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https://www.readbyqxmd.com/read/28214059/pharmacokinetic-alterations-of-rhubarb-anthraquinones-in-experimental-colitis-induced-by-dextran-sulfate-sodium-in-the-rat
#1
Wen-Jin Wu, Ru Yan, Ting Li, Ya-Ping Li, Rui-Na Zhou, Yi-Tao Wang
ETHNOPHARMACOLOGICAL RELEVANCE: Rhubarb (Rhei Rhizoma et Radix) is used for the treatment of digestive diseases in traditional medicinal practice in China. Recent studies also support its beneficial activities in alleviating ulcerative colitis (UC). AIM OF THE STUDY: This study aimed to characterize the oral pharmacokinetics of rhubarb anthraquinones, the main bioactive components of this herb, in the experimental chronic colitis rat model induced by dextran sulfate sodium (DSS) and to identify the factors causing the pharmacokinetic alterations...
February 14, 2017: Journal of Ethnopharmacology
https://www.readbyqxmd.com/read/28213944/separation-of-hydroxynorketamine-stereoisomers-using-capillary-electrophoresis-with-sulfated-%C3%AE-cyclodextrin-and-highly-sulfated-%C3%AE-cyclodextrin
#2
Friederike A Sandbaumhüter, Regula Theurillat, Wolfgang Thormann
The racemic N-methyl-d-aspartate receptor antagonist ketamine is used in anesthesia, analgesia and the treatment of depressive disorders. It is known that interactions of hydroxylated norketamine metabolites and 5,6-dehydronorketamine (DHNK) with the α7 -nicotinic acetylcholine receptor and the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor are responsible for the antidepressive effects. Ketamine and its first metabolite norketamine are not active on these receptors. As stereoselectivity plays a role in ketamine metabolism, a cationic capillary electrophoresis based method capable of resolving and analyzing the stereoisomers of four hydroxylated norketamine metabolites, norketamine and DHNK was developed...
February 18, 2017: Electrophoresis
https://www.readbyqxmd.com/read/28211700/from-genotype-to-phenotype-cytochrome-p450-2d6-mediated-drug-clearance-in-humans
#3
Jie Gao, Xin Tian, Jun Zhou, Ming-Zhu Cui, Hai-Feng Zhang, Na Gao, Qiang Wen, Hai-Ling Qiao
How genotypic variation results in phenotypic differences is still a challenge for biology. In the field of drug metabolism the means by which specific cytochrome P4502D6 (CYP2D6) genotypes yield different phenotypes at various levels (molecular, cellular, and organismal) is an important question, as differences in CYP2D6 activity can contribute to adverse drug reactions. Herein, the genotype of CYP2D6 was determined along with the absolute content of CYP2D6 and microsomal protein per gram of liver in human liver microsomes, the molecular, cellular (microsomal, tissue, organ), and organismal phenotype of CYP2D6 determined; the effect of genotype on each phenotype of CYP2D6-mediated dextromethorphan clearance (CL) was delineated, and the overall genotype-phenotype relationship for CYP2D6 was charted...
February 17, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28207929/optimisation-of-intestinal-microsomal-preparation-in-the-rat-a-systematic-approach-to-assess-the-influence-of-various-methodologies-on-metabolic-activity-and-scaling-factors
#4
Oliver J D Hatley, Christopher R Jones, Aleksandra Galetin, Amin Rostami-Hodjegan
The metabolic capacity of the intestine and its importance as the initial barrier to systemic exposure can lead to under-estimation of first-pass, and thus overestimation of oral bioavailability. However, the in vitro tools informing estimates of in vivo intestinal metabolism are limited by the complexity of the in vitro matrix preparation and uncertainty with the scaling factors for in vitro to in vivo extrapolation. A number of methods currently exist in the literature for the preparation of intestinal microsomes; however, the impact of key steps in the preparation procedure has not been critically assessed...
February 16, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28196829/marmoset-cytochrome-p450-3a4-expressed-in-liver-and-small-intestine-tissues-efficiently-metabolizes-midazolam-alprazolam-nifedipine-and-testosterone
#5
Shotaro Uehara, Yasuhiro Uno, Kazuyuki Nakanishi, Sakura Ishii, Takashi Inoue, Erika Sasaki, Hiroshi Yamazaki
Common marmosets (Callithrix jacchus), small New World primates, are increasingly attracting attention as potentially useful animal models for drug development. However, characterization of cytochrome P450 (P450) 3A enzymes involved in the metabolism of a wide variety of drugs has remained in marmosets. In this study, sequence homology, tissue distribution, and enzymatic property of marmoset P450 3A4 orthologue, 3A5 orthologue, and 3A90 were investigated. Marmoset P450 3A forms exhibited high amino acid sequence identities (88-90%) to the human and cynomolgus monkey P450 3A orthologues and evolutionary closeness to human and cynomolgus monkey P450 3A orthologues, compared with other P450 3A enzymes...
