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https://www.readbyqxmd.com/read/29458109/modulation-of-cyp1a1-metabolism-from-adverse-health-effects-to-chemoprevention-and-therapeutic-options
#1
Melina Mescher, Thomas Haarmann-Stemmann
The human cytochrome P450 (CYP) 1A1 gene encodes a monooxygenase that metabolizes multiple exogenous and endogenous substrates. CYP1A1 has become infamous for its oxidative metabolism of benzo[a]pyrene and related polycyclic aromatic hydrocarbons, converting these chemicals into very potent human carcinogens. CYP1A1 expression is mainly controlled by the aryl hydrocarbon receptor (AHR), a transcription factor whose activation is induced by binding of persistent organic pollutants, including polycyclic aromatic hydrocarbons and dioxins...
February 16, 2018: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/29458047/effects-of-cytochrome-p450-single-nucleotide-polymorphisms-on-methadone-metabolism-and-pharmacodynamics
#2
REVIEW
Taha Ahmad, Monica A Valentovic, Gary O Rankin
Methadone is a synthetic, long-acting opioid with a single chiral center forming two enantiomers, (R)-methadone and (S)-methadone, each having specific pharmacological actions. Concentrations of (R)- and (S)-methadone above therapeutic levels have the ability to cause serious, life-threatening, and fatal side effects. This toxicity can be due in part to the pharmacogenetics of an individual, which influences the pharmacokinetic and pharmacodynamic properties of the drug. Methadone is primarily metabolized in the liver by cytochrome P450 (CYP) enzymes, predominately by CYP2B6, followed by CYP3A4, 2C19, 2D6, and to a lesser extent, CYP2C18, 3A7, 2C8, 2C9, 3A5, and 1A2...
February 16, 2018: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29454920/design-synthesis-and-identification-of-silicon-containing-hcv-ns5a-inhibitors-with-pan-genotype-activity
#3
Baomin Liu, Kuo Gai, Hui Qin, Xushi Liu, Yuan Cao, Qin Lu, Dandan Lu, Deyang Chen, Hengqiao Shen, Wei Song, Yang Zhang, Xiaojin Wang, Hongjiang Xu, Yinsheng Zhang
Modification of a HCV NS5A inhibitor, ombitasvir, led to the identification of 10d with improved pan-genotype NS5A inhibition and better pharmacokinetic properties. The key structural changes to ombitasvir include bioisosteric replacement of carbon with silicon atom. Compared with ombitasvir, the activity of anti-HCV genotypes (GT 1 to 6) of 10d is increased to some extent, especially the inhibitory activity against genotype 3a and 6a is increased by more than seven times, and the dog's in vivo pharmacokinetics properties were also superior to ombitasvir...
February 10, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29454704/selective-inhibition-of-cyp2c8-by-fisetin-and-its-methylated-metabolite-geraldol-in-human-liver-microsomes
#4
Riya Shrestha, Ju-Hyun Kim, Wongshik Nam, Hye Suk Lee, Jae-Mok Lee, Sangkyu Lee
Fisetin is a flavonol compound commonly found in edible vegetables and fruits. It has anti-tumor, antioxidant, and anti-inflammatory effects. Geraldol, the O-methyl metabolite of fisetin in mice, is reported to suppress endothelial cell migration and proliferation. Although the in vivo and in vitro effects of fisetin and its metabolites are frequently reported, studies on herb-drug interactions have not yet been performed. This study was designed to investigate the inhibitory effect of fisetin and geraldol on eight isoforms of human cytochrome P450 (CYP) by using cocktail assay and LC-MS/MS analysis...
January 31, 2018: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29453779/mitochondrial-cytochrome-p450-cyp-1b1-is-responsible-for-melatonin-induced-apoptosis-in-neural-cancer-cells
#5
Zhenlong Yu, Xiangge Tian, Yuling Peng, Zheng Sun, Chao Wang, Ning Tang, Bin Li, Yuqing Jian, Wei Wang, Xiaokui Huo, Xiaochi Ma
Melatonin is an endogenous indoleamine with a wide range of biological functions in the various organisms from bacteria to mammals. Evidence indicates that melatonin facilitates apoptosis in cancer cells and enhances the anti-tumor activity of chemotherapy in animals and clinical studies. However, the melatonin metabolism and the key metabolic targets in cancer cells still remain unknown. In this study, U118 and SH-SY5Y tumor cell lines were used to investigate the metabolic pathways of melatonin in cancer cells...
