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https://www.readbyqxmd.com/read/29146463/age-dependent-in-vitro-metabolism-of-bifenthrin-in-rat-and-human-hepatic-microsomes
#1
Gopinath C Nallani, Appavu Chandrasekaran, Kelem Kassahun, Li Shen, Shaaban F ElNaggar, Zhiwei Liu
Bifenthrin, a pyrethroid insecticide, undergoes oxidative metabolism leading to the formation of 4'-hydroxy-bifenthrin (4'-OH-BIF) and hydrolysis leading to the formation of TFP acid in rat and human hepatic microsomes. In this study, age-dependent metabolism of bifenthrin in rats and humans were determined via the rates of formation of 4'-OH-BIF and TFP acid following incubation of bifenthrin in juvenile and adult rat (PND 15 and PND 90) and human (<5years and >18years) liver microsomes. Furthermore, in vitro hepatic intrinsic clearance (CLint) of bifenthrin was determined by substrate consumption method in a separate experiment...
November 13, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/29143854/in-vitro-biotransformation-of-pyrrolizidine-alkaloids-in-different-species-part%C3%A2-i-microsomal-degradation
#2
Franziska Kolrep, Jorge Numata, Carsten Kneuer, Angelika Preiss-Weigert, Monika Lahrssen-Wiederholt, Dieter Schrenk, Anja These
Pyrrolizidine alkaloids (PA) are secondary metabolites of certain flowering plants. The ingestion of PAs may result in acute and chronic effects in man and livestock with hepatotoxicity, mutagenicity, and carcinogenicity being identified as predominant effects. Several hundred PAs sharing the diol pyrrolizidine as a core structure are formed by plants. Although many congeners may cause adverse effects, differences in the toxic potency have been detected in animal tests. It is generally accepted that PAs themselves are biologically and toxicologically inactive and require metabolic activation...
November 16, 2017: Archives of Toxicology
https://www.readbyqxmd.com/read/29142407/molecular-docking-analysis-of-phytic-acid-and-4-hydroxyisoleucine-as-cyclooxygenase-2-microsomal-prostaglandin-e-synthase-2-tyrosinase-human-neutrophil-elastase-matrix-metalloproteinase-2-and-9-xanthine-oxidase-squalene-synthase-nitric-oxide-synthase-human
#3
Radhakrishnan Narayanaswamy, Lam Kok Wai, Norhaizan Mohd Esa
Background: The phytoconstituents phytic acid and 4-hydroxyisoleucine have been reported to posses various biological properties. Objective: This prompted us to carry out the docking study on these two ligands (phytic acid & 4-hydroxyisoleucine) against eleven targeted enzymes. Materials and Methods: Phytic acid & 4-hydroxyisoleucine were evaluated on the docking behaviour of cyclooxygenase-2 (COX-2), microsomal prostaglandin E synthase-2 (mPGES-2), tyrosinase, human neutrophil elastase (HNE), matrix metalloproteinase (MMP 2 and 9), xanthine oxidase (XO), squalene synthase (SQS), nitric oxide synthase (NOS), human aldose reductase (HAR) and lipoxygenase (LOX) using Discovery Studio Version 3...
October 2017: Pharmacognosy Magazine
https://www.readbyqxmd.com/read/29138972/stable-isotope-labeling-and-2-3-5-4-tetrahydroxystilbene-2-o-%C3%AE-d-glucopyranoside-biosynthetic-pathway-characterization-in-fallopia-multiflora
#4
Wanxia Xia, Wen Rui, Wei Zhao, Shujing Sheng, Lei Lei, Yifan Feng, Shujin Zhao
The THSG biosynthetic pathway in F. multiflora was characterized, and enzymatic activities responsible for the resveratrol synthesis, hydroxylation, and glycosylation reactions involved in THSG biosynthesis were confirmed in vitro. The biosynthetic origin of 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucopyranoside (THSG) and the enzymes involved in THSG biosynthesis in Fallopia multiflora were studied using stable isotope labeling and biocatalytic methods. UPLC-MS-based analyses were used to unravel the isotopologue composition of the biosynthetic intermediates and products, as well as to detect the products of the enzyme assay experiments...
