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Human carboxylesterase

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https://www.readbyqxmd.com/read/28838926/a-comprehensive-functional-assessment-of-carboxylesterase-1-nonsynonymous-polymorphisms
#1
Xinwen Wang, Nada Rida, Jian Shi, Audrey Wu, Barry Bleske, Hao-Jie Zhu
Carboxylesterase 1 (CES1) is the predominant human hepatic hydrolase responsible for the metabolism of many clinically important medications. CES1 expression and activity vary markedly among individuals; and genetic variation is a major contributing factor to CES1 interindividual variability. In the present study, we comprehensively examined the functions of CES1 nonsynonymous single nucleotide polymorphisms (nsSNPs) and haplotypes using transfected cell lines and individual human liver tissues. The 20 candidate variants include CES1 nsSNPs with a minor allele frequency (MAF) > 0...
August 24, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28820941/a-photoactivatable-probe-for-super-resolution-imaging-of-enzymatic-activity-in-live-cells
#2
Elias A Halabi, Zacharias Thiel, Nils Trapp, Dorothea Pinotsi, Pablo Rivera-Fuentes
A dual-activatable, fluorogenic probe was developed to sense esterase activity with single-molecule resolution. Without enzymatic pre-activation, the diazoindanone-based probe has an electron-poor core and, upon irradiation, undergoes Wolff rearrangement to give a ring-expanded xanthene core that is nonemissive. If the probe is pre-activated by carboxylesterases, the tricyclic core becomes electron-rich, and the photoinduced Wolff rearrangement produces a highly emissive rhodol dye. Live-cell and solution studies confirmed the selectivity of the probe and revealed that the photoactivated dye does not diffuse away from the original location of activation because the intermediate ketene forms a covalent bond with surrounding macromolecules...
September 5, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28782481/rational-approaches-design-strategies-structure-activity-relationship-and-mechanistic-insights-for-esterase-inhibitors
#3
Harbinder Singh, Jatinder Vir Singh, Navdeep Kaur, Mohit Sanduja, Gurpreet Singh, Preet Mohinder Singh Bedi, Sahil Sharma
BACKGROUND: Esterase is an enzyme that splits esters into an acid and alcohol. Varieties of esterases are present in human body to control diverse set of cellular processes and execute their specific functions. It can be seen that any increase in metabolites produced by these enzymes lead to severe pathological conditions like Alzheimer disease, hypercholesterolemia etc. OBJECTIVE: Numerous esterase inhibitors have been developed and reported by the researchers around the globe, but not systematically summarized yet...
August 7, 2017: Mini Reviews in Medicinal Chemistry
https://www.readbyqxmd.com/read/28760607/phenolic-glycosides-and-monoterpenoids-from-the-roots-of-euphorbia-ebracteolata-and-their-bioactivities
#4
An-Hua Wang, Xiao-Kui Huo, Lei Feng, Cheng-Peng Sun, Sa Deng, Hou-Li Zhang, Bao-Jing Zhang, Xiao-Chi Ma, Jing-Ming Jia, Chao Wang
The bioactive substance investigation of Euphorbia ebracteolata obtained 17 compounds by various chromatographic techniques. Their structures were elucidated using widely spectroscopic data, including ESI-MS, HRESI-MS, CD, 1D- and 2D-NMR, which gave 5 new phenolic glucosides and 4 new monoterpenoids. The phenolic glucosides and monoterpenoids showed the inhibitory effect against the human carboxylesterase-2 (hCE-2) using a fluorescence bioassay in vitro, with the strongest inhibitor compound 4 (IC50 7.17μM)...
July 28, 2017: Fitoterapia
https://www.readbyqxmd.com/read/28737453/the-metabolism-and-drug-drug-interaction-potential-of-the-selective-prostacyclin-receptor-agonist-selexipag
#5
Carmela Gnerre, Jérôme Segrestaa, Swen Seeland, Päivi Äänismaa, Thomas Pfeifer, Stephane Delahaye, Ruben de Kanter, Tomohiko Ichikawa, Tetsuhiro Yamada, Alexander Treiber
- The metabolism of selexipag has been studied in vivo in man and the main excreted metabolites were identified. Also, metabolites circulating in human plasma have been structurally identified and quantified. - The main metabolic pathway of selexipag in man is the formation of the active metabolite ACT-333679. Other metabolic pathways include oxidation and dealkylation reactions. All primary metabolites undergo subsequent hydrolysis of the sulphonamide moiety to their corresponding acids. ACT-333679 undergoes conjugation with glucuronic acid and aromatic hydroxylation to P10, the main metabolite detected in human faeces...
