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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
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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
https://www.readbyqxmd.com/read/29425287/perinatal-bisphenol-a-exposure-increases-atherosclerosis-in-adult-male-pxr-humanized-mice
#8
Yipeng Sui, Se-Hyung Park, Fang Wang, Changcheng Zhou
Bisphenol A (BPA) is a base chemical used extensively in numerous consumer products, and human exposure to BPA is ubiquitous. Higher BPA exposure has been associated with increased risk of atherosclerosis and cardiovascular disease (CVD) in multiple human population-based studies, but the underlying mechanisms responsible for the associations remain elusive. We previously reported that BPA activates the xenobiotic receptor pregnane X receptor (PXR) which has pro-atherogenic effects in animal models. Since BPA is a potent agonist for human PXR but does not affect rodent PXR activity, a suitable PXR-humanized Apolipoprotein E-deficient (huPXR•ApoE-/-) mouse model was developed to study BPA's atherogenic effects, and chronic BPA exposure indeed increased atherosclerosis in huPXR•ApoE-/- mice...
February 7, 2018: Endocrinology
https://www.readbyqxmd.com/read/29424600/comparison-of-the-hepatic-and-thyroid-gland-effects-of-sodium-phenobarbital-and-pregnenolone-16%C3%AE-carbonitrile-in-wild-type-and-constitutive-androstane-receptor-car-pregnane-x-receptor-pxr-knockout-rats
#9
Corinne Haines, Lynsey R Chatham, Audrey Vardy, Clifford R Elcombe, John R Foster, Brian G Lake
1. The hepatic and thyroid gland effects of the constitutive androstane receptor (CAR) activator sodium phenobarbital (NaPB) and the pregnane X receptor (PXR) activator pregnenolone-16α-carbonitrile (PCN) were examined in male Sprague-Dawley wild type (WT) and knockout (KO) rats lacking both hepatic CAR and PXR receptors (CAR KO/PXR KO rats). 2. The treatment of WT rats for 7 days with 500 ppm NaPB in the diet and 100 mg/kg/day PCN by gavage resulted in increased relative liver weight, hepatocyte hypertrophy, increased hepatocyte replicative DNA synthesis (RDS) and induction of cytochrome P450 CYP2B and CYP3A subfamily enzymes...
February 9, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29420809/unexpected-effects-of-propiconazole-tebuconazole-and-their-mixture-on-the-receptors-car-and-pxr-in-human-liver-cells
#10
Constanze Knebel, Jannika Neeb, Elisabeth Zahn, Flavia Schmidt, Alejandro Carazo, Ondej Holas, Petr Pavek, Gerhard P Püschel, Ulrich M Zanger, Roderich Süssmuth, Alfonso Lampen, Philip Marx-Stoelting, Albert Braeuning
Analyzing mixture toxicity requires an in-depth understanding of the mechanisms of action of its individual components. Substances with the same target organ, same toxic effect and same mode of action are believed to cause additive effects, whereas substances with different modes of action are assumed to act independently. Here, we tested two triazole fungicides, propiconazole and tebuconazole, for individual and combined effects on liver toxicity-related endpoints. Both triazoles are proposed to belong to the same cumulative assessment group (CAG) and are therefore thought to display similar and additive behavior...
February 6, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/29412999/using-tr-fret-to-investigate-protein-protein-interactions-a-case-study-of-pxr-coregulator-interaction
#11
Wenwei Lin, Taosheng Chen
Time-resolved fluorescence resonance energy transfer (TR-FRET) protein-protein interaction assays, especially in the format of receptor coregulator (coactivator and corepressor) recruitment/repression assays, have been widely used in nuclear receptor research to characterize the modes of action, efficacies, and binding affinities of ligands (including their properties as agonists, antagonists, and inverse agonists). However, there has been only limited progress in using this assay format for pregnane X receptor (PXR)...
