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cytochrom p450

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https://www.readbyqxmd.com/read/29240409/from-experiments-to-a-fast-easy-to-use-computational-methodology-to-predict-human-aldehyde-oxidase-selectivity-and-metabolic-reactions
#1
Gabriele Cruciani, Nicolò Milani, Paolo Benedetti, Susan Lepri, Lucia Cesarini, Massimo Baroni, Francesca Spyrakis, Sara Tortorella, Edoardo Mosconi, Laura Goracci
Aldehyde oxidase (AOX) is a molibdo-flavoenzyme that raised great interest in recent years, since its contribution in xenobiotics metabolism has not always been identified before clinical trials, with consequent negative effects on the fate of new potential drugs. The fundamental role of AOX in metabolizing xenobiotics is also due to the attempt of medicinal chemists to stabilize candidates toward cytochrome P450 activity, which increases the risk for new compounds to be susceptible to AOX nucleophile attack...
December 14, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29238104/indole-3-propionic-acid-suppresses-indoxyl-sulfate-induced-expression-of-fibrotic-and-inflammatory-genes-in-proximal-tubular-cells
#2
Maimaiti Yisireyili, Kyosuke Takeshita, Shinichi Saito, Toyoaki Murohara, Toshimitsu Niwa
Indoxyl sulfate (IS) induces fibrosis and inflammation in kidneys via oxidative stress through the induction of transforming growth factor-β1 (TGF-β1) and monocyte chemotactic protein-1 (MCP-1). Furthermore, IS is a potent endogenous agonist for aryl hydrocarbon receptor (AHR), which regulates the transcription of genes such as cytochrome P450 (CYP) 1A1. Indole-3-propionic acid (IPA) is an antioxidant and has been reported to be neuroprotective. We determined whether IPA suppresses IS-induced expression of AHR, CYP1A1, TGF-β1, and MCP-1 in proximal tubular cells...
November 2017: Nagoya Journal of Medical Science
https://www.readbyqxmd.com/read/29237272/bioactive-lipids-and-redox-signaling-molecular-mechanism-and-disease-pathogenesis
#3
Pin Lan Li, Erich Gulbins
SIGNIFICANCE: The actions of bioactive lipids and reactive oxygen species (ROS) are usually coupled and their interplay is a common and important mechanism mediating tissue injury, inflammation and other pathologies. Understanding the interplay of ROS and lipid mediators will extend horizons for researchers to clarify the pathogenesis of different diseases and help identify therapeutic targets for treatment of these diseases. Recent Advances: Some bioactive lipids are converted into oxidized lipids during cell or tissue oxidative stress such as isoprostanes and isoketals, which are even more bioactive compared to their precursors...
December 14, 2017: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/29237270/manganese-v-porphycene-complex-responsible-for-inert-c-h-bond-hydroxylation-in-a-myoglobin-matrix
#4
Koji Oohora, Hiroyuki Meichin, Yushi Kihira, Hiroshi Sugimoto, Yoshitsugu Shiro, Takashi Hayashi
A mechanistic study of H2O2-dependent C-H bond hydroxylation by myoglobin reconstituted with a manganese porphycene was carried out. The X-ray crystal structure of the reconstituted protein obtained at 1.5 Å resolution reveals tight incorporation of the complex into the myoglobin matrix at pH 8.5, the optimized pH value for the highest turnover number of hydroxylation of ethylbenzene. The protein generates a spectroscopically detectable two-electron oxidative intermediate in a reaction with peracid, which has a half-life up to 38 s at 10 °C...
December 14, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29236081/pharmacogenomics-guided-personalization-of-warfarin-and-tamoxifen
#5
REVIEW
Theodore J Wigle, Laura E Jansen, Wendy A Teft, Richard B Kim
The use of pharmacogenomics to personalize drug therapy has been a long-sought goal for warfarin and tamoxifen. However, conflicting evidence has created reason for hesitation in recommending pharmacogenomics-guided care for both drugs. This review will provide a summary of the evidence to date on the association between cytochrome P450 enzymes and the clinical end points of warfarin and tamoxifen therapy. Further, highlighting the clinical experiences that we have gained over the past ten years of running a personalized medicine program, we will offer our perspectives on the utility and the limitations of pharmacogenomics-guided care for warfarin and tamoxifen therapy...
