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Human carboxylesterase

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https://www.readbyqxmd.com/read/27895113/age-dependent-absolute-abundance-of-hepatic-carboxylesterases-ces1-and-ces2-by-lc-ms-ms-proteomics-application-to-pbpk-modeling-of-oseltamivir-in-vivo-pharmacokinetics-in-infants
#1
Mikael Boberg, Marc Vrana, Aanchal Mehrotra, Robin E Pearce, Andrea Gaedigk, Deepak Kumar Bhatt, J Steven Leeder, Bhagwat Prasad
The age-dependent absolute protein abundance of carboxylesterase 1 and 2 (CES1 and CES2) in human liver was investigated and applied to predict infant pharmacokinetics (PK) of oseltamivir. The CES absolute protein abundance was determined by LC-MS/MS proteomics in human liver microsomal and cytosolic fractions prepared from tissue samples obtained from 136 pediatric and 35 adult donors. Two surrogate peptides per protein were selected for the quantification of CES1 and CES2 protein abundance. Purified CES1 and CES2 protein standards were used as calibrators, and the heavy labeled peptides were used as the internal standards...
November 28, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27881673/sortilin-1-modulates-hepatic-cholesterol-lipotoxicity-in-mice-via-functional-interaction-with-liver-carboxylesterase-1
#2
Jibiao Li, Yifeng Wang, David Matye, Hemantkumar Chavan, Partha Krishnamurthy, Feng Li, Tiangang Li
Liver plays a key role in cholesterol metabolism. Impaired hepatic cholesterol homeostasis causes intracellular free cholesterol accumulation and hepatocyte injury. Sortilin 1 (Sort1) is an intracellular lysosomal trafficking receptor that was recently identified by GWAS as a novel regulator of cholesterol metabolism in humans. Here we report that Sort1 deficiency protected against cholesterol accumulation-induced liver injury and inflammation in mice. Using LC-MS/MS based proteomics approach, we identified liver carboxyesterase 1 (CES1) as a novel Sort1 interacting protein...
November 23, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27831961/nomenclature-for-alleles-of-the-human-carboxylesterase-1-gene
#3
Henrik B Rasmussen, Majbritt B Madsen, Peter R Hansen
No abstract text is available yet for this article.
November 9, 2016: Pharmacogenetics and Genomics
https://www.readbyqxmd.com/read/27800573/pharmacokinetic-modeling-and-monte-carlo-simulation-to-predict-interindividual-variability-in-human-exposure-to-oseltamivir-and-its-active-metabolite-ro-64-0802
#4
Mototsugu Ito, Hiroyuki Kusuhara, Atsushi Ose, Tsunenori Kondo, Kazunari Tanabe, Hideki Nakayama, Shigeru Horita, Takuya Fujita, Yuichi Sugiyama
Oseltamivir (Tamiflu®) is a prodrug of Ro 64-0802, a selective inhibitor of influenza virus neuraminidase. There is a possible relationship between oseltamivir treatment and neuropsychiatric adverse events; although this has not been established, close monitoring is recommended on the prescription label. The objective of this study was to predict interindividual variability of human exposure to oseltamivir and its active metabolite Ro 64-0802. By leveraging mathematical models and computations, physiological parameters in virtual subjects were generated with population means and coefficient of variations collected from the literature or produced experimentally...
October 31, 2016: AAPS Journal
https://www.readbyqxmd.com/read/27771568/effect-of-surfactant-in-mitigating-cadmium-oxide-nanoparticle-toxicity-implications-for-mitigating-cadmium-toxicity-in-environment
#5
Sricharani Rao Balmuri, Uthra Selvaraj, Vadivel Vinod Kumar, Savarimuthu Philip Anthony, Aristides Michael Tsatsakis, Kirill Sergeevich Golokhvast, Thiagarajan Raman
Cadmium (Cd), classified as human carcinogen, is an extremely toxic heavy metal pollutant, and there is an increasing environmental concern for cadmium exposure through anthropogenic sources including cigarette smoke. Though Cd based nanoparticles such as cadmium oxide (CdO) are being widely used in a variety of clinical and industrial applications, the toxicity of CdO nanoparticles has not been well characterized. Herein we report the toxicity of CdO nanoparticles employing zebrafish as a model. Two different CdO nanoparticles were prepared, calcination of Cd(OH)2 without any organic molecule (CdO-1) and calcination of Cd-citrate coordination polymer (CdO-2), to evaluate and compare the toxicity of these two different CdO nanoparticles...
