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https://www.readbyqxmd.com/read/29160833/taxon-and-site-specific-melatonin-catabolism
#1
REVIEW
Rüdiger Hardeland
Melatonin is catabolized both enzymatically and nonenzymatically. Nonenzymatic processes mediated by free radicals, singlet oxygen, other reactive intermediates such as HOCl and peroxynitrite, or pseudoenzymatic mechanisms are not species- or tissue-specific, but vary considerably in their extent. Higher rates of nonenzymatic melatonin metabolism can be expected upon UV exposure, e.g., in plants and in the human skin. Additionally, melatonin is more strongly nonenzymatically degraded at sites of inflammation...
November 21, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29160300/genome-wide-association-study-identifies-the-common-variants-in-cyp3a4-and-cyp3a5-responsible-for-variation-in-tacrolimus-trough-concentration-in-caucasian-kidney-transplant-recipients
#2
W S Oetting, B Wu, D P Schladt, W Guan, R P Remmel, R B Mannon, A J Matas, A K Israni, P A Jacobson
The immunosuppressant tacrolimus (TAC) is metabolized by both cytochrome P450 3A4 (CYP3A4) and CYP3A5 enzymes. It is common for European Americans (EA) to carry two CYP3A5 loss-of-function (LoF) variants that profoundly reduces TAC metabolism. Despite having two LoF alleles, there is still considerable variability in TAC troughs and identifying additional variants in genes outside of the CYP3A5 gene could provide insight into this variability. We analyzed TAC trough concentrations in 1345 adult EA recipients with two CYP3A5 LoF alleles in a genome-wide association study...
November 21, 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/29160125/effects-of-paeoniflorin-on-the-activities-and-mrna-expression-of-rat-cyp1a2-cyp2c11-and-cyp3a1-enzymes-in-vivo
#3
Sicong Li, Xuting Li, Dingsheng Yuan, Bin Wang, Rui Yang, Min Zhang, Jinliang Li, Fuqiang Zeng
1. Paeoniflorin is the major constituent in extracts of the peony root, the purpose of the present study was to assess the effects of paeoniflorin on the activities and mRNA expression of the rat hepatic drug-metabolizing enzymes cytochrome P450 (CYP1A2), CYP2C11 and CYP3A1 in vivo. 2. Sprague-Dawley (SD) male rats were treated with paeoniflorin at the dosage of 25, 50 and 100 mg/kg or 0.9% sodium chloride solution by intragastric administration for 7 days, then were given probe drugs phenacetin (CYP1A2), tolbutamide (CYP2C11), or midazolam (CYP3A1) orally on the eighth day...
November 21, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29159825/modulation-of-the-intestinal-bile-acid-fxr-fgf15-axis-improves-alcoholic-liver-disease-in-mice
#4
Phillipp Hartmann, Katrin Hochrath, Angela Horvath, Peng Chen, Caroline T Seebauer, Cristina Llorente, Lirui Wang, Yazen Alnouti, Derrick E Fouts, Peter Stärkel, Rohit Loomba, Sally Coulter, Christopher Liddle, Ruth T Yu, Lei Ling, Stephen J Rossi, Alex M DePaoli, Michael Downes, Ronald M Evans, David A Brenner, Bernd Schnabl
Alcoholic liver disease is associated with changes in the intestinal microbiota. Functional consequences of alcohol-associated dysbiosis are largely unknown. The aim of this study was to identify a mechanism of how changes in the intestinal microbiota contribute to alcoholic liver disease. Metagenomic sequencing of intestinal contents demonstrated that chronic ethanol feeding in mice is associated with an overrepresentation of bacterial genomic DNA encoding choloylglycine hydrolase, which deconjugates bile acids in the intestine...
November 21, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/29158519/biosynthesis-of-helvolic-acid-and-identification-of-an-unusual-c-4-demethylation-process-distinct-from-sterol-biosynthesis
#5
Jian-Ming Lv, Dan Hu, Hao Gao, Tetsuo Kushiro, Takayoshi Awakawa, Guo-Dong Chen, Chuan-Xi Wang, Ikuro Abe, Xin-Sheng Yao
Fusidane-type antibiotics represented by helvolic acid, fusidic acid and cephalosporin P1 are a class of bacteriostatic agents, which have drawn renewed attention because they have no cross-resistance to commonly used antibiotics. However, their biosynthesis is poorly understood. Here, we perform a stepwise introduction of the nine genes from the proposed gene cluster for helvolic acid into Aspergillus oryzae NSAR1, which enables us to isolate helvolic acid (~20 mg L(-1)) and its 21 derivatives. Anti-Staphylococcus aureus assay reveals that the antibacterial activity of three intermediates is even stronger than that of helvolic acid...