December 13, 2017: Journal of Personalized Medicine
https://www.readbyqxmd.com/read/29233819/characterization-of-interactions-among-cyp1a2-cyp2b4-and-nadph-cytochrome-p450-reductase-identification-of-specific-protein-complexes
#6
John Patrick Connick, James R Reed, Wayne L Backes
Cytochromes P450 catalyze oxygenation reactions via interactions with their redox partners. However, other proteins, particularly other P450s, also have been shown to form complexes that modulate P450 function. Previous studies showed that CYP1A2 and CYP2B4 form a complex when reconstituted into phospholipid vesicles; however, details of the interactions among the P450s and NADPH-cytochrome P450 reductase have not been fully characterized. The goal of this study was to examine P450 complex formation in living cells, using bioluminescence resonance energy transfer (BRET)...
December 12, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29233455/genetic-variation-of-cytochrome-p450-in-uyghur-chinese-population
#7
Guangzhao Qi, Duolu Li, Xiaojian Zhang
Interindividual and interethnic variability of drug responses could be attributed to the differences of genetic polymorphisms in the drug metabolizing enzymes and transporters genes among the populations. Here we reviewed the studies of genetic variations in Uyghur Chinese of fifteen CYP450 genes including CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP2J2, CYP2W1, CYP3A4, CYP3A5, CYP4A11, and CYP17A1, which totally covered 277 variants. We also collected the data of 277 variants covered in our study in two extensive population sequencing projects, the International HapMap Project (Hap-Map) and the 1000 Genomes Project and compared them with the data of Uyghur Chinese...
March 6, 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29232328/novel-cyp2a6-diplotypes-identified-through-next-generation-sequencing-are-associated-with-in-vitro-and-in-vivo-nicotine-metabolism
#8
Julie-Anne Tanner, Andy Z Zhu, Katrina G Claw, Bhagwat Prasad, Viktoriya Korchina, Jianhong Hu, HarshaVardhan Doddapaneni, Donna M Muzny, Erin G Schuetz, Caryn Lerman, Kenneth E Thummel, Steven E Scherer, Rachel F Tyndale
OBJECTIVES: Smoking patterns and cessation rates vary widely across smokers and can be influenced by variation in rates of nicotine metabolism [i.e. cytochrome P450 2A6 (CYP2A6), enzyme activity]. There is high heritability of CYP2A6-mediated nicotine metabolism (60-80%) owing to known and unidentified genetic variation in the CYP2A6 gene. We aimed to identify and characterize additional genetic variants at the CYP2A6 gene locus. METHODS: A new CYP2A6-specific sequencing method was used to investigate genetic variation in CYP2A6...
January 2018: Pharmacogenetics and Genomics
https://www.readbyqxmd.com/read/29232137/inhibition-of-human-cyp3a4-by-rationally-designed-ritonavir-like-compounds-impact-and-interplay-of-the-side-group-functionalities
#9
Eric R Samuels, Irina Sevrioukova
Structure-function relationships of nine rationally designed ritonavir-like compounds were investigated to better understand the ligand binding and inhibitory mechanism in human drug-metabolizing cytochrome P450 3A4 (CYP3A4). The analogs had a similar backbone and pyridine and tert-butyloxycarbonyl (Boc) as the heme-ligating and terminal groups, respectively. N-Isopropyl, N-cyclopentyl, or N-phenyl were the R1-side group substituents alone (compounds 5a-c) or in combination with phenyl or indole at the R2 position (8a-c and 8d-f subseries, respectively)...
December 12, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29229304/functional-characterization-of-the-g162r-and-d216h-genetic-variants-of-human-cyp17a1
#10
C P Capper, J Liu, L R McIntosh, J M Larios, M D Johnson, P F Hollenberg, Y Osawa, R J Auchus, J M Rae
Cytochrome P450 17A1 (CYP17A1) is a dual-function enzyme catalyzing reactions necessary for cortisol and androgen biosynthesis. CYP17A1 is a validated drug target for prostate cancer as CYP17A1 inhibition significantly reduces circulating androgens and improves survival in castration-resistant prostate cancer. Germline CYP17A1 genetic variants with altered CYP17A1 activity manifesting as various endocrinopathies are extremely rare; however, characterizing these variants provides critical insights into CYP17A1 protein structure and function...
December 8, 2017: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/29228347/exposure-of-mice-to-1-2-dichloropropane-induces-cyp450-dependent-proliferation-and-apoptosis-of-cholangiocytes
#11
Xiao Zhang, Cai Zong, Lingyi Zhang, Edwin Garner, Shigeyuki Sugie, Chinyen Huang, Wenting Wu, Jie Chang, Toshihiro Sakurai, Masashi Kato, Sahoko Ichihara, Shinji Kumagai, Gaku Ichihara
1, 2-Dichloropropane (1, 2-DCP) has been used as a paint remover in the industry. The International Agency for Research on Cancer reclassified this compound recently to Group 1 (carcinogenic to humans) based on epidemiological studies of cholangiocarcinoma among offset-color proof-printing workers exposed to 1, 2-DCP in Japan. Two-year rodent carcinogenicity bioassays demonstrated that 1, 2-DCP induced tumors in liver and lung, but not in bile duct. The present study was designed to assess the toxic effects of 1, 2-DCP on proliferation and apoptosis in mice bile duct and the role of cytochrome P450 (CYP450) in any such effect...