February 14, 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
#6
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/28193668/towards-selective-mycobacterial-clpp1p2-inhibitors-with-reduced-activity-against-the-human-proteasome
#7
Wilfried Moreira, Sridhar Santhanakrishnan, Grace J Y Ngan, Choon Bing Low, Kanda Sangthongpitag, Anders Poulsen, Brian W Dymock, Thomas Dick
Mycobacterium tuberculosis (TB) is responsible for the greatest number of deaths worldwide due to a bacterial agent. We recently identified bortezomib (1) as a promising anti-TB compound. We showed that 1 inhibits the mycobacterial caseinolytic protease ClpP1P2 and exhibits bactericidal activity and established 1 and ClpP1P2 as an attractive lead/target couple. However, 1 is a human proteasome inhibitor currently approved for cancer therapy, and as such exhibits significant toxicity. Selective inhibition of the bacterial protease over the human proteasome is desirable in order to maintain antibacterial activity while reducing toxicity...
February 13, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28190634/discovery-and-characterization-of-cyclopentyl-ethyl-benzoic-acid-inhibitors-of-microsomal-prostaglandin-e-synthase-1
#8
Katherine M Partridge, Stephen Antonysamy, Shobha N Bhattachar, Srinivasan Chandrasekhar, Matthew J Fisher, Adrian Fretland, Karen Gooding, Anita Harvey, Norman E Hughes, Steven L Kuklish, John G Luz, Peter R Manninen, James E McGee, Daniel R Mudra, Antonio Navarro, Bryan H Norman, Steven J Quimby, Matthew A Schiffler, Ashley V Sloan, Alan M Warshawsky, Jennifer M Weller, Jeremy S York, Xiao-Peng Yu
We describe a novel class of acidic mPGES-1 inhibitors with nanomolar enzymatic and human whole blood (HWB) potency. Rational design in conjunction with structure-based design led initially to the identification of anthranilic acid 5, an mPGES-1 inhibitor with micromolar HWB potency. Structural modifications of 5 improved HWB potency by over 1000×, reduced CYP2C9 single point inhibition, and improved rat clearance, which led to the selection of [(cyclopentyl)ethyl]benzoic acid compound 16 for clinical studies...
November 7, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28188299/novel-mechanism-of-decyanation-of-gdc-0425-by-cytochrome-p450
#9
Ryan H Takahashi, Jason S Halladay, Michael Siu, Yuan Chen, Cornelis Eca Hop, Siamak Cyrus Khojasteh, Shuguang Ma
GDC-0425 is an orally bioavailable small molecule inhibitor of checkpoint kinase 1 (Chk1) that was investigated as a novel co-therapy to potentiate chemotherapeutic drugs such as gemcitabine. In the radiolabeled ADME study in Sprague-Dawley rats, trace level but long-lived 14C-labeled plasma thiocyanate was observed. This thiocyanate originated from metabolic decyanation of GDC-0425 and rapid conversion of cyanide to thiocyanate. Excretion studies indicated decyanation was a minor metabolic pathway, but placing 14C at nitrile magnified its observation...
February 10, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28187835/lethal-and-sublethal-effects-of-the-chitin-synthesis-inhibitor-chlorfluazuron-on-bradysia-odoriphaga-yang-and-zhang-diptera-sciaridae
#10
Peng Zhang, Yun-He Zhao, Qiu-Hong Wang, Wei Mu, Feng Liu
Bradysia odoriphaga Yang and Zhang is the primary insect pest that affects Chinese chive in northern China. Nevertheless, very few studies have been conducted on the use of chitin synthesis inhibitors (CSIs) for the control of B. odoriphaga. Here, lethal and sublethal effects of the CSI chlorfluazuron on B. odoriphaga were studied to explore the use for integrated pest management (IPM) of B. odoriphaga. A contact and ingestion toxicity bioassay showed that chlorfluazuron was more active against B. odoriphaga than three other CSIs, with a 72h LC50 of 0...