November 14, 2017: Planta
https://www.readbyqxmd.com/read/29138287/clopidogrel-carboxylic-acid-glucuronidation-is-mediated-mainly-by-ugt2b7-ugt2b4-and-ugt2b17-implications-for-pharmacogenetics-and-drug-drug-interactions
#5
Helina Kahma, Anne M Filppula, Mikko Neuvonen, E Katriina Tarkiainen, Aleksi Tornio, Mikko T Holmberg, Matti K Itkonen, Moshe Finel, Pertti J Neuvonen, Mikko Niemi, Janne T Backman
The antiplatelet drug clopidogrel is metabolized to an acyl-β-D-glucuronide, which causes time-dependent inactivation of CYP2C8. Our aim was to characterize the UDP-glucuronosyltransferase (UGT) enzymes that are responsible for the formation of clopidogrel acyl-β-D-glucuronide. Kinetic analyses and targeted inhibition experiments were performed using pooled human liver and intestine microsomes (HLM and HIM, respectively) and selected human recombinant UGTs based on preliminary screening. The effects of relevant UGT polymorphisms on the pharmacokinetics of clopidogrel were evaluated in 106 healthy volunteers...
November 14, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29136681/assessment-of-multiple-cytochrome-p450-activities-in-metabolically-inactivated-human-liver-microsomes-and-roles-of-p450-2c-isoforms-in-reaction-phenotyping-studies
#6
Norie Murayama, Kanako Yajima, Mikiko Hikawa, Kanami Shimura, Yu Ishii, Masaki Takada, Yasuhiro Uno, Masahiro Utoh, Kazuhide Iwasaki, Hiroshi Yamazaki
The fraction of substrate metabolized (fm ) can be used to estimate drug interactions and can be determined by comparison of the intrinsic clearances (CLint ) of victim drugs obtained from inhibited and uninhibited hepatic enzymes. Commercially available human liver microsomes were recently developed in which one cytochrome P450 (P450) isoform is selectively inactivated. These inactivated liver microsomes were used to evaluate the roles of P450 2C isoforms in the depletion and oxidation of probe substrates...
November 14, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/29136555/non-targeted-metabolomics-guided-sildenafil-metabolism-study-in-human-liver-microsomes
#7
Ju-Hyun Kim, Jun Hyun Jo, Kyung-Ah Seo, Hayoung Hwang, Hye Suk Lee, Sangkyu Lee
Metabolomics combined with high-resolution mass spectrometry (HR-MS) and multivariate data analysis has broad applications in the study of xenobiotic metabolism. Although information about xenobiotic metabolism is essential to understand toxic mechanisms, pharmacokinetic parameters and excretion pathways, it is limited to predict all generated metabolites in biological fluids. Here, we revisited sildenafil metabolism in human liver microsomes using a metabolomics approach to achieve a global picture of sildenafil phase 1 metabolism...
November 7, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/29134244/modulation-of-cyp3a-enzyme-activity-by-diosmin-and-its-consequence-on-carbamazepine-pharmacokinetics-in-rats
#8
Satish Kumar Bedada, Prasad Neerati
Diosmin is a widely used flavonoid for the treatment of varicose veins and hemorrhoids. Epileptic patients with hemorrhoids and varicose veins may use diosmin along with carbamazepine (CBZ) therapy, which leads to pharmacokinetic interaction between diosmin and CBZ. Therefore, the present study was performed to evaluate the effect of diosmin on the pharmacokinetics of CBZ in rats. Diosmin-mediated altered CYP3A enzyme activity in human and rat liver microsomes was examined using CYP3A dependent erythromycin N-demethylase assay...
