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o-demethylation

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https://www.readbyqxmd.com/read/28495902/regio-and-stereo-selective-oxidation-of-a-cardiovascular-drug-metoprolol-mediated-by-cytochrome-p450-2d-and-3a-enzymes-in-marmoset-livers
#1
Shotaro Uehahara, Sakura Ishii, Yasuhiro Uno, Takashi Inoue, Erika Sasaki, Hiroshi Yamazaki
A β-blocker metoprolol is one of the in vivo probes for human cytochrome P450 (P450) 2D6. Investigation of non-human primate P450 enzymes helps improve accuracy of the extrapolation of pharmacokinetic data from animals into humans. Common marmosets (Callithrix jacchus) are a potential primate model for preclinical research, but detailed roles of marmoset P450 enzymes in metoprolol oxidations remained unknown. In this study, regio- and stereo-selectivity of metoprolol oxidations by a variety of P450 enzymes in marmoset and human livers were investigated in vitro...
May 11, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28488816/characterization-of-a-methyltransferase-almcii-in-chalcomycin-biosynthesis-the-first-o-methyltransferase-in-tylf-family-works-on-a-4-deoxysugar
#2
Ping Dai, Chuan-Xi Wang, Hao Gao, Qiao-Zhen Wang, Xiao-Long Tang, Guo-Dong Chen, Kui Hong, Dan Hu, Xin-Sheng Yao
Sugar O-methylation is a ubiquitous modification in natural products and has diverse roles. This realization has inspired many attempts to search for novel methyltransferases. Chalcomycins are a group of 16-membered macrolides containing two methylated sugars, which requires three methyltransferases for their biosynthesis. Here, we identified that AlmCII, a sugar O-methyltransferase belonging to the TylF family which thus far only methylates sugars with a 4'-hydroxyl group, can methylate a 4',6'-dideoxysugar in the biosynthesis of chalcomycins...
May 10, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28472358/metabolic-profile-determination-of-nbome-compounds-using-human-liver-microsomes-and-comparison-with-findings-in-authentic-human-blood-and-urine
#3
Keith-Dane H Temporal, Karen S Scott, Amanda L A Mohr, Barry K Logan
The emergence of novel psychoactive substances (NPS) such as hallucinogenic NBOMes (N-methoxybenzyl derivatives of 2C phenethylamines) in the past few years into the recreational drug market has introduced various challenges in forensic analytical toxicology in regard to adequate and timely detection of these compounds. This is especially true in samples from individuals who have experienced severe and fatal intoxications. The aim of this research was to identify the major Phase I metabolites of selected NBOMe compounds to generate a predicted human metabolic pathway of these substances...
May 3, 2017: Journal of Analytical Toxicology
https://www.readbyqxmd.com/read/28455804/microbial-catalyzed-regio-selective-demethylation-of-colchicine-by-streptomyces-griseus-atcc-13273
#4
Chao Zhang, Xian Sun, Shao Hua Xu, Bo Yang Yu, Jian Zhang
Colchicinoids and their derivatives are of great importance in pharmaceutical applications, and colchicine is usually used as the first choice for the treatment of gout. To expand the structural diversities and clinical application of colchicinoids, many attempts have been established for the derivatives with better activity or less toxicity. Herein, in this paper, we report a direct microbial transformation of colchicine into 2-O-demethyl-colchicine (M1) and 3-O-demethl-colchicine (M2) by Streptomyces griseus ATCC 13273...
April 28, 2017: Applied Biochemistry and Biotechnology
https://www.readbyqxmd.com/read/28441491/a-naturally-occurring-isoform-specific-probe-for-highly-selective-and-sensitive-detection-of-human-cytochrome-p450-3a5
#5
Jing-Jing Wu, Yun-Feng Cao, Liang Feng, Yu-Qi He, James Y Hong, Tong-Yi Dou, Ping Wang, Da-Cheng Hao, Guang-Bo Ge, Ling Yang
Cytochrome P450 (CYP) 3A5 characterized with polymorphic and extensive expression in multiple tissues is the most important P450 enzyme among the minor CYP3A isoforms. However, a selective and sensitive probe for CYP3A5 remains unavailable. In this study, we identified and characterized a naturally occurring lignan 12 (schisantherin E) as an isoform-specific probe for selective detection of CYP3A5 activity in complex biological samples. With thorough characterization including LC-MS and NMR, we found that 12 can be metabolized by CYP3A5 to generate a major metabolite 2-O-demethylated 12...