November 21, 2017: Nature Communications
https://www.readbyqxmd.com/read/29158357/evidence-for-a-role-of-vascular-endothelium-in-the-control-of-arterial-wall-viscosity-in-humans
#6
Frederic Roca, Michele Iacob, Isabelle Remy-Jouet, Jeremy Bellien, Robinson Joannides
Arterial wall viscosity (AWV) is a major cause of energy dissipation along the arterial tree. Its determinants remain controversial but an active endothelial regulation has been suggested. Our objective was to assess in humans the physiological role of endothelium-derived nitric oxide (NO), epoxyeicosatrienoic acids and the effect of modulating smooth muscle tone in the regulation of AWV. We simultaneously measured radial artery diameter, wall thickness, and arterial pressure in healthy volunteers during the local infusion of inhibitors of NO-synthase (N(G)-monomethyl-l-arginine), epoxyeicosatrienoic acids synthesis by cytochrome P450 (fluconazole), the epoxyeicosatrienoic acids cellular targets calcium-activated potassium channels (tetraethylammonium), alone and in combination...
November 20, 2017: Hypertension
https://www.readbyqxmd.com/read/29158256/heart-failure-induced-activation-of-phospholipase-ipla2%C3%AE-%C3%A2-generates-hydroxyeicosatetraenoic-acids-opening-the-mitochondrial-permeability-transition-pore
#7
Sung Ho Moon, Xinping Liu, Ari M Cedars, Kui Yang, Michael A Kiebish, Susan M Joseph, John Kelley, Christopher M Jenkins, Richard W Gross
Congestive heart failure typically arises from cardiac myocyte necrosis/apoptosis, associated with the pathological opening of the mitochondrial permeability transition pore (mPTP). mPTP opening decreases the mitochondrial membrane potential leading to the activation of Ca(2+)-independent phospholipase A2γ (iPLA2γ) and the production of downstream toxic metabolites. However, the array of enzymatic mediators and the exact chemical mechanisms responsible for modulating myocardial mPTP opening remain unclear...
November 20, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29158022/activation-of-the-nrf2-signaling-pathway-and-neuroprotection-of-nigral-dopaminergic-neurons-by-a-novel-synthetic-compound-kms99220
#8
Ji Ae Lee, Hyo Jin Son, Ji Won Choi, Jinwoo Kim, Se Hee Han, Nari Shin, Ji Hyun Kim, Soo Jeong Kim, Jun Young Heo, Dong Jin Kim, Ki Duk Park, Onyou Hwang
The transcription factor Nrf2 is known to induce gene expression of antioxidant enzymes and proteasome subunits. Because both oxidative stress and protein aggregation have damaging effects on neurons, activation of the Nrf2 signaling should be beneficial against neurodegeneration. In this study, we report a novel synthetic morpholine-containing chalcone KMS99220 that confers neuroprotection. It showed high binding affinity to the Nrf2 inhibitory protein Keap-1 and increased nuclear translocation of Nrf2 and gene expression of the antioxidant enzymes heme oxygenase-1, NAD(P)H:quinone oxidoreductase-1, and the catalytic and modifier subunits of glutamate-cysteine ligase in dopaminergic CATH...
November 17, 2017: Neurochemistry International
https://www.readbyqxmd.com/read/29157826/modulation-of-pregnane-x-receptor-pxr-and-constitutive-androstane-receptor-car-activation-by-ursolic-acid-ua-attenuates-rifampin-isoniazid-cytotoxicity
#9
Hsiao-Yun Chang, Chao-Jung Chen, Wei-Chih Ma, Wai-Kok Cheng, Yen-Ning Lin, Ying-Ray Lee, Jih-Jung Chen, Yun-Ping Lim
BACKGROUND: Interactions between transcriptional inducers of cytochrome P450 (CYP450) enzymes and therapeutic drugs may be prevented by antagonizing the activation of a nuclear receptor (NR), pregnane X receptor (PXR, NR1I2), thus improving therapeutic efficacy. PURPOSE: In the present study, we aim to identify that ursolic acid (UA), a widely distributed pentacyclic triterpene, may act as an effective antagonist of PXR and its sister NR receptor, constitutive androstane receptor (CAR, NR1I3)...
December 1, 2017: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
https://www.readbyqxmd.com/read/29157132/in-planta-functions-of-cytochrome-p450-monooxygenase-genes-in-the-phytocassane-biosynthetic-gene-cluster-on-rice-chromosome-2
#10
Zhongfeng Ye, Kohei Yamazaki, Hiromi Minoda, Koji Miyamoto, Sho Miyazaki, Hiroshi Kawaide, Arata Yajima, Hideaki Nojiri, Hisakazu Yamane, Kazunori Okada
In response to environmental stressors such as blast fungal infections, rice produces phytoalexins, an antimicrobial diterpenoid compound. Together with momilactones, phytocassanes are among the major diterpenoid phytoalexins. The biosynthetic genes of diterpenoid phytoalexin are organized on the chromosome in functional gene clusters, comprising diterpene cyclase, dehydrogenase, and cytochrome P450 monooxygenase genes. Their functions have been studied extensively using in vitro enzyme assay systems. Specifically, P450 genes (CYP71Z6, Z7; CYP76M5, M6, M7, M8) on rice chromosome 2 have multifunctional activities associated with ent-copalyl diphosphate-related diterpene hydrocarbons, but the in planta contribution of these genes to diterpenoid phytoalexin production remains unknown...