February 17, 2018: Journal of Pineal Research
https://www.readbyqxmd.com/read/29453687/impact-of-boosted-antiretroviral-therapy-on-the-pharmacokinetics-and-efficacy-of-clopidogrel-and-prasugrel-active-metabolites
#6
Niloufar Marsousi, Youssef Daali, Pierre Fontana, Jean-Luc Reny, Virginie Ancrenaz-Sirot, Alexandra Calmy, Serge Rudaz, Jules Alexandre Desmeules, Caroline Flora Samer
BACKGROUND AND OBJECTIVES: Prasugrel and clopidogrel are inhibitors of the ADP-P 2 Y 12 platelet receptor used in acute coronary syndrome patients. They require bioactivation via isoenzymes such as cytochrome P450 (CYP) 3A4, CYP2C19 and CYP2B6. Ritonavir and cobicistat are potent CYP3A inhibitors, prescribed as pharmacokinetic (PK) enhancers in the treatment of human immunodeficiency virus (HIV) infection. METHODS: In this study, the impact of boosted antiretroviral therapies (ARTs) on the PK of clopidogrel and prasugrel active metabolites (AMs), and on the efficacy of prasugrel and clopidogrel, were evaluated in a randomized crossover clinical trial...
February 16, 2018: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/29453492/application-of-physiologically-based-pharmacokinetic-modeling-to-the-prediction-of-drug-drug-and-drug-disease-interactions-for-rivaroxaban
#7
Ruijuan Xu, Weihong Ge, Qing Jiang
PURPOSE: Rivaroxaban is a direct oral anticoagulant with a large inter-individual variability. The present study is to develop a physiologically based pharmacokinetic (PBPK) model to predict several scenarios in clinical practice. METHODS: A whole-body PBPK model for rivaroxaban, which is metabolized by the cytochrome P450 (CYP) 3A4/5, 2J2 pathways and excreted via kidneys, was developed to predict the pharmacokinetics at different doses in healthy subjects and patients with hepatic or renal dysfunction...
February 17, 2018: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29453199/simultaneous-assessment-of-clearance-metabolism-induction-and-drug-drug-interaction-potential-using-a-long-term-in-vitro-liver-model-for-a-novel-hepatitis-b-virus-inhibitor
#8
Nicole A Kratochwil, Miriam Triyatni, Martina B Mueller, Florian Klammers, Brian Leonard, Dan Turley, Josephine Schmaler, Aynur Ekiciler, Birgit Molitor, Isabelle Walter, Pierre-Alexis Gonsard, Charles A Tournillac, Alexandre Durrwell, Michaela Marschmann, Russell Jones, Mohammed Ullah, Franziska Boess, Giorgio Ottaviani, Yuyan Yin, Neil J Parrott, Stephen Fowler
Long-term in vitro liver models are now widely explored for human hepatic metabolic clearance prediction, enzyme phenotyping, cross species metabolism, comparison of low clearance drugs as well as induction studies. Here, we present studies using a long-term liver model which show how metabolism and active transport, drug-drug interactions and enzyme induction in healthy and diseased states, e.g. hepatitis B virus (HBV) infection, may be assessed in a single test system to enable effective data integration for PBPK modeling...
February 16, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29452159/cyp27a1-acts-on-the-pre-vitamin-d3-photoproduct-lumisterol-producing-biologically-active-hydroxy-metabolites
#9
Robert C Tuckey, Wei Li, Dejian Ma, Chloe Y S Cheng, Katie M Wang, Tae-Kang Kim, Saowanee Jeayeng, Andrzej T Slominski
Prolonged exposure of the skin to UV radiation causes previtamin D3, the initial photoproduct formed by opening of the B ring of 7-dehydrocholesterol, to undergo a second photochemical reaction where the B-ring is reformed giving lumisterol3 (L3), a stereoisomer of 7-dehydrocholesterol. L3 was believed to be an inactive photoproduct of excessive UV radiation whose formation prevents excessive vitamin D production. Recently, we reported that L3 is present in serum and that CYP11A1 can act on L3 producing monohydroxy- and dihydroxy-metabolites which inhibit skin cell proliferation similarly to 1α,25-dihydroxyvitamin D3...