May 11, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28396528/human-enterocytes-as-an-in-vitro-model-for-the-evaluation-of-intestinal-drug-metabolism-characterization-of-drug-metabolizing-enzyme-activities-of-cryopreserved-human-enterocytes-from-twenty-four-donors
#6
Ming-Chih David Ho, Nick Ring, Kirsten Amaral, Utkarsh Doshi, Albert Li
We report here successful isolation and cryopreservation of enterocytes from human small intestine. The enterocytes were isolated by enzyme digestion of the intestinal lumen followed by partial purification via differential centrifugation. The enterocytes were cryopreserved directly after isolation without culturing to maximize retention of in vivo drug metabolizing enzyme activities. Post-thaw viability of the cryopreserved enterocytes was consistently over 80% based on trypan blue exclusion. Cryopreserved enterocytes pooled from 8 donors (4 male and 4 female) were evaluated for their metabolism of 14 pathway-selective substrates: CYP1A2 (phenacetin hydroxylation), CYP2A6 (coumarin 7-hydroxylation), CYP2B6 (bupropion hydroxylation), CYP2C8 (paclitaxel 6α-hydroxylation), CYP2C9 (diclofenac 4-hydroxylation), CYP2C19 (s-mephenytoin 4-hydroxylation), CYP2D6 (dextromethorphan hydroxylation), CYP2E1 (chlorzoxazone 6-hydroxylation), CYP3A4 (midazolam 1'-hydroxylation and testosterone 6β-hydroxylation), CYP2J2 (astemizole O-demethylation), UDP-glucuronosyltransferase (UGT; 7-hydroxycoumarin glucuronidation), sulfotransferase (SULT; 7-hydroxycoumarin sulfation), and carboxylesterase 2 (CES2; irinotecan hydrolysis) activities...
April 10, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28373573/structure-of-aryl-o-demethylase-offers-molecular-insight-into-a-catalytic-tyrosine-dependent-mechanism
#7
Amanda C Kohler, Matthew J L Mills, Paul D Adams, Blake A Simmons, Kenneth L Sale
Some strains of soil and marine bacteria have evolved intricate metabolic pathways for using environmentally derived aromatics as a carbon source. Many of these metabolic pathways go through intermediates such as vanillate, 3-O-methylgallate, and syringate. Demethylation of these compounds is essential for downstream aryl modification, ring opening, and subsequent assimilation of these compounds into the tricarboxylic acid (TCA) cycle, and, correspondingly, there are a variety of associated aryl demethylase systems that vary in complexity...
April 18, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28342193/metabolism-of-the-tryptamine-derived-new-psychoactive-substances-5-meo-2-me-dalt-5-meo-2-me-alcht-and-5-meo-2-me-dipt-and-their-detectability-in-urine-studied-by-gc-ms-lc-ms-n-and-lc-hr-ms-ms
#8
Achim T Caspar, Jonas B Gaab, Julian A Michely, Simon D Brandt, Markus R Meyer, Hans H Maurer
Many N,N-dialkylated tryptamines show psychoactive properties and were encountered as new psychoactive substances. The aims of the presented work were to study the phase I and II metabolism and the detectability in standard urine screening approaches (SUSA) of 5-methoxy-2-methyl-N,N-diallyltryptamine (5-MeO-2-Me-DALT), 5-methoxy-2-methyl-N-allyl-N-cyclohexyltryptamine (5-MeO-2-Me-ALCHT), and 5-methoxy-2-methyl-N,N-diisopropyltryptamine (5-MeO-2-Me-DIPT) using GC-MS, LC-MS(n) , and LC-HR-MS/MS. For metabolism studies, urine was collected over a 24-h period after administration of the compounds to male Wistar rats at 20 mg/kg body weight (BW)...