December 7, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/29228183/plasma-oxysterols-biomarkers-for-diagnosis-and-treatment-in-spastic-paraplegia-type-5
#12
Cecilia Marelli, Foudil Lamari, Dominique Rainteau, Alexandre Lafourcade, Guillaume Banneau, Lydie Humbert, Marie-Lorraine Monin, Elodie Petit, Rabab Debs, Giovanni Castelnovo, Elisabeth Ollagnon, Julie Lavie, Julie Pilliod, Isabelle Coupry, Patrick J Babin, Claire Guissart, Imen Benyounes, Urielle Ullmann, Gaetan Lesca, Christel Thauvin-Robinet, Pierre Labauge, Sylvie Odent, Claire Ewenczyk, Claude Wolf, Giovanni Stevanin, David Hajage, Alexandra Durr, Cyril Goizet, Fanny Mochel
The hereditary spastic paraplegias are an expanding and heterogeneous group of disorders characterized by spasticity in the lower limbs. Plasma biomarkers are needed to guide the genetic testing of spastic paraplegia. Spastic paraplegia type 5 (SPG5) is an autosomal recessive spastic paraplegia due to mutations in CYP7B1, which encodes a cytochrome P450 7α-hydroxylase implicated in cholesterol and bile acids metabolism. We developed a method based on ultra-performance liquid chromatography electrospray tandem mass spectrometry to validate two plasma 25-hydroxycholesterol (25-OHC) and 27-hydroxycholesterol (27-OHC) as diagnostic biomarkers in a cohort of 21 patients with SPG5...
December 8, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/29228021/inheritance-mode-and-mechanisms-of-resistance-to-imidacloprid-in-the-house-fly-musca-domestica-diptera-muscidae-from-china
#13
Zhuo Ma, Jing Li, Yi Zhang, Chao Shan, Xiwu Gao
Imidacloprid is a neonicotinoid insecticide that is effective against house fly, Musca domestica L., which is a major pest with the ability to develop resistance to insecticides. In the present study, we investigated the inheritance mode, the cross-resistance pattern and the mechanisms of resistance to imidacloprid. A near-isogenic house fly line (N-IRS) with 78-fold resistance to imidacloprid was used to demonstrate the mode of inheritance. The overlapping confidence limits of LC50 values and the slopes of the log concentration-probit lines between the reciprocal F1 and F1' progenies suggest that imidacloprid resistance is inherited autosomally in the house fly...
2017: PloS One
https://www.readbyqxmd.com/read/29227996/generation-and-phenotypic-characterisation-of-a-cytochrome-p450-4x1-knockout-mouse
#14
Himanshu Kharkwal, Farhat Batool, Frank Koentgen, David R Bell, David A Kendall, Francis J P Ebling, Ian R Duce
Cytochrome P450 4x1 (Cyp4x1) is expressed at very high levels in the brain but the function of this protein is unknown. It has been hypothesised to regulate metabolism of fatty acids and to affect the activity of endocannabinoid signalling systems, which are known to influence appetite and energy metabolism. The objective of the present investigation was to determine the impact of Cyp4x1 on body weight and energy metabolism by developing a line of transgenic Cyp4x1-knock out mice. Mice were developed with a global knock-out of the gene; the full-length RNA was undetectable, and mice were viable and fertile...
2017: PloS One
https://www.readbyqxmd.com/read/29227633/a-distal-loop-controls-product-release-chemo-and-regio-selectivity-in-cytochrome-p450-decarboxylases
#15
Jose A Amaya, Cooper D Rutland, Nic Leschinsky, Thomas M Makris
The cytochrome P450 OleT utilizes hydrogen peroxide (H2O2) to catalyze the decarboxylation or hydroxylation of fatty acid (FA) substrates. Both reactions are initiated through the abstraction of a substrate hydrogen atom by the high-valent iron-oxo intermediate known as Compound I. Here, we specifically probe the influence of substrate coordination on OleT reaction partitioning through the combined use of fluorescent and EPR-active FA probes, and mutagenesis of a structurally disordered F-G loop that is distal from the heme-iron active-site...
