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https://www.readbyqxmd.com/read/29744741/effect-of-naltrexone-hydrochloride-on-cytochrome-p450-1a2-2c9-2d6-and-3a4-activity-in-human-liver-microsomes
#1
Haitham AlRabiah, Abdul Ahad, Gamal A E Mostafa, Fahad I Al-Jenoobi
BACKGROUND AND OBJECTIVE: Cytochrome P450 (CYP) 1A2, 2C9, 2D6, and 3A4 are the most important phase I drug-metabolizing enzymes in the liver, but there is a dearth of literature available on the effects of naltrexone hydrochloride on these major enzymes present in the human liver. Thus, in the present study, the effect of naltrexone hydrochloride on the activity of CYP1A2, 2C9, 2D6, and 3A4 using human liver microsomes (HLM) was investigated. METHODS: A selective probe for CYP1A2, 2C9, 2D6, and 3A4 was incubated with HLM with or without naltrexone hydrochloride...
May 9, 2018: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29726954/heterologous-co-expression-of-cyp6b7-and-nadph-dependent-cytochrome-p450-reductase-from-helicoverpa-armigera-lepidoptera-noctuidae-in-pichia-pastoris
#2
Chunqing Zhao, Genmiao Song, Kristopher Silver, Tao Tang, Chen Wang, Lihong Qiu
As important metabolic enzymes, the function of cytochrome P450 monooxygenases (CYPs) has been demonstrated repeatedly through various means, including heterologous expression systems. Unfortunately, most model systems typically lack expression of a conspecific NADPH-dependent cytochrome P450 reductase (CPR), which is the electron transfer partner of CYPs. As a result, the activities of heterologously expressed insect CYPs may not accurately reflect detoxification activities in vivo. Previously, CYP6B7 from Helicoverpa armigera (Hübner) (Lepidoptera: Noctuidae) (HaCYP6B7) has been expressed in the Pichia pastoris GS115 strain and shown to detoxify bifenthrin, fenvalerate and chlorpyrifos...
May 3, 2018: Journal of Economic Entomology
https://www.readbyqxmd.com/read/29719052/effect-of-single-walled-carbon-nanotubes-on-cytochrome-p450-activity-in-human-liver-microsomes-in-vitro
#3
Yuki Asai, Yukiko Sakakibara, Rina Inoue, Rikako Inoue, Masayuki Nadai, Miki Katoh
Single-walled carbon nanotubes (SWCNTs) are made from a rolled single sheet of graphene with a diameter in the nanometer range. SWCNTs are potential carriers for drug delivery systems because antibodies or drugs can be loaded on their surface; however, their effect on the activities of cytochrome P450 (CYP) remains unclear. The aim of this study was to investigate the effect of two kinds of SWCNTs with different lengths (FH-P- and SO-SWCNTs) on human CYP activity. In addition, other nano-sized carbon materials, such as carbon black, fullerene-C60 , and fullerene-C70 were also evaluated to compare their effects on CYP activities...
May 2, 2018: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/29671780/phytotoxic-and-antifungal-metabolites-from-curvularia-crepinii-qtyc-1-isolated-from-the-gut-of-pantala-flavescens
#4
Caiping Yin, Liping Jin, Feifei Sun, Xiao Xu, Mingwei Shao, Yinglao Zhang
Four metabolites ( 1 ⁻ 4 ), including a new macrolide, O -demethylated-zeaenol ( 2 ), and three known compounds, zeaenol ( 1 ), adenosine ( 3 ), and ergosta-5,7,22-trien-3b-ol ( 4 ) were isolated and purified from Curvularia crepinii QTYC-1, a fungus residing in the gut of Pantala flavescens . The structures of isolated compounds were identified on the basis of extensive spectroscopic analysis and by comparison of the corresponding data with those reported in the literature previously. The new compound 2 showed good phytotoxic activity against Echinochloa crusgalli with an IC50 value of less than 5 µg/mL, which was comparable to that of positive 2,4-dichlorophenoxyacetic acid (2,4-D)...
