg F Schlaak, Oren Shibolet, Ella H Sklan, Merav Cohen, Joerg Timm, Nir Friedman, Yaakov Nahmias
Viruses lack the basic machinery needed to replicate and therefore must hijack the host's metabolism to propagate. Virus-induced metabolic changes have yet to be systematically studied in the context of host transcriptional regulation, and such studies shoul offer insight into host-pathogen metabolic interplay. In this work we identified hepatitis C virus (HCV)-responsive regulators by coupling system-wide metabolic-flux analysis with targeted perturbation of nuclear receptors in primary human hepatocytes. We found HCV-induced upregulation of glycolysis, ketogenesis and drug metabolism, with glycolysis controlled by activation of HNF4α, ketogenesis by PPARα and FXR, and drug metabolism by PXR...
October 10, 2016: Nature Chemical Biology
https://www.readbyqxmd.com/read/27714977/the-long-chain-%C3%AE-tocopherol-metabolite-%C3%AE-13-cooh-and-%C3%AE-tocotrienol-induce-p-glycoprotein-expression-and-activity-by-activation-of-the-pregnane-x-receptor-in-the-intestinal-cell-line-ls-180
#20
Maren C Podszun, Metta Jakobi, Marc Birringer, Johanna Weiss, Jan Frank
SCOPE: Members of the vitamin E family or their metabolites may induce the xenobiotic transporter P-glycoprotein (P-gp), which can limit the bioavailability of drugs and phytochemicals. This study aimed to investigate if α- and γ-tocopherol, α- and γ-tocotrienol, the long chain metabolite α-tocopherol-13'-COOH, the short chain metabolites α- and γ-carboxyethylhydroxychromanol and plastochromanol-8 activate the pregnane X receptor (PXR) and thereby modulate P-gp expression and/or activity...
October 6, 2016: Molecular Nutrition & Food Research
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