January 2017: Environmental Research
https://www.readbyqxmd.com/read/27702666/identification-and-characterization-of-naturally-occurring-inhibitors-against-human-carboxylesterase-2-in-white-mulberry-root-bark
#6
Ya-Jing Liu, Shi-Yang Li, Jie Hou, Yan-Fang Liu, Dan-Dan Wang, Yong-Shan Jiang, Guang-Bo Ge, Xin-Miao Liang, Ling Yang
White Mulberry Root-bark (WMR) is an edible Chinese herbal used for the treatment of inflammation, nephritis and asthma. This study aimed to investigate the inhibitory effects of ethanol extract from WMR against human carboxylesterase 2 (hCE2), as well as to identity and character natural hCE2 inhibitors in this herbal. Our results demonstrated that the ethanol extract of WMR displayed potent inhibitory effects against hCE2, while three major bioactive constitutes in WMR were identified on the basis of LC fingerprinting combined with activity-based screening of LC fractions...
October 1, 2016: Fitoterapia
https://www.readbyqxmd.com/read/27659534/tumor-specific-gene-therapy-for-pancreatic-cancer-using-human-neural-stem-cells-encoding-carboxylesterase
#7
Sung S Choi, Kichul Yoon, Seon-A Choi, Seung-Bin Yoon, Seung U Kim, Hong J Lee
Advanced pancreatic cancer is one of the most lethal malignant human diseases lacking effective treatment. Its extremely low survival rate necessitates development of novel therapeutic approach. Human neural stem cells (NSCs) are known to have tumor-tropic effect. We genetically engineered them to express rabbit carboxyl esterase (F3.CE), which activates prodrug CPT-11(irinotecan) into potent metabolite SN-38. We found significant inhibition of the growth of BxPC3 human pancreatic cancer cell line in vitro by F3...
September 21, 2016: Oncotarget
https://www.readbyqxmd.com/read/27638507/establishment-and-characterization-of-a-novel-caco-2-subclone-with-a-similar-low-expression-level-of-human-carboxylesterase-1-to-human-small-intestine
#8
Kayoko Ohura, Hikaru Nishiyama, Saori Saco, Keisuke Kurokawa, Teruko Imai
Caco-2 cells predominantly express human carboxylesterase 1 (hCE1), unlike the human intestine which predominantly expresses human carboxylesterase 2 (hCE2). Transport experiments using Caco-2 cell monolayers often lead to mis-estimation of the intestinal absorption of prodrugs because of this difference, as prodrugs designed to increase the bioavailability of parent drugs are made to be resistant to hCE2 in the intestine, so that they can be hydrolyzed by hCE1 in the liver. In the present study, we tried to establish a new Caco-2 subclone, with a similar pattern of carboxylase expression to human intestine, to enable a more accurate estimation of the intestinal absorption of prodrugs...
September 16, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27614009/dabigatran-etexilate-activation-is-affected-by-the-ces1-genetic-polymorphism-g143e-rs71647871-and-gender
#9
Jian Shi, Xinwen Wang, Jenny-Hoa Nguyen, Barry E Bleske, Yan Liang, Li Liu, Hao-Jie Zhu
The oral anticoagulant prodrug dabigatran etexilate (DABE) is sequentially metabolized by intestinal carboxylesterase 2 (CES2) and hepatic carboxylesterase 1 (CES1) to form its active metabolite dabigatran (DAB). A recent genome-wide association study reported that the CES1 single nucleotide polymorphisms (SNPs) rs2244613 and rs8192935 were associated with lower DAB plasma concentrations in the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) study participants. In addition, gender differences in exposure to DAB were observed in clinical studies...
November 1, 2016: Biochemical Pharmacology
https://www.readbyqxmd.com/read/27495117/challenges-and-opportunities-with-non-cyp-enzymes-aldehyde-oxidase-carboxylesterase-and-udp-glucuronosyltransferase-focus-on-reaction-phenotyping-and-prediction-of-human-clearance
#10
Upendra A Argikar, Philip M Potter, J Matthew Hutzler, Punit H Marathe
Over the years, significant progress has been made in reducing metabolic instability due to cytochrome P450-mediated oxidation. High-throughput metabolic stability screening has enabled the advancement of compounds with little to no oxidative metabolism. Furthermore, high lipophilicity and low aqueous solubility of presently pursued chemotypes reduces the probability of renal excretion. As such, these low microsomal turnover compounds are often substrates for non-CYP-mediated metabolism. UGTs, esterases, and aldehyde oxidase are major enzymes involved in catalyzing such metabolism...
