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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
Jiří Novák, Branislav Vrana, Tatsiana Rusina, Krzysztof Okonski, Roman Grabic, Peta A Neale, Beate I Escher, Miroslava Macová, Selim Ait-Aissa, Nicolas Creusot, Ian Allan, Klára Hilscherová
Many aquatic pollutants can be present at low concentrations, but their mixtures can still affect health or behavior of exposed organisms. In this study, toxicological and chemical analyses were combined for spatial contamination profiling using an innovative passive sampling approach. A novel Dynamic Passive Sampler (DPS) was employed as a mobile sampler from a ship cruising along 2130km of the Danube river during the Joint Danube Survey 3 (JDS3). The sampling was performed in eight subsequent river stretches with two types of complementary passive samplers: silicone rubber sheets (SR) used for non-polar chemicals and SDB-RPS Empore™ disks (ED) for more hydrophilic compounds...
March 9, 2018: Science of the Total Environment
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
Qinghao Jin, Xiang Hua Han, Cheong-Yong Yun, Chul Lee, Jin Woo Lee, Dongho Lee, Mi Kyeong Lee, Sang-Hun Jung, Jin Tae Hong, Youngsoo Kim, Bang Yeon Hwang
Bioassay-guided fractionation of the methanolic extract from the roots of Cynanchum atratum has resulted in the isolation of three new pregnane glycosides (1-3) along with four known compounds (4-7). Their structures were identified by analysis of the spectroscopic data including extensive 2D NMR. All of the isolates were evaluated for their potential to inhibit the melanin production in α-melanocyte stimulating hormone (α-MSH)-activated B16 melanoma cells. Of these, compounds 4-7 dose-dependently inhibited the melanin production with the IC50 values ranging from 4 μM to 33 μM...
January 4, 2018: Bioorganic & Medicinal Chemistry Letters
Alfonso T Garcia-Sosa
Leishmaniasis, malaria, and fungal diseases are burdens on individuals and populations and can present severe complications. Easily accessible chemical treatments for these diseases are increasingly sought-after. Targeting the parasite N-myristoyl transferase while avoiding the human enzyme and other anti-targets may allow the prospect of compounds with pan-activity against these diseases, which would simplify treatments and costs. Developing chemical libraries, both virtual and physical, that have been filtered and flagged early on in the drug discovery process (before virtual screening) could reduce attrition rates of compounds being developed and failing late in development stages due to problems of side-effects or toxicity...
March 8, 2018: Current Computer-aided Drug Design
Nagarajan Muthukaman, Sanjay Deshmukh, Macchindra Tambe, Dnyandeo Pisal, Shital Tondlekar, Mahamadhanif Shaikh, Neelam Sarode, Vidya G Kattige, Pooja Sawant, Monali Pisat, Vikas Karande, Srinivasa Honnegowda, Abhay Kulkarni, Dayanidhi Behera, Satyawan B Jadhav, Ramchandra R Sangana, Girish S Gudi, Neelima Khairatkar-Joshi, Laxmikant A Gharat
In an effort to identify CYP and hERG clean mPGES-1 inhibitors from the dihydrofuran-fused tricyclic benzo[d]imidazole series lead 7, an extensive structure-activity relationship (SAR) studies were performed. Optimization of A, D and E-rings in 7 afforded many potent compounds with human whole blood potency in the range of 160-950 nM. Selected inhibitors 21d, 21j, 21m, 21n, 21p and 22b provided selectivity against COX-enzymes and mPGES-1 isoforms (mPGES-2 and cPGES) along with sufficient selectivity against prostanoid synthases...
February 28, 2018: Bioorganic & Medicinal Chemistry Letters
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
Ari L Mendell, Beryl Y T Chung, Carolyn E Creighton, Bettina E Kalisch, Craig D C Bailey, Neil J MacLusky
Gonadal steroid hormones exert neurotrophic and neuroprotective effects on the brain. Recent work suggests potential neuroprotective roles for the 3α-hydroxy, 5α-reduced metabolites of these hormones. Two such metabolites are 5α-androstane-3α,17β-diol (3α-diol) and 5α-pregnan-3α-ol-20-one (allopregnanolone; Allo), which may contribute to the overall protection conferred by their precursors (testosterone and progesterone, respectively) through mechanisms including potentiation of gamma-aminobutyric acid (GABA)A receptor (GABAA R) activity...
February 22, 2018: Brain Research
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
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
Oscar J Pozo, Josep Marcos, Olha Khymenets, Andy Pranata, Christopher Fitzgerald, Malcolm Donald McLeod, Cedric Shackleton
The steroid disulfates (aka bis-sulfates or bis(sulfates)) are a significant but minor fraction of the urinary steroid metabolome that have not been widely studied because major components are not hydrolyzed by the commercial sulfatases commonly used in steroid metabolomics. In early studies, conjugate fractionation followed by hydrolysis using acidified solvent (solvolysis) was used for the indirect detection of this fraction by GC-MS. This paper describes the application of a specific LC-MS/MS method for the direct identification of disulfates in urine, and their use as markers for the prenatal diagnosis of disorders causing reduced estriol production: STSD (Steroid Sulfatase Deficiency), SLOS (Smith-Lemli-Opitz Syndrome) and PORD (P450 Oxido-Reductase Deficiency)...
February 19, 2018: Journal of Molecular Endocrinology
Dorota Zolkowska, Chun-Yi Wu, Michael A Rogawski
Allopregnanolone (5α-pregnan-3α-ol-20-one) and its synthetic 3β-methyl analog, ganaxolone, are positive allosteric modulators of synaptic and extrasynaptic γ-aminobutyric acid (GABA)A receptors that exhibit antiseizure activity in diverse animal seizure models, including models of status epilepticus (SE). The 2 neuroactive steroids are being investigated as treatments for SE, including as a treatment for SE induced by chemical threat agents. Intramuscular injection is the preferred route of administration in the prehospital treatment of SE...
February 17, 2018: Epilepsia
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
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
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
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
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
Lixia Xie, Yucheng He, Xiaoqiao Zhou, Xiaowen Li, Xiue Jin, Xiliang Wang, Deshi Shi
1. Cytochrome P450, which is expressed in humans and other animals, is a superfamily of drug-metabolizing enzymes that plays important roles in the metabolism of endogenous and xenobiotic substrates via oxidation, peroxidation, and reduction. Of endogenous substrates, interleukin (IL)-6 is a crucial cytokine involved in inflammation in the liver. The present study aims to elucidate the mechanisms through which IL-6 modulates cytochrome P450 expression. 2. CYP2C33 expression was found to be increased in HepLi cells and primary porcine hepatocytes treated with IL-6 in a concentration-dependent manner...
February 12, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
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
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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