February 13, 2018: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/29451681/verification-of-a-physiologically-based-pharmacokinetic-model-of-ritonavir-to-estimate-drug-drug-interaction-potential-of-cyp3a4-substrates
#10
Ken-Ichi Umehara, Felix Huth, Christina S Won, Tycho Heimbach, Handan He
Ritonavir is one of several ketoconazole alternatives used to evaluate strong CYP3A4 inhibition potential in clinical drug-drug interaction (DDI) studies. In this study, four physiologically-based pharmacokinetic (PBPK) models of ritonavir as an in vivo time-dependent inhibitor of CYP3A4 were created and verified for the oral doses of 20, 50, 100 and 200 mg using fraction absorbed (Fa) and oral clearance (CLoral) values reported in the literature, as transporter and CYP enzyme reaction phenotyping data were not available...
February 16, 2018: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/29451361/development-of-a-focused-library-of-triazole-linked-privileged-structure-based-conjugates-leading-to-the-discovery-of-novel-phenotypic-hits-against-protozoan-parasitic-infections
#11
Elisa Uliassi, Lorna Piazzi, Federica Belluti, Andrea Mazzanti, Marcel Kaiser, Reto Brun, Carolina B Moraes, Lucio H Freitas-Junior, Sheraz Gul, Maria Kuzikov, Bernhard Ellinger, Chiara Borsari, Maria Paola Costi, Maria Laura Bolognesi
Protozoan infections caused by Plasmodium, Leishmania, and Trypanosoma spp. contribute significantly to the burden of infectious diseases worldwide, causing severe morbidity and mortality. The inadequacy of available treatments calls for cost- and time-effective drug discovery endeavors. To this end, we envisaged the triazole linkage of privileged structures as an effective drug design strategy to generate a focused library of high-quality compounds. The versatility of this approach was combined with the feasibility of a phenotypic assay, integrated with early ADME-tox profiling...
February 16, 2018: ChemMedChem
https://www.readbyqxmd.com/read/29451034/cytochrome-p450-in-the-central-nervous-system-as-a-therapeutic-target-in-neurodegenerative-diseases
#12
Cynthia Navarro-Mabarak, Rafael Camacho-Carranza, Jesús Javier Espinosa-Aguirre
Cytochromes P450 (CYPs) constitute a family of enzymes that can be found in the endoplasmic reticulum (ER), mitochondria or the cell surface of the cells. CYPs are characterized by carrying out the oxidation of organic compounds and they are mainly recognized as mediators of the biotransformation of xenobiotics to polar hydrophilic metabolites that can be eliminated from the organism. However, these enzymes play a key role in many other physiological processes, being involved in diverse indispensable metabolic pathways since they metabolize many endogenous substrates...
February 16, 2018: Drug Metabolism Reviews
https://www.readbyqxmd.com/read/29449808/suppressive-effects-of-clerodendrum-volubile-p-beauv-labiatae-methanolic-extract-and-its-fractions-on-type-2-diabetes-and-its-complications
#13
Ochuko L Erukainure, Rahman M Hafizur, Nurul Kabir, M Iqbal Choudhary, Olubunmi Atolani, Priyanka Banerjee, Robert Preissner, Chika I Chukwuma, Aliyu Muhammad, Eric O Amonsou, Md Shahidul Islam
Type 2 diabetes is the most prominent of all diabetes types, contributing to global morbidity and mortality. Availability and cost of treatment with little or no side effect especially in developing countries, remains a huge burden. This has led to the search of affordable alternative therapies especially from medicinal plants. In this study, the antidiabetic effect of the methanolic extract, dichloromethane (DCM), butanol (BuOH) and aqueous fractions of Clerodendrum volubile leaves were investigated in type 2 diabetic rats for their effect on glucose homeostasis, serum insulin level and hepatic biomarkers, lipid profile, pancreatic redox balance and Ca 2+ levels, and β-cell distribution and function...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29449127/evaluating-the-effect-of-six-proton-pump-inhibitors-on-the-antiplatelet-effects-of-clopidogrel
#14
Eugene R Przespolewski, Erica S Westphal, Michelle Rainka, Nicholas M Smith, Vernice Bates, Fran M Gengo
BACKGROUND AND GOAL: Cytochrome P450 (CYP) enzymes are responsible for the conversion of clopidogrel into its active metabolite and the metabolism of proton pump inhibitors (PPIs), which may also inhibit CYP enzymes. A current Food and Drug Administration advisory suggests avoiding esomeprazole and omeprazole while taking clopidogrel because of concerns that PPIs may compromise clopidogrel's antiplatelet effects. The objective of the present study was to examine the robustness of this interaction using a well-controlled study design in a population of participants free of confounders...