2018: Advances in Protein Chemistry and Structural Biology
https://www.readbyqxmd.com/read/29369785/pregnane-x-receptor-mediates-sorafenib-resistance-in-advanced-hepatocellular-carcinoma
#12
Fan Feng, Qiyu Jiang, Shuang Cao, Yu Cao, Ruisheng Li, Lijun Shen, Hua Zhu, Tao Wang, Lijun Sun, Erguang Liang, Huiwei Sun, Yantao Chai, Xiaojuan Li, Genyan Liu, Ruichang Yang, Zhi Yang, Yongping Yang, Shaojie Xin, Bo-An Li
BACKGROUND: Kinase inhibitor sorafenib is the most widely used drug for advanced HCC clinical treatment nowadays. However, sorafenib administration is only effective for a small portion of HCC patients, and the majority develop sorafenib-resistance during treatment. Thus, it is urgent to discover the endogenous mechanism and identify new pharmaceutical targets of sorafenib-resistance. METHODS: Pregnane X receptor (PXR) was detected by immunohistochemistry and quantitative PCR...
January 21, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29367103/forskolin-convalesces-memory-in-high-fat-diet-induced-dementia-in-wistar-rats-plausible-role-of-pregnane-x-receptors
#13
Jaspreet Kaur, Rupinder Kaur Sodhi, Jitender Madan, Simerjeet Kaur Chahal, Ravinder Kumar
BACKGROUND: Studies have signified that high serum cholesterol plays an intriguing role in amyloid β metabolism and accumulation. Ligand activation of pregnane x receptors (PXRs), up-regulates the expression of P- glycoprotein and has a crucial role in amyloid β efflux. The present study has been undertaken to investigate the effect of forskolin, a PXR agonist in experimental dementia. METHODS: Wistar rats were allowed free access to cholesterol-rich High Fat Diet (HFD) for 90 days to induce dementia...
July 22, 2017: Pharmacological Reports: PR
https://www.readbyqxmd.com/read/29360809/targeting-the-pxr-tlr4-signaling-pathway-to-reduce-intestinal-inflammation-in-an-experimental-model-of-necrotizing-enterocolitis
#14
Kezhen Huang, Subhajit Mukherjee, Vera DesMarais, Joseph M Albanese, Ektor Rafti, Andrew Draghi, Leigh A Maher, Kamal M Khanna, Sridhar Mani, Adam P Matson
BACKGROUND: There is substantial evidence that signaling through Toll-like receptor 4 (TLR4) contributes to the pathogenesis of necrotizing enterocolitis (NEC). Pregnane X receptor (PXR), a xenobiotic sensor and signaling intermediate for certain host-bacterial metabolites, has been shown to negatively regulate TLR4 signaling. Here we investigated the relationship between PXR and TLR4 in the developing murine intestine and explored the capacity of PXR to modulate inflammatory pathways involved in experimental NEC...
January 23, 2018: Pediatric Research
https://www.readbyqxmd.com/read/29358328/a-human-xenobiotic-nuclear-receptor-contributes-to-nonresponsiveness-of-mycobacterium-tuberculosis-to-the-antituberculosis-drug-rifampicin
#15
Ella Bhagyaraj, Drishti Tiwari, Nancy Ahuja, Ravikanth Nanduri, Ankita Saini, Rashi Kalra, Sumit Kumar, Ashok Kumar Janmeja, Pawan Gupta
Mycobacterium tuberculosis is the causative agent of tuberculosis (TB). It acquires phenotypic drug resistance inside macrophages, and this resistance mainly arises from host-induced stress. However, whether cellular drug efflux mechanisms in macrophages contribute to nonresponsiveness of M. tuberculosis to anti-TB drugs is unclear. Here, we report that xenobiotic nuclear receptors mediate TB drug nonresponsiveness by modulating drug efflux transporters in macrophages. This was evident from expression analysis of drug efflux transporters in macrophages isolated from TB patients...