April 19, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29667811/in-vitro-and-in-vivo-studies-of-the-electrophilicity-of-physcion-and-its-oxidative-metabolites
#5
Xiaotong Qin, Ying Peng, Jiang Zheng
Physcion (1,8-dihydroxy-3-methoxy-6-methyl-9,10-anthracenedione) is a bioactive component found in Polygoni Multiflori Radix (PMR) which has been widely used as traditional Chinese medicine. Unfortunately, studies showed hepatotoxicity of PMR during its clinical use. The mechanisms of its toxic action remain unknown. The major objectives of this study were to characterize oxidative metabolites of physcion in vitro and in vivo and to determine the electrophilicity of the parent compound and its oxidative metabolites...
April 18, 2018: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/29655687/the-inhibitory-potential-of-broussochalcone-a-for-the-human-cytochrome-p450-2j2-isoform-and-its-anti-cancer-effects-via-foxo3-activation
#6
See-Hyoung Park, Jongsung Lee, Jong Cheol Shon, Nguyen Minh Phuc, Jun Goo Jee, Kwang-Hyeon Liu
BACKGROUND: Broussonetia papyrifera (L.) Ventenat, a traditional medicinal herb, has been applied as a folk medicine to treat various diseases. Broussochalcone A (BCA), a chalcone compound isolated from the cortex of Broussonetia papyrifera (L.) Ventenat, exhibits several biological activities including potent anti-oxidant, antiplatelet, and cytotoxic effects. PURPOSE: The purpose of this study is to elucidate the inhibitory effect of BCA against CYP2J2 enzyme which is predominantly expressed in human tumor tissues and carcinoma cell lines...
March 15, 2018: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
https://www.readbyqxmd.com/read/29627557/investigating-in-sewer-transformation-products-formed-from-synthetic-cathinones-and-phenethylamines-using-liquid-chromatography-coupled-to-quadrupole-time-of-flight-mass-spectrometry
#7
Juliet Kinyua, Noelia Negreira, Ann-Kathrin McCall, Tim Boogaerts, Christoph Ort, Adrian Covaci, Alexander L N van Nuijs
Recent studies have demonstrated the role of biofilms on the stability of drug residues in wastewater. These factors are pertinent in wastewater-based epidemiology (WBE) when estimating community-level drug use. However, there is scarce information on the biotransformation of drug residues in the presence of biofilms and the potential use of transformation products (TPs) as biomarkers in WBE. The purpose of this work was to investigate the formation of TPs in sewage reactors in the presence of biofilm mimicking conditions during in-sewer transport...
April 5, 2018: Science of the Total Environment
https://www.readbyqxmd.com/read/29549742/metabolism-of-the-synthetic-cannabinoids-amb-chmica-and-5c-akb48-in-pooled-human-hepatocytes-and-rat-hepatocytes-analyzed-by-uhplc-ims-hr-ms-e
#8
Marie Mardal, Petur Weihe Dalsgaard, Bing Qi, Christian Brinch Mollerup, Pieter Annaert, Kristian Linnet
The main analytical targets of synthetic cannabinoids are often metabolites. With the high number of new psychoactive substances entering the market, suitable workflows are needed for analytical target identification in biological samples. The aims of this study were to identify the main metabolites of the synthetic cannabinoids, AMB-CHMICA and 5C-AKB48, using an in silico-assisted workflow with analytical data acquired using ultra-high-performance liquid chromatography-(ion mobility spectroscopy)-high resolution-mass spectrometry in data-independent acquisition mode (UHPLC-(IMS)-HR-MSE )...