March 2017: Pesticide Biochemistry and Physiology
https://www.readbyqxmd.com/read/28185143/characterization-of-1-aminobenzotriazole-and-ketoconazole-as-novel-inhibitors-of-monoamine-oxidase-mao-an-in-vitro-investigation
#11
Abdul Naveed Shaik, Barbara W LeDuc, Ansar A Khan
BACKGROUND AND OBJECTIVES: 1-Aminobenzotriazole, a known time-dependent inhibitor of cytochrome P450 (CYP) enzymes, and ketoconazole, a strong inhibitor of the human CYP3A4 isozyme, are used as standard probe inhibitors to characterize the CYP and/or non-CYP-mediated metabolism of xenobiotics. In the present investigation, 1-Aminobenzotriazole and ketoconazole are characterized as potent monoamine oxidase (MAO) inhibitors in vitro using mouse, rat and human liver microsomes and S9 fractions...
February 9, 2017: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28183046/distribution-isomerization-and-enantiomer-selectivity-of-hexabromocyclododecane-hbcd-diastereoisomers-in-different-tissue-and-subcellular-fractions-of-earthworms
#12
Bing Li, Hao Chen, Hongwen Sun, Zhonghui Lan
In this study, earthworms Eisenia fetida (E. fetida) were exposed to a soil artificially contaminated with individual hexabromocyclododecane (HBCD) diastereoisomers (α-, β- and γ-HBCDs) to investigate the distribution, isomerization and enantiomer selectivity of HBCDs at tissue and subcellular levels. At the tissue level, the concentrations of HBCDs all followed the order of gut>bodyfluid>body wall, which suggested that earthworms accumulated HBCDs mainly via ingesting soil particles. At the subcellular level, the concentrations of HBCDs in an extracellular fraction consisting of granules, tissue fragment, cell membrane and intact cells (fraction A) were higher than those in an intracellular fractions consisting of the microsomal and cytosol (fraction B+C)...
February 6, 2017: Ecotoxicology and Environmental Safety
https://www.readbyqxmd.com/read/28182990/design-synthesis-and-biological-evaluation-of-novel-non-peptide-boronic-acid-derivatives-as-proteasome-inhibitors
#13
Ying Ge, Aibo Li, Jianwei Wu, Haiwei Feng, Letian Wang, Hongwu Liu, Yungen Xu, Qingxiang Xu, Li Zhao, Yuyan Li
A novel series of non-peptide proteasome inhibitors bearing the 1, 4-naphthoquinone scaffold and boronic acid warhead was developed. In the biological evaluation on the chymotrypsin-like activity of human 20S proteasome, five compounds showed IC50 values in the nanomolar range. Docking experiments into the yeast 20S proteasome rationalized their biological activities and allowed further optimization of this interesting class of inhibitors. Within the cellular proliferation inhibition assay and western blot analysis, compound 3e demonstrated excellent anti-proliferative activity against solid tumor cells and clear accumulation of ubiquitinated cellular proteins...
January 23, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28180138/er-microsome-preparation-and-subsequent-iaa-quantification-in-maize-coleoptile-and-primary-root-tissue
#14
Verena Kriechbaumer
Auxin is a major growth hormone in plants and the first plant hormone to be discovered and studied (Darwin and Darwin, 1880). The auxin molecule in plants was first identified as indole-3-acetic acid (IAA) by Kögl et al. (1934). Active research over nearly a decade has shed light on many of the molecular mechanisms of its action but the complexity and redundancy of the auxin biosynthetic network raises questions about control of this system. We have shown that some enzymes involved in the YUCCA-route of auxin biosynthesis are not cytosolic but localised to the endoplasmic reticulum (ER) in both Arabidopsis thaliana (YUCCA4...
May 5, 2016: Bio-protocol
https://www.readbyqxmd.com/read/28179134/inhibition-of-cytochrome-p450-enzymes-by-saturated-and-unsaturated-fatty-acids-in-human-liver-microsomes-characterization-of-enzyme-kinetics-in-the-presence-of-bovine-serum-albumin-0-1-and-1-0-w-v-and-in-vitro-in-vivo-extrapolation-of-hepatic-clearance
#15
Raghava Choudary Palacharla, Venkatesham Uthukam, Arunkumar Manoharan, Ranjith Kumar Ponnamaneni, Nagasurya Prakash Padala, Rajesh Kumar Boggavarapu, Gopinadh Bhyrapuneni, Devender Reddy Ajjala, Ramakrishna Nirogi
The objective of the study was to determine the effect of fatty acids on CYP enzymes and the effect of BSA on intrinsic clearance of probe substrates. The inhibitory effect of thirteen fatty acids including saturated, mono-unsaturated and polyunsaturated fatty acids on CYP enzymes, kinetic parameters and intrinsic clearance values of nine CYP marker probe substrate reactions in the absence and presence of BSA (0.1 and 1.0% w/v) were characterized in human liver microsomes. The results demonstrate that most of the unsaturated fatty acids showed marked inhibition towards CYP2C8 mediated amodiaquine N-deethylation followed by inhibition of CYP2C9 and CYP2B6 mediated activities...