November 20, 2017: Bioscience, Biotechnology, and Biochemistry
https://www.readbyqxmd.com/read/29157013/prediction-of-metabolites-of-epoxidation-reaction-in-metatox
#11
A V Rudik, A V Dmitriev, V M Bezhentsev, A A Lagunin, D A Filimonov, V V Poroikov
Biotransformation is a process of the chemical modifications which may lead to the reactive metabolites, in particular the epoxides. Epoxide reactive metabolites may cause the toxic effects. The prediction of such metabolites is important for drug development and ecotoxicology studies. Epoxides are formed by some oxidation reactions, usually catalysed by cytochromes P450, and represent a large class of three-membered cyclic ethers. Identification of molecules, which may be epoxidized, and indication of the specific location of epoxide functional group (which is called SOE - site of epoxidation) are important for prediction of epoxide metabolites...
November 20, 2017: SAR and QSAR in Environmental Research
https://www.readbyqxmd.com/read/29156454/site-selective-and-stereoselective-functionalization-of-non-activated-tertiary-c-h-bonds
#12
Kuangbiao Liao, Thomas C Pickel, Vyacheslav Boyarskikh, John Bacsa, Djamaladdin G Musaev, Huw M L Davies
The synthesis of complex organic compounds usually relies on controlling the reactions of the functional groups. In recent years, it has become possible to carry out reactions directly on the C-H bonds, previously considered to be unreactive. One of the major challenges is to control the site-selectivity because most organic compounds have many similar C-H bonds. The most well developed procedures so far rely on the use of substrate control, in which the substrate has one inherently more reactive C-H bond or contains a directing group or the reaction is conducted intramolecularly so that a specific C-H bond is favoured...
November 20, 2017: Nature
https://www.readbyqxmd.com/read/29155491/variation-in-the-response-of-clozapine-biotransformation-pathways-in-human-hepatic-microsomes-to-cyp1a2-and-cyp3a4-selective-inhibitors
#13
Michael Murray, Wei V Zhang, Robert J Edwards
The atypical antipsychotic agent clozapine (CLZ) is effective in many patients who are resistant to conventional antipsychotic drugs. Cytochromes P450 (CYPs) 1A2 and 3A4 oxidise CLZ to norCLZ and CLZ N-oxide in human liver. Concurrent treatment with inducers and inhibitors of CYP1A2 modulates CLZ elimination that disrupts therapy. Drug-drug interactions involving CYP3A4 are also significant but less predictable. To further characterise the factors underlying these interactions, we used samples from a cohort of human livers to assess variation in CLZ oxidation pathways in relation to intrinsic CYP3A4 and CYP1A2 activities and the effects of the corresponding selective inhibitors ketoconazole (0...
November 20, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/29154136/transcriptional-activity-of-detoxification-genes-is-altered-by-ultraviolet-filters-in-chironomus-riparius
#14
José-Luis Martínez-Guitarte
Ultraviolet (UV) filters are compounds used to prevent the damage produced by UV radiation in personal care products, plastics, etc. They have been associated with endocrine disruption, showing anti-estrogen activity in vertebrates and altering the ecdysone pathway in invertebrates. Although they have attracted the attention of multiple research teams there is a lack of data about how animals activate detoxification systems, especially in invertebrates. Here, analysis of the effects of two UV filters, benzophenone-3 (BP3) and 4-methylbenzylidene camphor (4MBC), on the transcriptional activity of nine genes covering the three steps of the detoxification process has been performed...
November 15, 2017: Ecotoxicology and Environmental Safety
https://www.readbyqxmd.com/read/29152048/structure-based-design-and-synthesis-of-new-estrane-pyridine-derivatives-as-cytochrome-p450-cyp-1b1-inhibitors
#15
Raphaël Dutour, Francisco Cortés-Benítez, Jenny Roy, Donald Poirier
Inhibition of cytochrome P450 (CYP) 1B1 is a promising therapeutic strategy, as such an inhibitor could modulate the bioactivation of procarcinogens while reducing drug resistance. Based on docking studies, the synthesis of 12 estra-1,3,5(10)-triene derivatives containing a pyridin-3-/4-yl moiety at position C2, C3, or C4 was performed, and we measured their inhibitory activity on CYP1B1 using the ethoxyresorufin-O-deethylase (EROD) assay. The position of the nitrogen atom in the aromatic ring has little influence on their inhibition potency, but compounds with a pyridinyl at C2 of the steroid nucleus are more potent CYP1B1 inhibitors than those with a pyridinyl at C3 or C4...