November 14, 2017: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/29133569/efficacy-of-tilorone-dihydrochloride-against-ebola-virus-infection
#9
Sean Ekins, Mary A Lingerfelt, Jason E Comer, Alexander N Freiberg, Jon C Mirsalis, Kathleen O'Loughlin, Anush Harutyunyan, Claire McFarlane, Carol E Green, Peter B Madrid
Tilorone dihydrochloride (tilorone) is a small-molecule, orally bioavailable drug that is used clinically as an antiviral outside of the US. A machine learning model trained on anti-Ebola virus (EBOV) screening data previously identified tilorone as a potent in vitro EBOV inhibitor, making it a candidate for the treatment of Ebola virus disease (EVD). In the present study, a series of in vitro ADMET (absorption, distribution, metabolism, excretion, toxicity) assays demonstrated the drug has excellent solubility, high Caco-2 permeability, was not a P-glycoprotein substrate and had no inhibitory activity against five human CYP450 enzymes (3A4, 2D6, 2C19, 2C9 and 1A2)...
November 13, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29131945/enantioselectivity-of-2-2-3-5-6-pentachlorobiphenyl-pcb-95-atropisomers-toward-ryanodine-receptors-ryrs-and-their-influences-on-hippocampal-neuronal-networks
#10
Wei Feng, Jing Zheng, Gaelle Robin, Yao Dong, Makoto Ichikawa, Yoshihisa Inoue, Tadashi Mori, Takeshi Nakano, Isaac N Pessah
Nineteen ortho-substituted PCBs are chiral and found enantioselectively enriched in ecosystems. Their differential actions on biological targets are not understood. PCB 95 (2,2',3,5',6-pentachlorobiphenyl), a chiral PCB of current environmental relevance, is among the most potent towards modifying ryanodine receptors (RyR) function and Ca2+ signaling. PCB 95 atropisomers are separated and assigned aR- and aS-PCB 95 using 3 chiral-columns HPLC and circular dichroism spectroscopy. Studies of RyR1-enriched microsomes show aR-PCB 95 with >4X greater potency (EC50=0...
November 13, 2017: Environmental Science & Technology
https://www.readbyqxmd.com/read/29130831/a-predominant-oxidative-renal-metabolite-of-empagliflozin-in-male-mice-is-cytotoxic-in-mouse-renal-tubular-cells-but-not-genotoxic
#11
James D Smith, Zimei Huang, Patricia A Escobar, Pamela Foppiano, Hlaing Maw, William Loging, Hongbin Yu, Jonathan A Phillips, Mitchell Taub, Warren W Ku
In a previously reported CD-1 mouse 2-year carcinogenicity study with the sodium glucose cotransporter-2 inhibitor empagliflozin, an increased incidence of renal tubular adenomas and carcinomas was identified only in the male high-dose group. Follow-up investigative studies have shown that the renal tumors in male high-dose mice were preceded by a number of renal degenerative/regenerative findings. Prior cross-species in vitro metabolism studies using microsomes identified an oxidative metabolite (M466/2) predominantly formed in the male mouse kidney and which spontaneously degrades to a metabolite (M380/1) and reactive 4-OH crotonaldehyde (CTA)...
January 1, 2017: International Journal of Toxicology
https://www.readbyqxmd.com/read/29129850/prostaglandin-terminal-synthases-as-novel-therapeutic-targets
#12
Shuntaro Hara
Non-steroidal anti-inflammatory drugs (NSAIDs) exert their anti-inflammatory and anti-tumor effects by reducing prostaglandin (PG) production via the inhibition of cyclooxygenase (COX). However, the gastrointestinal, renal and cardiovascular side effects associated with the pharmacological inhibition of the COX enzymes have focused renewed attention onto other potential targets for NSAIDs. PGH2, a COX metabolite, is converted to each PG species by species-specific PG terminal synthases. Because of their potential for more selective modulation of PG production, PG terminal synthases are now being investigated as a novel target for NSAIDs...