February 4, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28177686/pharmacokinetics-of-metformin-in-the-rat-assessment-of-the-effect-of-hyperlipidemia-and-evidence-for-its-metabolism-to-guanylurea
#16
Raniah Q Gabr, Ahmed A El-Sherbeni, Mohamed Ben-Eltriki, Ayman Os El-Kadi, Dion R Brocks
Metformin pharmacokinetics are highly dependent upon organic cationic transporters. There is evidence of a change in its renal clearance in hyperlipidemic obese patients, and no information on its metabolic fate. To study some of these aspects, the influence of poloxamer 407 (P407)-induced hyperlipidemia on metformin pharmacokinetics was assessed. Control and P407 treated adult male rats were administered 30 mg/kg metformin intravenously (iv). The pharmacokinetic assessments were performed at 2 time points, 36 and 108 h, following the intraperitoneal dose of P407 (1 g/kg)...
December 15, 2016: Canadian Journal of Physiology and Pharmacology
https://www.readbyqxmd.com/read/28174066/discovery-of-4-chloro-2-2-4-dichloro-6-methylphenoxy-1-methyl-7-pentan-3-yl-1h-benzimidazole-a-novel-crf1-receptor-antagonist
#17
Michiyo Mochizuki, Takuto Kojima, Katsumi Kobayashi, Etsuo Kotani, Yuji Ishichi, Naoyuki Kanzaki, Hideyuki Nakagawa, Teruaki Okuda, Yohei Kosugi, Takahiko Yano, Yuu Sako, Maiko Tanaka, Kazuyoshi Aso
Compound 1 exhibits potent binding inhibition activity against a corticotropin-releasing factor 1 (CRF1) receptor (IC50=9.5nM) and in vitro antagonistic activity (IC50=88nM) but is rapidly metabolized by human hepatic microsomes (182μL/min/mg). Here we identified metabolically stable compounds with potent CRF binding inhibitory activity. Structure-activity relationship (SAR) studies considering in vitro metabolic stability revealed that 4-chloro-2-(2,4-dichloro-6-methylphenoxy)-1-methyl-7-(pentan-3-yl)-1H-benzimidazole 24d was more stable in human microsomes (87μL/min/mg) than compound 1...
November 8, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28165233/the-bibenzyl-canniprene-inhibits-the-production-of-pro-inflammatory-eicosanoids-and-selectively-accumulates-in-some-cannabis-sativa-strains
#18
Gianna Allegrone, Federica Pollastro, Gianmaria Magagnini, Orazio Taglialatela-Scafati, Julia Seegers, Andreas Koeberle, Oliver Werz, Giovanni Appendino
Canniprene (1), an isoprenylated bibenzyl unique to Cannabis sativa, can be vaporized and therefore potentially inhaled from marijuana. Canniprene (1) potently inhibited the production of inflammatory eicosanoids via the 5-lipoxygenase pathway (IC50 0.4 μM) and also affected the generation of prostaglandins via the cyclooxygenase/microsomal prostaglandin E2 synthase pathway (IC50 10 μM), while the related spiranoid bibenzyls cannabispiranol (2) and cannabispirenone (3) were almost inactive in these bioassays...
February 6, 2017: Journal of Natural Products
https://www.readbyqxmd.com/read/28161444/human-tissue-distribution-of-carbonyl-reductase-1-using-proteomic-approach-with-lc-ms-ms
#19
Wenyi Hua, Hui Zhang, Sangwoo Ryu, Xin Yang, Li Di
Human tissue distribution of carbonyl reductase 1 (CBR1) is quite controversial in the literature. To understand the differences, CBR1 protein abundance in human intestine, liver and kidney has been determined using a proteomic approach with LC-MS/MS. The results show that CBR1 distribution in the three tissues is relatively similar, within 2-3 folds of each other. Intestine has the highest CBR1 enzyme level (106 pmol/mg protein) followed by liver (76 pmol/mg protein) and kidney (39 pmol/mg protein). The high abundance of CBR1 in the intestine and kidney suggests the critical role of this enzyme in gut first-pass metabolism and extra-hepatic clearance...
February 1, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28160853/identification-of-acetylshikonin-as-the-novel-cyp2j2-inhibitor-with-anti-cancer-activity-in-hepg2-cells
#20
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
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