March 10, 2018: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/29433675/plant-natural-product-plumbagin-presents-potent-inhibitory-effect-on-human-cytochrome-p450-2j2-enzyme
#9
Jian Lu, Daozhi Liu, Xiaojing Zhou, Ang Chen, Zhenran Jiang, Xiyun Ye, Mingyao Liu, Xin Wang
BACKGROUND: Cytochrome P450 2J2 (CYP2J2) is not only highly expressed in many kinds of human tumors, but also promotes tumor cell growth via regulating the metabolism of arachidonic acids. CYP2J2 inhibitors can significantly reduce proliferation, migration and promote apoptosis of tumor cells by inhibiting epoxyeicosatrienoic acids (EETs) biosynthesis. Therefore screening CYP2J2 inhibitors is a significant way for the development of anti-cancer drug. PURPOSE: The aim of this study was to identify a new CYP2J2 inhibitor from fifty natural compounds obtained from plants...
January 15, 2018: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
https://www.readbyqxmd.com/read/29414024/metabolism-of-flavonolignans-in-human-hepatocytes
#10
Jiří Vrba, Barbora Papoušková, Lenka Roubalová, Martina Zatloukalová, David Biedermann, Vladimír Křen, Kateřina Valentová, Jitka Ulrichová, Jan Vacek
This study examined the in vitro biotransformation of eight structurally related flavonolignans, namely silybin, 2,3-dehydrosilybin, silychristin, 2,3-dehydrosilychristin, silydianin, 2,3-dehydrosilydianin, isosilybin A and isosilybin B. The metabolic transformations were performed using primary cultures of human hepatocytes and recombinant human cytochromes P450 (CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4). The metabolites produced were analyzed by ultra-performance liquid chromatography coupled with tandem mass spectrometry...
April 15, 2018: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/29408320/crystal-structure-of-thebaine-6-o-demethylase-from-the-morphine-biosynthesis-pathway
#11
Anna Kluza, Ewa Niedzialkowska, Katarzyna Kurpiewska, Zuzanna Wojdyla, Matthew Quesne, Ewa Kot, Przemyslaw J Porebski, Tomasz Borowski
Thebaine 6-O-demethylase (T6ODM) from Papaver somniferum (opium poppy), which belongs to the non-heme 2-oxoglutarate/Fe(II)-dependent dioxygenases (ODD) family, is a key enzyme in the morphine biosynthesis pathway. Initially, T6ODM was characterized as an enzyme catalyzing O-demethylation of thebaine to neopinone and oripavine to morphinone. However, the substrate range of T6ODM was recently expanded to a number of various benzylisoquinoline alkaloids. Here, we present crystal structures of T6ODM in complexes with 2-oxoglutarate (T6ODM:2OG, PDB: 5O9W) and succinate (T6ODM:SIN, PDB: 5O7Y)...
February 14, 2018: Journal of Structural Biology
https://www.readbyqxmd.com/read/29327072/naproxen-is-transformed-via-acetogenesis-and-syntrophic-acetate-oxidation-by-a-methanogenic-wastewater-consortium
#12
Sarah J Wolfson, Abigail W Porter, Julia K Campbell, Lily Y Young
Over-the-counter pharmaceutical compounds can serve as microbial substrates in wastewater treatment processes as well as in the environment. The metabolic pathways and intermediates produced during their degradation, however, are poorly understood. In this study, we investigate an anaerobic wastewater community that metabolizes naproxen via demethylation. Enriched cultures, established from anaerobic digester inocula receiving naproxen as the sole carbon source, transformed naproxen to 6-O-desmethylnaproxen (DMN) within 22 days...
January 11, 2018: Microbial Ecology
https://www.readbyqxmd.com/read/29311137/late-occurring-and-long-circulating-metabolites-of-gaba-a-%C3%AE-2-3-receptor-modulator-azd7325-involving-metabolic-cyclization-and-aromatization-relevance-to-mist-analysis-and-application-for-patient-compliance
#13
Chungang Gu, Markus Artelsmair, Charles S Elmore, Richard J Lewis, Patty Davis, James E Hall, Bruce T Dembofsky, Greg Christoph, Mark A Smith, Marc Chapdelaine, Maria Sunzel
AZD7325 [4-amino-8-(2-fluoro-6-methoxyphenyl)- N -propylcinnoline-3-carboxamide] is a selective GABAA α 2,3 receptor modulator intended for the treatment of anxiety disorders through oral administration. An interesting metabolic cyclization and aromatization pathway led to the tricyclic core of M9, i.e., 2-ethyl-7-(2-fluoro-6-methoxyphenyl)pyrimido[5,4-c]cinnolin-4(3H)-one. Further oxidative metabolism generated M10 via O -demethylation and M42 via hydroxylation. An authentic standard of M9 was synthesized to confirm the novel structure of M9 and that of M10 and M42 by liver microsomal incubation of the M9 standard...