March 24, 2017: Drug Testing and Analysis
https://www.readbyqxmd.com/read/28333075/metabolic-profile-of-skimmianine-in-rats-determined-by-ultra-performance-liquid-chromatography-coupled-with-quadrupole-time-of-flight-tandem-mass-spectrometry
#9
Aihua Huang, Hui Xu, Ruoting Zhan, Weiwen Chen, Jiawei Liu, Yuguang Chi, Daidi Chen, Xiaoyu Ji, Chaoquan Luo
Skimmianine is a furoquinoline alkaloid present mainly in the Rutaceae family. It has been reported to have analgesic, antispastic, sedative, anti-inflammatory, and other pharmacologic activities. Despite its critical pharmacological function, its metabolite profiling is still unclear. In this study, the in vivo metabolite profiling of skimmianine in rats was investigated using ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC/Q-TOF-MS). The metabolites were predicted using MetabolitePilot(TM) software...
March 23, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28322046/structure-oxidative-metabolism-relationships-of-substituted-flavones-by-aspergillus-niger
#10
Da-Som Lim, Do-Hyung Lim, Ji-Ho Lee, Eun-Tae Oh, Young-Soo Keum
Aspergillus niger is a rich source of oxidative enzymes, which are important for many industrial applications. However, systematic evaluation of their metabolic characteristics is limited. In this study, structure-dependent metabolism of flavones by Aspergillus niger were investigated with synthetic substrates. Metabolic inhibitor studies suggested that cytochrome P450s are the major enzymes in oxidative metabolism. The reactions include ring hydroxylation, O-demethylation, sulfone/sulfoxide formation, and oxidation of alkyls to carboxy groups...
March 28, 2017: Journal of Agricultural and Food Chemistry
https://www.readbyqxmd.com/read/28270565/midostaurin-a-novel-protein-kinase-inhibitor-for-the-treatment-of-acute-myelogenous-leukemia-insights-from-human-absorption-metabolism-and-excretion-studies-of-a-bddcs-ii-drug
#11
Handan He, Phi Tran, Helen Gu, Vivienne Tedesco, Jin Zhang, Wen Lin, Ewa Gatlik, Kai Klein, Tycho Heimbach
The absorption, metabolism, and excretion of midostaurin, a potent class III tyrosine protein kinase inhibitor for acute myelogenous leukemia, were evaluated in healthy subjects. A microemulsion formulation was chosen to optimize absorption. After a 50-mg [(14)C]midostaurin dose, oral absorption was high (>90%) and relatively rapid. In plasma, the major circulating components were midostaurin (22%), CGP52421 (32.7%), and CGP62221 (27.7%). Long plasma half-lives were observed for midostaurin (20.3 hours), CGP52421 (495 hours), and CGP62221 (33...
May 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28195395/heterologous-expression-of-helicoverpa-armigera-cytochrome-p450-cyp6b7-in-pichia-pastoris-and-interactions-of-cyp6b7-with-insecticides
#12
Chunqing Zhao, Genmiao Song, Hongxia Duan, Tao Tang, Chen Wang, Lihong Qiu
BACKGROUND: Previous studies indicated that constitutive overexpression of cytochrome P450 CYP6B7 was involved in fenvalerate resistance in Helicoverpa armigera. In this study, the CYP6B7 gene from H. armigera (namely HaCYP6B7), was heterologously expressed in Pichia pastoris GS115. A vector pPICZA-HaCYP6B7 was constructed and transformed into P. pastoris GS115, the transformant of pPICZA-HaCYP6B7-GS115 was then cultured and induced by 1% (v/v) methanol and the heterologous expression of HaCYP6B7 protein in P...