August 5, 2016: AAPS Journal
https://www.readbyqxmd.com/read/27483321/hydrolytic-fate-of-3-15-acetyldeoxynivalenol-in-humans-specific-deacetylation-by-the-small-intestine-and-liver-revealed-using-in-vitro-and-ex-vivo-approaches
#11
El Hassan Ajandouz, Stéphane Berdah, Vincent Moutardier, Thierry Bege, David Jérémie Birnbaum, Josette Perrier, Eric Di Pasquale, Marc Maresca
In addition to deoxynivalenol (DON), acetylated derivatives, i.e., 3-acetyl and 15-acetyldexynivalenol (or 3/15ADON), are present in cereals leading to exposure to these mycotoxins. Animal and human studies suggest that 3/15ADON are converted into DON after their ingestion through hydrolysis of the acetyl moiety, the site(s) of such deacetylation being still uncharacterized. We used in vitro and ex vivo approaches to study the deacetylation of 3/15ADON by enzymes and cells/tissues present on their way from the food matrix to the blood in humans...
2016: Toxins
https://www.readbyqxmd.com/read/27454346/differences-in-intestinal-hydrolytic-activities-between-cynomolgus-monkeys-and-humans-evaluation-of-substrate-specificities-using-recombinant-carboxylesterase-2-isozymes
#12
Yoshiyuki Igawa, Seiya Fujiwara, Kayoko Ohura, Takatsugu Hirokawa, You Nishizawa, Shotaro Uehara, Yasuhiro Uno, Teruko Imai
Cynomolgus monkeys, used as an animal model to predict human pharmacokinetics, occasionally show different oral absorption patterns to humans due to differences in their intestinal metabolism. In this study, we investigated the differences between intestinal hydrolytic activities in cynomolgus monkeys and humans, in particular the catalyzing activities of their carboxylesterase 2 (CES2) isozymes. For this purpose we used both human and monkey microsomes and recombinant enzymes derived from a cell culture system...
September 6, 2016: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/27423046/tumour-selective-targeting-of-drug-metabolizing-enzymes-to-treat-metastatic-cancer
#13
REVIEW
Monika Wierdl, Lyudmila Tsurkan, M Jason Hatfield, Philip M Potter
Carboxylesterases (CEs) are ubiquitous enzymes responsible for the detoxification of ester-containing xenobiotics. This hydrolysis reaction results in the formation of the corresponding carboxylic acid and alcohol. Due to their highly plastic active site, CEs can hydrolyze structurally very distinct and complex molecules. Because ester groups significantly increase the water solubility of compounds, they are frequently used in the pharmaceutical industry to make relatively insoluble compounds more bioavailable...
October 2016: British Journal of Pharmacology
https://www.readbyqxmd.com/read/27329304/metabolic-profile-of-3-acetyl-11-keto-%C3%AE-boswellic-acid-and-11-keto-%C3%AE-boswellic-acid-in-human-preparations-in-vitro-species-differences-and-bioactivity-variation
#14
Yonglei Cui, Xiangge Tian, Jing Ning, Chao Wang, Zhenlong Yu, Yan Wang, Xiaokui Huo, Lingling Jin, Sa Deng, Baojing Zhang, Xiaochi Ma
3-Acetyl-11-keto-β-boswellic acid (AKBA) and 11-keto-β-boswellic acid (KBA) are widely used in the clinic as anti-inflammatory drugs. However, these drugs have the poor bioavailability, which may be caused by their extensive metabolism. In this study, we systemically characterized both phase I and II metabolism of AKBA and KBA in vitro. In total, four major metabolites were firstly biosynthesized and identified using 1D and 2D NMR spectroscopy. Among them, three metabolites were novel. The kinetic parameters (K m , V max , CL int, and K i ) were also analyzed systematically in various biological samples...
September 2016: AAPS Journal
https://www.readbyqxmd.com/read/27228223/association-of-oseltamivir-activation-with-gender-and-carboxylesterase-1-genetic-polymorphisms
#15
Jian Shi, Xinwen Wang, Rachel F Eyler, Yan Liang, Li Liu, Bruce A Mueller, Hao-Jie Zhu
Oseltamivir, an inactive anti-influenza virus prodrug, is activated (hydrolysed) in vivo by carboxylesterase 1 (CES1) to its active metabolite oseltamivir carboxylate. CES1 functions are significantly associated with certain CES1 genetic variants and some non-genetic factors. The purpose of this study was to investigate the effect of gender and several CES1 genetic polymorphisms on oseltamivir activation using a large set of individual human liver samples. CES1-mediated oseltamivir hydrolysis and CES1 genotypes, including the G143E (rs71647871), rs2244613, rs8192935, the -816A>C (rs3785161) and the CES1P1/CES1P1VAR, were determined in 104 individual human livers...