January 22, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29356861/identification-of-approved-drugs-as-potent-inhibitors-of-pregnane-x-receptor-activation-with-differential-receptor-interaction-profiles
#16
Oliver Burk, Maria Kuzikov, Thales Kronenberger, Judith Jeske, Oliver Keminer, Wolfgang E Thasler, Matthias Schwab, Carsten Wrenger, Björn Windshügel
Activation of pregnane X receptor (PXR) results in the induction of first-pass metabolism and drug efflux. Hereby, PXR may cause adverse drug reactions or therapeutic failure of drugs. PXR inhibition is thus an attractive option to minimise adverse effects or to improve therapeutic efficiencies; however, only a limited number of antagonists have been identified so far. We performed a cell-based high-throughput screen to identify PXR antagonists, using a library of approved and investigational drugs. Two approved drugs, pimecrolimus and pazopanib, emerged as novel potent antagonists of PXR activation, with IC50 values of 1...
January 22, 2018: Archives of Toxicology
https://www.readbyqxmd.com/read/29330220/regulation-of-drug-metabolism-by-the-interplay-of-inflammatory-signaling-steatosis-and-xeno-sensing-receptors-in-heparg-cells
#17
Norman Tanner, Lisa Kubik, Claudia Luckert, Maria Thomas, Ute Hofmann, Ulrich M Zanger, Linda Bohmert, Alfonso Lampen, Albert Braeuning
Non-alcoholic fatty liver disease (NAFLD), characterized by triglyceride deposition in hepatocytes due to imbalanced lipid homeostasis, is of increasing concern in Western countries, with progression to non-alcoholic steatohepatitis (NASH), liver fibrosis, and cirrhosis. Previous studies suggest a complex, mutual influence of hepatic fat accumulation, NASH-related inflammatory mediators, and drug-sensing receptors regulating xenobiotic metabolism. Here, we investigated the suitability of human HepaRG hepatocarcinoma cells as a model for NAFLD and NASH...
January 12, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29286073/proteasome-inhibition-protects-against-diet-induced-gallstone-formation-through-modulation-of-cholesterol-and-bile-acid-homeostasis
#18
Eun-Ji Lee, Min Hee Kim, Ye-Ryung Kim, Joo-Won Park, Woo-Jae Park
Gallstone disease is one of the most prevalent and costly gastrointestinal disorders worldwide. Gallstones are formed in the biliary system by cholesterol secretions in bile, which result from excess cholesterol, a deficiency in bile salts or a combination of the two. The present study examined the effects of proteasome inhibition on gallstone formation using the proteasome inhibitors bortezomib (BT) and carfilzomib (CF). C57BL/6J mice were fed a lithogenic diet to generate gallstones and injected with BT or CF for 12 weeks...
December 15, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/29273149/pxr-a-new-player-in-atopic%C3%A2-dermatitis
#19
Landon K Oetjen, Anna M Trier, Brian S Kim
Epidemiological evidence suggests that environmental pollutants contribute to atopic dermatitis, but mechanistic details are currently lacking. Elentner et al. show that PXR, a key transcription factor involved in pollutant metabolism, drives features of subclinical atopic dermatitis. These observations provide new insight into how environmental insults may predispose individuals to atopic dermatitis.
January 2018: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/29247817/generation-of-a-pxr-reporter-human-induced-pluripotent-stem-cell-line-pxr-mcherry-hipsc-using-the-crispr-cas9-system
#20
Hyemin Kim, Ji-Woo Kim, So-Jin Kim, Young-Jun Choi, Dae-Sung Kim, Han-Jin Park
Pregnane X receptor (PXR) is a key nuclear receptor that mediates drug metabolism and stimulates hepatocyte proliferation. However, the lack of PXR expression in human pluripotent stem cell-derived hepatocytes limits their application for drug screening and toxicity testing. Here, we generated a PXR-mCherry reporter human induced pluripotent stem cell (hiPSC) line using the CRISPR/Cas9 system. PXR-mCherry hiPSCs were pluripotent and had differentiation potential and a normal karyotype. This cell line is an important tool for identifying factors that increase PXR-mediated drug metabolism and hepatocyte proliferation...
December 6, 2017: Stem Cell Research
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