March 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29248503/method-validation-in-quantitative-analysis-of-phase-i-and-phase-ii-metabolites-of-mitragynine-in-human-urine-using-liquid-chromatography-tandem-mass-spectrometry
#14
Mei Jin Lee, Surash Ramanathan, Sharif Mahsufi Mansor, Keng Yoon Yeong, Soo Choon Tan
A method using solid phase extraction and liquid chromatography-tandem mass spectrometry to quantitatively detect mitragynine, 16-carboxy mitragynine, and 9-O-demethyl mitragynine in human urine samples was developed and validated. The relevant metabolites were identified using multiple reaction monitoring in positive ionization mode using nalorphine as an internal standard. The method was validated for accuracy, precision, recovery, linearity, and lower limit of quantitation. The intra- and inter-day accuracy and precision were found in the range of 83...
February 15, 2018: Analytical Biochemistry
https://www.readbyqxmd.com/read/29248296/synthesis-and-biological-evaluation-of-4%C3%AE-thiazol-2-yl-amino-4-o-demethyl-4-deoxypodophyllotoxins-as-topoisomerase-ii-inhibitors
#15
Chun-Yan Sang, Heng-Zhi Tian, Yue Chen, Jian-Fei Liu, Shi-Wu Chen, Ling Hui
A series of 4β-(thiazol-2-yl)amino-4'-O-demethyl-4-deoxypodophyllotoxins were synthesized, and their cytotoxicities were evaluated against four human cancer cell lines (A549, HepG2, HeLa, and LOVO cells) and normal human diploid fibroblast line WI-38. Some of the compounds exhibited promising antitumor activity and less toxicity than the anticancer drug etoposide. Among them, compounds 15 and 17 were found to be the most potent synthetic derivatives as topo-II inhibitors, and induced DNA double-strand breaks via the p73/ATM pathway as well as the H2AX phosphorylation in A549 cells...
January 15, 2018: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29206565/absorption-distribution-metabolism-and-excretion-of-mtor-kinase-inhibitor-cc-223-in-rats-dogs-and-humans
#16
Zeen Tong, Christian Atsriku, Usha Yerramilli, Xiaomin Wang, Jim Nissel, Yan Li, Sekhar Surapaneni
1. The absorption, distribution, metabolism, and excretion of CC-223 were studied following a single oral dose of [14 C]CC-223 to rats (3 mg/kg; 90 μCi/kg), dogs (1.5 mg/kg; 10 μCi/kg), and healthy volunteers (20 mg; 200 nCi). 2. CC-223-derived radioactivity was widely distributed in rats. Excretion of radioactivity was rapid and nearly complete from rats (87%), dogs (78%), and humans (97%). Feces was the major excretion pathway for rats (67%) and dogs (70%), whereas urine (57.6%) was the major elimination route for humans...
December 19, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29157071/metabolism-of-metofluthrin-in-rats-ii-excretion-distribution-and-amount-of-metabolites
#17
Jun Abe, Yoshitaka Tomigahara, Hirokazu Tarui, Hirohisa Nagahori, Motohiro Kurosawa, Kenji Sugimoto, Naohiko Isobe
1. (14 )C-Labelled E/Z isomers of a synthetic pyrethroid metofluthrin ((E/Z)-(1 R,3 R)-2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl 2,2-dimethyl-3-(1-propenyl)-cyclopropanecarboxylate, abbreviated as RTE/RTZ, respectively) were used for rat metabolism studies. (14 )C-RTE or RTZ labelled at the carbonyl-carbon [acid-(14)C] or the methoxymethylbenzyl-α-carbon [alcohol-(14 )C] was administered orally to rats at 1 and 20 mg/kg. 2. Dosed compounds were mostly absorbed, metabolised, and rapidly excreted...