December 2016: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/27214158/analysis-of-gene-expression-for-microminipig-liver-transcriptomes-using-parallel-long-read-technology-and-short-read-sequencing
#16
Chizuka Sakai, Shunsuke Iwano, Makiko Shimizu, Jun Onodera, Masashi Uchida, Eri Sakurada, Yuri Yamazaki, Yoshiji Asaoka, Naoko Imura, Yasuhiro Uno, Norie Murayama, Ryoji Hayashi, Hiroshi Yamazaki, Yohei Miyamoto
The microminipig is one of the smallest minipigs that has emerged as a possible experimental animal model, because it shares many anatomical and/or physiological similarities with humans, including the coronary artery distribution in the heart, the digestive physiology, the kidney size and its structure, and so on. However, information on gene expression profiles, including those on drug-metabolizing phase I and II enzymes, in the microminipig is limited. Therefore, the aim of the present study was to identify transcripts in microminipig livers and to determine gene expression profiles...
May 2016: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/27199904/biologically-based-methods-for-control-of-fumonisin-producing-fusarium-species-and-reduction-of-the-fumonisins
#17
REVIEW
Johanna F Alberts, Willem H van Zyl, Wentzel C A Gelderblom
Infection by the fumonisin-producing Fusarium spp. and subsequent fumonisin contamination of maize adversely affect international trade and economy with deleterious effects on human and animal health. In developed countries high standards of the major food suppliers and retailers are upheld and regulatory controls deter the importation and local marketing of fumonisin-contaminated food products. In developing countries regulatory measures are either lacking or poorly enforced, due to food insecurity, resulting in an increased mycotoxin exposure...
2016: Frontiers in Microbiology
https://www.readbyqxmd.com/read/27183507/permethrin-induced-oxidative-stress-and-toxicity-and-metabolism-a-review
#18
REVIEW
Xu Wang, María-Aránzazu Martínez, Menghong Dai, Dongmei Chen, Irma Ares, Alejandro Romero, Victor Castellano, Marta Martínez, José Luis Rodríguez, María-Rosa Martínez-Larrañaga, Arturo Anadón, Zonghui Yuan
Permethrin (PER), the most frequently used synthetic Type I pyrethroid insecticide, is widely used in the world because of its high activity as an insecticide and its low mammalian toxicity. It was originally believed that PER exhibited low toxicity on untargeted animals. However, as its use became more extensive worldwide, increasing evidence suggested that PER might have a variety of toxic effects on animals and humans alike, such as neurotoxicity, immunotoxicity, cardiotoxicity, hepatotoxicity, reproductive, genotoxic, and haematotoxic effects, digestive system toxicity, and cytotoxicity...
August 2016: Environmental Research
https://www.readbyqxmd.com/read/27132127/esterase-detoxication-of-acetylcholinesterase-inhibitors-using-human-liver-samples-in-vitro
#19
Virginia C Moser, Stephanie Padilla
Organophosphorus (OP) and N-methylcarbamate pesticides inhibit acetylcholinesterase (AChE), but differences in metabolism and detoxication can influence potency of these pesticides across and within species. Carboxylesterase (CaE) and A-esterase (paraoxonase, PON1) are considered factors underlying age-related sensitivity differences. We used an in vitro system to measure detoxication of AChE-inhibiting pesticides mediated via these esterases. Recombinant human AChE was used as a bioassay of inhibitor concentration following incubation with detoxifying tissue: liver plus Ca(+2) (to stimulate PON1s, measuring activity of both esterases) or EGTA (to inhibit PON1s, thereby measuring CaE activity)...
April 15, 2016: Toxicology
https://www.readbyqxmd.com/read/27130352/biotransformation-capacity-of-carboxylesterase-in-skin-and-keratinocytes-for-the-penta-ethyl-ester-prodrug-of-dtpa
#20
Jing Fu, Matthew Sadgrove, Lesley Marson, Michael Jay
The penta-ethyl ester prodrug of the chelating agent diethylene triamine pentaacetic acid (DTPA), referred to as C2E5, effectively accelerated clearance of americium after transdermal delivery. Carboxylesterases (CESs) play important roles in facilitating C2E5 hydrolysis. However, whether CESs in human skin hydrolyze C2E5 remains unknown. We evaluated the gene and protein expression of CESs in distinctive human epidermal cell lines: HEKa, HEKn, HaCaT, and A431. The substrates p-nitrophenyl acetate (pNPA) and 4-nitrophenyl valerate (4-NPV) were used to access esterase and CES activity...
August 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
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