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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
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...
January 30, 2018: Journal of Pharmaceutical and Biomedical Analysis
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 2, 2018: Journal of Structural Biology
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
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 GABAAα2,3 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...
January 8, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
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...
December 14, 2017: Analytical Biochemistry
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...
December 7, 2017: Bioorganic & Medicinal Chemistry Letters
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
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
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 (k cat/K M) toward palmitic acid compared to wild-type, respectively...
January 2018: Applied Microbiology and Biotechnology
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
Václav Martínek, František Bárta, Petr Hodek, Eva Frei, Heinz H Schmeiser, Volker M Arlt, Marie Stiborová
Abstract: 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...
2017: Monatshefte Für Chemie
J W Han, B G Ng, J K Sohng, Y J Yoon, G J Choi, B S Kim
AIMS: To identify the roles of the two O-methyltransferase homologous genes pdmF and pdmT in the pradimicin biosynthetic gene cluster of Actinomadura hibisca P157-2. METHODS AND RESULTS: Pradimicins are pentangular polyphenol antibiotics synthesized by bacterial type II polyketide synthases (PKSs) and tailoring enzymes. Pradimicins are naturally derivatized by combinatorial O-methylation at two positions (i.e., 7-OH and 11-OH) of the benzo[α]naphthacenequinone structure...
January 2018: Journal of Applied Microbiology
Naofumi Kamimura, Kenji Takahashi, Kosuke Mori, Takuma Araki, Masaya Fujita, Yudai Higuchi, Eiji Masai
Lignin is the most abundant phenolic polymer; thus, its decomposition by microorganisms is fundamental to carbon cycling on earth. Lignin breakdown is initiated by depolymerization catalysed by extracellular oxidoreductases secreted by white-rot basidiomycetous fungi. On the other hand, bacteria play a predominant role in the mineralization of lignin-derived heterogeneous low-molecular-weight aromatic compounds. The outline of bacterial catabolic pathways for lignin-derived bi- and monoaryls are typically composed of the following sequential steps: (i) funnelling of a wide variety of lignin-derived aromatics into vanillate and syringate, (ii) O demethylation of vanillate and syringate to form catecholic derivatives and (iii) aromatic ring-cleavage of the catecholic derivatives to produce tricarboxylic acid cycle intermediates...
December 2017: Environmental Microbiology Reports
Madhuri Vaghela, Krishna Iyer, Nancy Pandita
BACKGROUND AND OBJECTIVES: Gymnema sylvestre R. Br. is a well-known Indian medicinal herb. Gymnemic acids are pentacyclic triterpenes saponins and active phytoconstituents of Gymnema sylvestre. The study aimed at evaluation of the in vitro rat liver cytochrome P450 (CYP) inhibition potential of extracts and total gymnemic acid (TA)-enriched fractions from G. sylvestre. METHODS: Standardization of G. sylvestre [ethanolic (EL), hydroethanolic (HE), total acid of ethanolic (TAE), total acid of hydroethanolic (TAHE) and total acid of aqueous (TAAQ) extract] was done with respect to deacyl gymnemic acid (DAGA), using reverse phase-high performance liquid chromatography (RP-HPLC)...
October 10, 2017: European Journal of Drug Metabolism and Pharmacokinetics
Huanyu Guan, Kaitong Li, Xiaoming Wang, Xiaomei Luo, Meifeng Su, Wenting Tan, Xiaoyan Chang, Yue Shi
Dehydrocorydaline (DHC), a quaternary alkaloid from Corydalis yanhusuo, has been demonstrated to be the active constituent in the treatment of coronary heart disease. In this study, a high-performance liquid chromatography-electrospray ionization-triple quadrupole linear ion trap mass spectrometry (HPLC-ESI-QTRAP MS) technique was used to identify DHC metabolites in plasma and bile after oral administration of DHC to rats. A total of 18 metabolites (M1 to M18) were identified and characterized by LC-MS/MS in the positive ion mode...
October 10, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Areej Mohammad Al-Taweel, Shagufta Perveen, Ghada Ahmed Fawzy, Attiq Ur Rehman, Afsar Khan, Rashad Mehmood, Laila Mohamed Fadda
Calotropis procera is traditionally used for treating many diseases including ulcers and tumors. It was thus deemed of interest to investigate and compare the antiulcer and cytotoxic activities of C. procera leaf, flower, and fruit extracts in an attempt to verify its traditional uses. Phytochemical studies on the fruits, flowers, and leaves of C. procera, collected from the desert of Saudi Arabia, led to the isolation of one new lignan 7'-methoxy-3'-O-demethyl-tanegool-9-O-β-d-glucopyranoside and five known compounds from the flowers, four compounds from leaves, and a flavonoid glycoside and a lignan glycoside from the fruits...
2017: Evidence-based Complementary and Alternative Medicine: ECAM
Anam Fayyaz, Seddy Makwinja, Seppo Auriola, Hannu Raunio, Risto O Juvonen
Scoparone is a natural bioactive compound in Chinese herbal medicines. It has numerous pharmacological actions, including liver protective, hypolipidemic, antitumor, and anti-inflammatory effects. The primary metabolism route of scoparone is O-demethylation to scopoletin or isoscopoletin catalyzed by CYP enzymes. The aims of our study were to identify the human CYP enzymes catalyzing scoparone 7-O-demethylation to scopoletin and to compare this oxidation reaction in liver microsomes among different species...
September 26, 2017: Planta Medica
Jae-Kyung Heo, Phi-Hung Nguyen, Won Cheol Kim, Nguyen Minh Phuc, Kwang-Hyeon Liu
Selaginella tamariscina (Beauv.) has been used for traditional herbal medicine for treatment of cancer, hepatitis, and diabetes in the Orient. Numerous bioactive compounds including alkaloids, flavonoids, lignans, and selaginellins have been identified in this medicinal plant. Among them, selaginellins having a quinone methide unit and an alkylphenol moiety have been known to possess anticancer, antidiabetic, and neuroprotective activity. Although there have been studies on the biological activities of selaginellins, their modulatory potential of cytochrome P450 (P450) and uridine 5'-diphosphoglucuronosyltransferase (UGT) activities have not been previously evaluated...
September 21, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Achim T Caspar, Folker Westphal, Markus R Meyer, Hans H Maurer
4-EA-NBOMe (N-(2-methoxybenzyl)-4-ethylamphetamine, 1-(4-ethylphenyl-)-N-[(2-methoxyphenyl)methyl]propane-2-amine) is an amphetamine-derived new psychoactive substance (NPS) of the N-methoxybenzyl (NBOMe) group first seized by German custom authorities. In contrast to the phenethylamine NBOMes, studies on the pharmacological, toxicological, or metabolic properties are not yet published. The aims of the presented work were the use of LC-HR-MS/MS for identification of the phase I and II metabolites of 4-EA-NBOMe in rat urine and pooled human S9 fraction (pS9) incubations, to compare metabolite formation in both models, to identify involved monooxygenases, and to elucidate its detectability in standard urine screening approaches (SUSAs) using GC-MS, LC-MS(n), and LC-HR-MS/MS...
July 31, 2017: Analytical and Bioanalytical Chemistry
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