February 13, 2017: Pest Management Science
https://www.readbyqxmd.com/read/28177407/transformation-of-sulfonamides-and-tetracyclines-during-anaerobic-fermentation-of-liquid-manure
#13
Astrid Spielmeyer, Franziska Stahl, Madeleine S Petri, Walter Zerr, Hubertus Brunn, Gerd Hamscher
Liquid manure is frequently used as soil fertilizer due to its high nutrient content. It can also contain residues of pharmaceuticals, such as antibiotics, if farm animals are medicated. The anaerobic fermentation process in biogas plants is discussed as one way to reduce the input of antibiotics into the environment. Therefore, 10 worldwide-applied sulfonamides (sulfachloropyridazine, sulfadiazine, sulfadimethoxine, sulfaguanidine, sulfamerazine, sulfamethazine, sulfamethoxazole, sulfamethoxypyridazine, sulfapyridine, and sulfathiazole) and four frequently used tetracyclines (chlortetracycline, doxycycline, oxytetracycline, and tetracycline) were investigated concerning their elimination pattern during anaerobic fermentation...
January 2017: Journal of Environmental Quality
https://www.readbyqxmd.com/read/28160853/identification-of-acetylshikonin-as-the-novel-cyp2j2-inhibitor-with-anti-cancer-activity-in-hepg2-cells
#14
See-Hyoung Park, Nguyen Minh Phuc, Jongsung Lee, Zhexue Wu, Jieun Kim, Hyunkyoung Kim, Nam Doo Kim, Taeho Lee, Kyung-Sik Song, Kwang-Hyeon Liu
BACKGROUND: Acetylshikonin is one of the biologically active compounds derived from the root of Lithospermum erythrorhizon, a medicinal plant with anti-cancer and anti-inflammation activity. Although there have been a few previous reports demonstrating that acetylshikonin exerts anti-cancer activity in vitro and in vivo, it is still not clear what is the exact molecular target protein of acetylshikonin in cancer cells. PURPOSE: The purpose of this study is to evaluate the inhibitory effect of acetylshikonin against CYP2J2 enzyme which is predominantly expressed in human tumor tissues and carcinoma cell lines...
January 15, 2017: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
https://www.readbyqxmd.com/read/28129979/investigation-of-the-anti-angiogenesis-effects-induced-by-deoxypodophyllotoxin-5-fu-conjugate-c069-against-huve-cells
#15
Rong Xiang, Xiao-Wen Guan, Ling Hui, Yong-Xin Jin, Shi-Wu Chen
We have found that the deoxypodophyllotoxin-5-fluorouracil conjugate, 4'-O-demethyl-4-deoxyppodophyllotoxin-4'-yl 4-((6-(2-(5-fluorouracil-yl)acetamido) hexyl)amino)-4-oxobutanoate (C069), possessed superior cytotoxicities and less toxicity compared with etoposide. In this paper, the anti-angiogenic and vascular disrupting activities of C069 were examined with several in vitro and in vivo models. First, we demonstrated that C069 significantly inhibited the proliferation, migration, tube formation and disrupted the formed tube-like structures of HUVE cells, and inhibited angiogenesis in chicken chorioallantoic membrane assay...
January 17, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28121440/dioncophyllines-c2-d2-and-f-and-related-naphthylisoquinoline-alkaloids-from-the-congolese-liana-ancistrocladus-ileboensis-with-potent-activities-against-plasmodium-falciparum-and-against-multiple-myeloma-and-leukemia-cell-lines
#16
Jun Li, Raina Seupel, Doris Feineis, Virima Mudogo, Marcel Kaiser, Reto Brun, Daniela Brünnert, Manik Chatterjee, Ean-Jeong Seo, Thomas Efferth, Gerhard Bringmann
Dioncophylline F (1), the first 5,8'-coupled dioncophyllaceous alkaloid (i.e., lacking an oxygen function at C-6 and possessing an R-configuration at C-3), was isolated from the recently described Congolese liana Ancistrocladus ileboensis. Two further, likewise Dioncophyllaceae-type, alkaloids, the dioncophyllines C2 (2) and D2 (3), were identified, along with the Ancistrocladaceae-type compound ancistrocladisine B (4), which is oxygenated at C-6 and S-configured at C-3. The structures of the new compounds were determined by spectroscopic, chemical, and chiroptical methods...