2017: Proceedings of the Japan Academy. Series B, Physical and Biological Sciences
https://www.readbyqxmd.com/read/29129847/effects-of-ketoconazole-on-cyclophosphamide-metabolism-evaluation-of-cyp3a4-inhibition-effect-using-the-in-vitro-and-in-vivo-models
#13
Le Yang, Chenyang Yan, Feng Zhang, Bo Jiang, Shouhong Gao, Youtian Liang, Lifeng Huang, Wansheng Chen
Cyclophosphamide (CP) is widely used in anticancer therapy regimens and 2-dechloroethylcyclophosphamide (DECP) is its side-chain dechloroethylated metabolite. N-dechloroethylation of CP mediated by the enzyme CYP3A4 yields nephrotoxic and neurotoxic chloroacetaldehyde (CAA) in equimolar amount to DECP. This study aimed to evaluate the inhibitory effect of ketoconazole (KTZ) on CP metabolism through in vitro and in vivo drug-drug interaction (DDI) research. Long-term treatment of KTZ induces hepatic injury; thus single doses of KTZ at low, middle, and high levels (10, 20, and 40 mg/kg) were investigated for pharmacokinetic DDI with CP...
November 13, 2017: Experimental Animals
https://www.readbyqxmd.com/read/29128830/metabolism-of-the-synthetic-cannabinoid-5f-py-pica-by-human-and-rat-hepatocytes-and-identification-of-biliary-analytical-targets-by-directional-efflux-in-sandwich-cultured-rat-hepatocytes-using-uhplc-hr-ms-ms
#14
Marie Mardal, Pieter Annaert, Carolina Noble, Marlies Oorts, Kristian Linnet
Analytical strategies for detecting drugs in biological samples rely on information on metabolism and elimination. 5F-PY-PICA belongs to the group of synthetic cannabinoids that are known to undergo excretion into the bile. The aims of this study were the in vitro identification of metabolites of 5F-PY-PICA and to determine which analytical targets are excreted into the bile and urine. Metabolites identified after incubation of 5F-PY-PICA with pooled human liver microsomes (pHLM), pooled human hepatocytes (pHH), or suspended and sandwich-cultured rat hepatocytes (SCRH)...
November 7, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/29128804/hexachlorobenzene-as-a-persistent-organic-pollutant-toxicity-and-molecular-mechanism-of-action
#15
REVIEW
Beata Starek-Świechowicz, Bogusława Budziszewska, Andrzej Starek
Hexachlorobenzene (HCB) is an organochlorine pesticide widely distributed in the environment. Chronic exposure of humans to HCB leads to a number of effects, such as triggering of porphyria, microsomal enzyme induction, thyroid dysfunctions, neurological symptoms, and immunological disorders. In animals, HCB induced hepatic porphyria, neurotoxic effects, and toxic effects on the thyroid function, reproductive system, and immune system. HCB as a dioxin-like compound and a weak ligand of the aryl hydrocarbon receptor (AhR) is a hormonal disruptor...
July 1, 2017: Pharmacological Reports: PR
https://www.readbyqxmd.com/read/29127460/hepatic-metabolism-of-licochalcone-a-a-potential-chemopreventive-chalcone-from-licorice-glycyrrhiza-inflata-determined-using-liquid-chromatography-tandem-mass-spectrometry
#16
Lingyi Huang, Dejan Nikolic, Richard B van Breemen
The metabolism of the chemoprevention agent licochalcone A, which is a chemopreventive chalcone found in abundance in the licorice species Glycyrrhiza inflata, was investigated using human liver microsomes and human hepatocytes combined with analysis using high performance liquid chromatography-mass spectrometry (LC-MS). Five oxygenated phase I metabolites of licochalcone A were formed by human liver microsomes, including a catechol on the A-ring, two intramolecular cyclization products following epoxidation of the exocyclic alkene at position 5 of the B-ring, and two dioxygenated products...