December 11, 2017: Biochemistry
https://www.readbyqxmd.com/read/29227563/expression-and-enzyme-activity-of-cytochrome-p450-enzymes-cyp3a4-and-cyp3a5-in-human-skin-and-tissue-engineered-skin-equivalents
#16
Sarah A Smith, Helen E Colley, Parveen Sharma, Klaudia M Slowik, Rowena Sison-Young, Andrew Sneddon, Steven D Webb, Craig Murdoch
CYP3A4 and CYP4A5 share specificity for a wide range of xenobiotics with the CYP3 subfamily collectively involved in the biotransformation of approximately 30% of all drugs. CYP3A4/5 mRNA transcripts have been reported in the skin yet knowledge of their protein expression and function is lacking. In this study, we observed gene and protein expression of CYP3A4/5 in both human skin and tissue-engineered skin equivalents (TESE), and enzyme activity was detected using the model substrate benzyl-O-methyl-cyanocoumarin...
December 11, 2017: Experimental Dermatology
https://www.readbyqxmd.com/read/29227181/effects-of-fuel-components-and-combustion-particle-physicochemical-properties-on-toxicological-responses-of-lung-cells
#17
Isabel C Jaramillo, Anne Sturrock, Hossein Ghiassi, Diana J Woller, Cassandra E Deering-Rice, JoAnn S Lighty, Robert Paine, Christopher Reilly, Kerry E Kelly
The physicochemical properties of combustion particles that promote lung toxicity are not fully understood, hindered by the fact that combustion particles vary based on the fuel and combustion conditions. Real-world combustion-particle properties also continually change as new fuels are implemented, engines age, and engine technologies evolve. This work used laboratory-generated particles produced under controlled combustion conditions in an effort to understand the relationship between different particle properties and the activation of established toxicological outcomes in human lung cells (H441 and THP-1)...
December 11, 2017: Journal of Environmental Science and Health. Part A, Toxic/hazardous Substances & Environmental Engineering
https://www.readbyqxmd.com/read/29226313/model-based-assessments-of-cyp-mediated-drug-drug-interaction-risk-of-alectinib-physiologically-based-pharmacokinetic-modeling-supported-clinical-development
#18
Yumi Cleary, Michael Gertz, Peter N Morcos, Li Yu, Kuresh Youdim, Alex Phipps, Stephen Fowler, Neil Parrott
Alectinib is a selective anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of ALK-positive non-small cell lung cancer. Alectinib and its major active metabolite M4 exhibited drug-drug interaction (DDI) potential through cytochrome P450 (CYP) enzymes CYP3A4 and CYP2C8 in vitro. Clinical relevance of the DDI risk was investigated as part of a rapid development program to fulfil the breakthrough therapy designation. Therefore, a strategy with a combination of physiologically based pharmacokinetic (PBPK) modeling and limited clinical trials focused on generating informative data for modeling was taken to ensure extrapolation ability of DDI risk...
December 11, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29225727/the-genomic-study-of-an-environmental-isolate-of-scedosporium-apiospermum-shows-its-metabolic-potential-to-degrade-hydrocarbons
#19
Laura T Morales, Laura N González-García, María C Orozco, Silvia Restrepo, Martha J Vives
Crude oil contamination of soils and waters is a worldwide problem, which has been actively addressed in recent years. Sequencing genomes of microorganisms involved in the degradation of hydrocarbons have allowed the identification of several promoters, genes, and degradation pathways of these contaminants. This knowledge allows a better understanding of the functional dynamics of microbial degradation. Here, we report a first draft of the 44.2 Mbp genome assembly of an environmental strain of the fungus Scedosporium apiospermum...
2017: Standards in Genomic Sciences
https://www.readbyqxmd.com/read/29224921/effects-of-acrylamide-on-oxidant-antioxidant-parameters-and-cyp2e1-expression-in-rat-pancreatic-endocrine-cells
#20
Jelena Marković, Milena Stošić, Danijela Kojić, Milica Matavulj
Oxidative stress is one of the principle mechanism of acrylamide-induced toxicity. Acrylamide is metabolized by cytochrome P450 2E1 (CYP2E1) to glycidamide or by direct conjugation with glutathione. Bearing in mind that up to now the effects of acrylamide on oxidative stress status and CYP2E1 level in endocrine pancreas have not been studied we performed qualitative and quantitative immunohistochemical evaluation of inducible nitric oxide synthase (iNOS), superoxide dismutase 1 (SOD1), superoxide dismutase 2 (SOD2), catalase (CAT) and CYP2E1 expression in islets of Langerhans of rats subchronically treated with 25 or 50mg/kg bw of acrylamide...
December 7, 2017: Acta Histochemica
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