February 24, 2017: Journal of Natural Products
https://www.readbyqxmd.com/read/28092216/metabolism-of-metofluthrin-in-rats-i-identification-of-metabolites
#17
Jun Abe, Hirohisa Nagahori, Hirokazu Tarui, Yoshitaka Tomigahara, Naohiko Isobe
1. Metofluthrin (2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl (Z/E)-(1R)-trans-2,2-dimethyl-3-(1-propenyl)-cyclopropanecarboxylate) is a novel pyrethroid insecticide, which has E/Z isomers at prop-1-enyl group. 2. Rats were orally dosed with each [(14)C]-labelled E/Z isomer, and the excreta were collected for isolation and identification of metabolites. Analysis of the excreta by LC/MS and NMR revealed formation of 33 and 23 (total 42) metabolites from rats dosed with Z-isomer and E-isomer, respectively...
February 5, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28010169/consequences-of-daily-corticosteroid-dosing-with-or-without-pre-treatment-with-quinidine-on-the-in-vivo-cytochrome-p450-2d-cyp2d-enzyme-in-rats-effect-on-o-demethylation-activity-of-dextromethorphan-and-expression-levels-of-cyp2d1-mrna
#18
Poonam Giri, Prashant Delvadia, Laxmikant Gupta, Nirmal Patel, Priyal Trivedi, Krishna Lad, Hiren M Patel, Nuggehally R Srinivas
1. Present investigation was carried out in rats to study influence of corticosteroids after repeated dosing with/without pre-treatment with CYP2D inhibitor quinidine on the CYP2D1 mRNA levels and CYP2D enzyme activity using dextromethorphan as probe substrate. 2. CYP2D1 mRNA was measured in liver homogenate using quantitative real-time polymerase chain reaction [qRT-PCR] and enzymatic reaction was studied ex vivo in liver S-9 fractions of rats treated with oral 10 mg/kg dexamethasone or prednisolone for five days or pre-treated with quinidine and followed by treatment with oral 10 mg/kg corticosteroids for five days...
January 19, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27966376/production-of-17-o-demethyl-geldanamycin-a-cytotoxic-ansamycin-polyketide-by-streptomyces-hygroscopicus-dem20745
#19
Aron Baksh, Bernhard Kepplinger, Hadiza A Isah, Michael R Probert, William Clegg, Corinne Wills, Michael Goodfellow, Jeff Errington, Nick Allenby, Michael J Hall
The actinomycete DEM20745, collected from non-rhizosphere soil adjacent to Paraserianthes falactaria trees (Cangkringan, Indonesia), is an efficient producer of the anticancer ansamycin polyketide 17-O-demethyl-geldanamycin (17-O-DMG), a biosynthetic precursor of the Hsp90 inhibitor geldanamycin (GDM). In DEM20745, 17-O-DMG is the major ansamycin product observed reaching a maximum titre of 17 mg/L in the fermentation broth. 17-O-DMG has the potential to be a key starting material for the semi-synthesis of GDM analogues for use in anticancer therapy...
December 14, 2016: Natural Product Research
https://www.readbyqxmd.com/read/27915193/metabolic-fate-and-detectability-of-the-new-psychoactive-substances-2-4-bromo-2-5-dimethoxyphenyl-n-2-methoxyphenyl-methyl-ethanamine-25b-nbome-and-2-4-chloro-2-5-dimethoxyphenyl-n-2-methoxyphenyl-methyl-ethanamine-25c-nbome-in-human-and-rat-urine-by-gc-ms
#20
Achim T Caspar, Simon D Brandt, Andreas E Stoever, Markus R Meyer, Hans H Maurer
25B-NBOMe and 25C-NBOMe are potent 5-HT2A receptor agonists that have been associated with inducing hallucinogenic effects in drug users and severe intoxications. This paper describes the identification of their metabolites in rat and human urine by liquid chromatography (LC)-high resolution (HR)-MS/MS, the comparison of metabolite formation in vitro and in vivo and in different species, the general involvement of human cytochrome-P450 (CYP) isoenzymes on their metabolism steps, and their detectability by standard urine screening approaches (SUSAs) using GC-MS, LC-MS(n), or LC-HR-MS/MS...
February 5, 2017: Journal of Pharmaceutical and Biomedical Analysis
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