November 10, 2017: Analytical and Bioanalytical Chemistry
https://www.readbyqxmd.com/read/29127056/metabolites-identificaion-of-two-bioactive-constituents-in-trollius-ledebourii-in-rats-using-ultra-high-performance-liquid-chromatography-coupled-to-quadrupole-time-of-flight-mass-spectrometry
#17
Man Liao, Xiaoye Cheng, Xinpeng Diao, Yupeng Sun, Lantong Zhang
Orientin and vitexin, 4'-hydroxyl-2-phenylchromen-4-one, are both major flavones derivatives found in Trollius ledebourii possessing definite pharmacological activities. In this study, in vitro metabolisms investigated on rat liver microsomes (RLMs) and in vivo metabolisms explored on Male Sprague Dawley rats of orientin and vitexin were tested, respectively. A systematic method based on ultra-high-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) was developed to characterize metabolites by means of electrospray ionization (ESI) mass spectrometry in positive ion mode...
November 2, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/29126801/species-differences-between-rat-and-human-in-vitro-metabolite-profile-in-vivo-predicted-clearance-cyp450-inhibition-and-cyp450-isoforms-that-metabolize-benzanthrone-implications-in-risk-assessment
#18
Isha Taneja, Kajal Karsauliya, Mamunur Rashid, Ashish Kumar Sonkar, Kanumuri Siva Rama Raju, Sandeep Kumar Singh, Mukul Das, Muhammad Wahajuddin, Sheelendra Pratap Singh
Benzanthrone (BNZ) is a polycyclic aromatic hydrocarbon found in industrial effluent causing skin, respiratory, gastrointestinal, genitourinary, nervous and hemopoietic toxicity. While its toxicity has been well studied, its metabolism in humans has not been investigated. The aim of this study was to characterize species differences in the in vitro metabolism of BNZ in rat and human liver microsomes and to identify the CYP isoforms involved in its metabolism. Upon incubation in liver microsomes, BNZ was found to be a direct substrate of phase I metabolism in both rat and human, undergoing oxidation and reduction...
November 7, 2017: Food and Chemical Toxicology
https://www.readbyqxmd.com/read/29125184/hepatic-and-hippocampal-cytochrome-p450-enzyme-overexpression-during-spontaneous-recurrent-seizures
#19
Leonie Runtz, Benoit Girard, Marion Toussenot, Julie Espallergues, Alexis Fayd'Herbe De Maudave, Alexandre Milman, Frederic deBock, Chaitali Ghosh, Nathalie C Guérineau, Jean-Marc Pascussi, Federica Bertaso, Nicola Marchi
OBJECTIVE: Available evidence points to a role of cytochrome P450 (Cyp) drug biotransformation enzymes in central nervous system diseases, including epilepsy. Deviations in drug pharmacokinetic profiles may impact therapeutic outcomes. Here, we ask whether spontaneous recurrent seizure (SRS) activity is sufficient to modulate the expression of major Cyp enzymes in the liver and brain. METHODS: Unilateral intrahippocampal (IH) kainic acid (KA) injections were used to elicit nonconvulsive status epilepticus (SE), epileptogenesis, and SRS, as monitored by video-electroencephalography...
November 10, 2017: Epilepsia
https://www.readbyqxmd.com/read/29123032/pregnane-x-receptor-promotes-ethanol-induced-hepatosteatosis-in-mice
#20
Sora Choi, Prince Neequaye, Samuel W French, Frank J Gonzalez, Maxwell A Gyamfi
The pregnane X receptor (PXR, NR1I2) is a xenobiotic-sensing nuclear receptor that modulates the metabolic response to drugs and toxic agents. Both PXR activation and deficiency promote hepatic triglyceride accumulation, a hallmark feature of alcoholic liver disease (ALD). However, the molecular mechanism of PXR-mediated activation of ethanol (EtOH)-induced steatosis is unclear. Here, using male wild type (WT) and Pxr-null mice we examined PXR-mediated regulation of chronic EtOH-induced hepatic lipid accumulation and hepatotoxicity...
November 9, 2017: Journal of Biological Chemistry
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