February 12, 2018: Journal of Stroke and Cerebrovascular Diseases: the Official Journal of National Stroke Association
https://www.readbyqxmd.com/read/29445375/the-role-of-cytochromes-p450-in-infection
#15
REVIEW
Elisavet Stavropoulou, Gratiela G Pircalabioru, Eugenia Bezirtzoglou
Cytochromes are expressed in many different tissues of the human body. They are found mostly in intestinal and hepatic tissues. Cytochromes P450 (CYPs) are enzymes that oxidize substances using iron and are able to metabolize a large variety of xenobiotic substances. CYP enzymes are linked to a wide array of reactions including and O-dealkylation, S-oxidation, epoxidation, and hydroxylation. The activity of the typical P450 cytochrome is influenced by a variety of factors, such as genus, environment, disease state, herbicide, alcohol, and herbal medications...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29445054/comparison-of-drug-metabolism-and-its-related-hepatotoxic-effects-in-heparg-cryopreserved-human-hepatocytes-and-hepg2-cell-cultures
#16
Yuichi Yokoyama, Yoshifumi Sasaki, Natsuko Terasaki, Taku Kawataki, Koji Takekawa, Yumiko Iwase, Toshinobu Shimizu, Seigo Sanoh, Shigeru Ohta
Differentiated HepaRG cells maintain liver-specific functions such as drug-metabolizing enzymes. In this study, the feasibility of HepaRG cells as a human hepatocyte model for in vitro toxicity assessment was examined using selected hepatotoxic compounds. First, basal drug-metabolizing enzyme activities (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, uridine 5'-diphospho-glucuronosyltransferase [UGT], and sulfotransferases [SULT]) were measured in HepaRG, human hepatocytes, and HepG2 cells. Enzyme activities in differentiated HepaRG cells were comparable to those in human hepatocytes and much higher than those in HepG2 cells, except for SULT activity...
February 14, 2018: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/29441980/computational-prediction-of-new-cyp17-inhibitors-based-on-pharmacophore-modeling-virtual-screening-and-docking-approach
#17
S Haidar, R W Hartmann
17α-Hydroxylase/C17-20-lyase (P450 17, CYP 17) is an important enzyme in the androgen biosynthesis and inhibitors of this enzyme can be used for the treatment of prostate cancer. With the aim of developing new inhibitors for the target enzyme, we generated a structure-based pharmacophore model to further explain the binding requirements for human CYP17 inhibitors. Seven common features of steroidal CYP17 inhibitors were determined using MOE software. This pharmacophore model was then used to search the Cambridge Structural Database (CSD) with the aim of developing more potent and selective CYP17 inhibitors by identifying new hits...
September 1, 2017: Die Pharmazie
https://www.readbyqxmd.com/read/29441960/carbamazepine-10-11-epoxidation-in-human-liver-microsomes-influence-of-the-cyp3a5-3-polymorphism
#18
Y Miyata-Nozaka, S Mohd Zain, M Taguchi, M Shigeyama, T Isobe, N Hanioka
Carbamazepine (CBZ) is a commonly prescribed antiepileptic drug, and is mainly metabolized to 10,11-CBZ epoxide in humans. Its biotransformation is catalyzed by cytochrome P450 (CYP) enzymes, with the predominant isoforms being CYP3A4 and CYP3A5. In the present study, the effects of the CYP3A5*3 (rs776746) polymorphism on CBZ 10,11-epoxidation in human liver microsomes genotyped as CYP3A5*3 were examined using a kinetic analysis. The kinetics for CBZ 10,11-epoxidation fit the Hill model with n of approximately 1...
December 1, 2017: Die Pharmazie
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
#19
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/29439676/evolution-of-cyp2j19-a-gene-involved-in-colour-vision-and-red-coloration-in-birds-positive-selection-in-the-face-of-conservation-and-pleiotropy
#20
Hanlu Twyman, Staffan Andersson, Nicholas I Mundy
BACKGROUND: Exaggerated signals, such as brilliant colours, are usually assumed to evolve through antagonistic coevolution between senders and receivers, but the underlying genetic mechanisms are rarely known. Here we explore a recently identified "redness gene", CYP2J19, that is highly interesting in this context since it encodes a carotenoid-modifying enzyme (a C4 ketolase involved in both colour signalling and colour discrimination in the red (long wavelength) spectral region...
February 13, 2018: BMC Evolutionary Biology
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