November 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29151343/deuterium-labelling-studies-reveal-the-mechanism-of-cytochrome-p450-catalyzed-formation-of-2-aminoacetophenone-from-3-methyl-indole-skatole-in-porcine-liver-microsomes
#16
Christoph Gerlach, Matthias Wuest
2-Aminoacetophenone, a product of the hepatic 3-methylindole (skatole) clearance in pigs, contributes to the specific aroma of fat from tainted boar meat. Surprisingly, high formation rates for 2-aminoacetophenone from 3-methylindole in microsomal preparations from Pietrain × Baden-Württemberg hybrid type boars have been previously demonstrated but the mechanism of this cytochrome P450-mediated reaction remained unknown. Therefore, microsomal fractions from boars were incubated with deuterium labelled skatole and with possible reaction intermediates...
November 18, 2017: Journal of Agricultural and Food Chemistry
https://www.readbyqxmd.com/read/29150709/simultaneous-detection-of-nadph-consumption-and-h2o2-production-using-the-ampliflu%C3%A2-red-assay-for-screening-of-p450-activities-and-uncoupling
#17
Lisa K Morlock, Dominique Böttcher, Uwe T Bornscheuer
Cytochrome P450s belong to a large and diverse group of heme-containing enzymes. These monooxygenases catalyze the incorporation of a single atom of molecular oxygen into their substrate. In contrast to most other enzymes, the activity of P450 enzymes is not only dependent on substrate and cofactor availability and reaction conditions, but also depends on the coupling efficiency of the catalytic cycle itself. Through the electron transfer from NAD(P)H to the heme-center of the P450, the enzyme becomes activated and binds oxygen...
November 17, 2017: Applied Microbiology and Biotechnology
https://www.readbyqxmd.com/read/29150398/glycyrrhiza-glabra-extract-and-quercetin-reverses-cisplatin-resistance-in-triple-negative-mda-mb-468-breast-cancer-cells-via-inhibition-of-cytochrome-p450-1b1-enzyme
#18
Rajni Sharma, Linda Gatchie, Ibidapo S Williams, Shreyans K Jain, Ram A Vishwakarma, Bhabatosh Chaudhuri, Sandip B Bharate
The development of multi-drug resistance to existing anticancer drugs is one of the major challenges in cancer treatment. The over-expression of cytochrome P450 1B1 enzyme has been reported to cause resistance to cisplatin. With an objective to discover cisplatin-resistance reversal agents, herein, we report the evaluation of Glycyrrhiza glabra (licorice) extracts and its twelve chemical constituents for inhibition of CYP1B1 (and CYP1A1) enzyme in Sacchrosomes and live human cells. The hydroalcoholic extract showed potent inhibition of CYP1B1 in both Sacchrosomes as well as in live cells with IC50 values of 21 and 16 µg/mL, respectively...
November 7, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29149962/impact-of-acute-infection-requiring-hospitalization-on-tacrolimus-blood-levels-in-kidney-transplant-recipients
#19
C Percy, Z Hassoun, M Mourad, M De Meyer, C Beguin, M Jadoul, E Goffin, P Wallemacq, N Kanaan
BACKGROUND: Tacrolimus is metabolized by members of the cytochrome p450 3A subfamily, and its bioavailability depends also on P-glycoprotein. We have observed that some patients admitted for infection presented with increased tacrolimus trough levels (TLs). The aim of the study was to assess the impact of infection on tacrolimus TLs and to determine the factors involved in TL fluctuations. METHODS: This retrospective cohort study included patients transplanted with a kidney between 2009 and 2011 who were hospitalized for an acute infection...
November 2017: Transplantation Proceedings
https://www.readbyqxmd.com/read/29149798/reconstructing-biosynthetic-pathway-of-the-plant-derived-cancer-chemopreventive-precursor-glucoraphanin-in-escherichia-coli
#20
Han Yang, Feixia Liu, Yin Li, Bo Yu
Epidemiological data confirmed a strong correlation between regular consumption of cruciferous vegetables and lower cancer risk. This cancer preventive property is mainly attributed to the glucosinolate products, such as glucoraphanin found in broccoli that is derived from methionine. Here we report the first successful reconstruction of the complete biosynthetic pathway of glucoraphanin from methionine in Escherichia coli via gene selection, pathway design, and protein engineering. We used branched-chain amino transferase 3 to catalyze two transamination steps to ensure the purity of precursor molecules and used cysteine as a sulfur donor to simplify the synthesis pathway...
November 17, 2017: ACS Synthetic Biology
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