November 20, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29124283/semi-rational-engineering-of-cyp153a35-to-enhance-%C3%AF-hydroxylation-activity-toward-palmitic-acid
#18
Eunok Jung, Beom Gi Park, Hee-Wang Yoo, Joonwon Kim, Kwon-Young Choi, Byung-Gee Kim
CYP153A35 from Gordonia alkanivorans was recently characterized as fatty acid ω-hydroxylase. To enhance the catalytic activity of CYP153A35 toward palmitic acid, site-directed saturation mutagenesis was attempted using a semi-rational approach that combined structure-based computational analysis and subsequent saturation mutagenesis. Using colorimetric high-throughput screening (HTS) method based on O-demethylation activity of P450, CYP153A35 D131S and D131F mutants were selected. The best mutant, D131S, having a single mutation on BC-loop, showed 13- and 17-fold improvement in total turnover number (TTN) and catalytic efficiency (kcat /KM ) toward palmitic acid compared to wild-type, respectively...
January 2018: Applied Microbiology and Biotechnology
https://www.readbyqxmd.com/read/29115994/exploring-venlafaxine-pharmacokinetic-variability-with-a-phenotyping-approach-a-multicentric-french-swiss-study-marvel-study
#19
Célia Lloret-Linares, Youssef Daali, Sylvie Chevret, Isabelle Nieto, Fanny Molière, Philippe Courtet, Florence Galtier, Raphaëlle-Marie Richieri, Sophie Morange, Pierre-Michel Llorca, Wissam El-Hage, Thomas Desmidt, Frédéric Haesebaert, Philippe Vignaud, Jerôme Holtzmann, Jean-Luc Cracowski, Marion Leboyer, Antoine Yrondi, Fabienne Calvas, Liova Yon, Philippe Le Corvoisier, Olivier Doumy, Kyle Heron, Damien Montange, Siamak Davani, Julien Déglon, Marie Besson, Jules Desmeules, Emmanuel Haffen, Frank Bellivier
BACKGROUND: It is well known that the standard doses of a given drug may not have equivalent effects in all patients. To date, the management of depression remains mainly empirical and often poorly evaluated. The development of a personalized medicine in psychiatry may reduce treatment failure, intolerance or resistance, and hence the burden and costs of mood depressive disorders. The Geneva Cocktail Phenotypic approach presents several advantages including the "in vivo" measure of different cytochromes and transporter P-gp activities, their simultaneous determination in a single test, avoiding the influence of variability over time on phenotyping results, the administration of low dose substrates, a limited sampling strategy with an analytical method developed on DBS analysis...
November 7, 2017: BMC Pharmacology & Toxicology
https://www.readbyqxmd.com/read/29104318/comparison-of-the-oxidation-of-carcinogenic-aristolochic-acid-i-and-ii-by-microsomal-cytochromes-p450-in-vitro-experimental-and-theoretical-approaches
#20
Václav Martínek, František Bárta, Petr Hodek, Eva Frei, Heinz H Schmeiser, Volker M Arlt, Marie Stiborová
The herbal drug aristolochic acid, a natural mixture of 8-methoxy-6-nitrophenanthro[3,4- d ]-1,3-dioxole-5-carboxylic acid (AAI) and 6-nitrophenanthro[3,4- d ]-1,3-dioxole-5-carboxylic acid (AAII), is derived from Aristolochia species and is the cause of two nephropathies. Ingestion of aristolochic acid is associated with the development of urothelial tumors linked with aristolochic acid nephropathy and is implicated in the development of Balkan endemic nephropathy-associated urothelial tumors. The O -demethylated metabolite of AAI, 8-hydroxyaristolochic acid (AAIa), is the detoxification product of AAI generated by its oxidative metabolism...
2017: Monatshefte Für Chemie
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