July 24, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28713276/structure-activity-relationships-of-pentacyclic-triterpenoids-as-potent-and-selective-inhibitors-against-human-carboxylesterase-1
#6
Li-Wei Zou, Tong-Yi Dou, Ping Wang, Wei Lei, Zi-Miao Weng, Jie Hou, Dan-Dan Wang, Yi-Ming Fan, Wei-Dong Zhang, Guang-Bo Ge, Ling Yang
Human carboxylesterase 1 (hCE1), one of the most important serine hydrolases distributed in liver and adipocytes, plays key roles in endobiotic homeostasis and xenobiotic metabolism. This study aimed to find potent and selective inhibitors against hCE1 from phytochemicals and their derivatives. To this end, a series of natural triterpenoids were collected and their inhibitory effects against human carboxylesterases (hCEs) were assayed using D-Luciferin methyl ester (DME) and 6,8-dichloro-9,9-dimethyl-7-oxo-7,9-dihydroacridin-2-yl benzoate (DDAB) as specific optical substrate for hCE1, and hCE2, respectively...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28677105/carboxylesterases-in-lipid-metabolism-from-mouse-to-human
#7
REVIEW
Jihong Lian, Randal Nelson, Richard Lehner
Mammalian carboxylesterases hydrolyze a wide range of xenobiotic and endogenous compounds, including lipid esters. Physiological functions of carboxylesterases in lipid metabolism and energy homeostasis in vivo have been demonstrated by genetic manipulations and chemical inhibition in mice, and in vitro through (over)expression, knockdown of expression, and chemical inhibition in a variety of cells. Recent research advances have revealed the relevance of carboxylesterases to metabolic diseases such as obesity and fatty liver disease, suggesting these enzymes might be potential targets for treatment of metabolic disorders...
July 4, 2017: Protein & Cell
https://www.readbyqxmd.com/read/28667306/crystal-structure-of-pelagibacterium-halotolerans-pe8-new-insight-into-its-substrate-binding-pattern
#8
Ying-Yi Huo, Suhua Li, Jing Huang, Zhen Rong, Zhao Wang, Zhengyang Li, Rui Ji, Siyun Kuang, Heng-Lin Cui, Jixi Li, Xue-Wei Xu
Lysophospholipase_carboxylesterase (LPCE) has highly conserved homologs in many diverse species ranging from bacteria to humans, as well as substantial biological significance and potential therapeutic implications. However, its biological function and catalytic mechanism remain minimally investigated because of the lack of structural information. Here, we report the crystal structure of a bacterial esterase PE8 belonging to the LPCE family. The crystal structure of PE8 was solved with a high resolution of 1...
June 30, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28647665/comparative-metabolism-of-ddao-benzoate-in-liver-microsomes-from-various-species
#9
Hong-Ying Ma, Jia-Da Yang, Jie Hou, Li-Wei Zou, Qiang Jin, Da-Cheng Hao, Jing Ning, Guang-Bo Ge, Ling Yang
DDAB (6,8-dichloro-9,9-dimethyl-7-oxo-7,9-dihydroacridin-2-yl benzoate) is a newly developed near-infrared fluorescent probe for human carboxylesterase 2 (hCE2), exhibiting high specificity and good reactivity for real-time monitoring the enzymatic activities of hCE2 in complex biological systems. In order to explore the applicability of DDAB in commonly used animal species, the interspecies difference in DDAB hydrolysis was carefully investigated by using liver microsomes from human and five experimental animals including mouse, rat, dog, minipig and monkey...
October 2017: Toxicology in Vitro: An International Journal Published in Association with BIBRA
https://www.readbyqxmd.com/read/28619281/metabolism-of-ko143-an-abcg2-inhibitor
#10
Ke Liu, Junjie Zhu, Yixian Huang, Chaoyue Li, Jie Lu, Madhav Sachar, Song Li, Xiaochao Ma
The ATP-binding cassette sub-family G member 2 (ABCG2) plays an important role in modulating drug disposition and endobiotic homeostasis. KO143 is a potent and relatively selective ABCG2 inhibitor. We found that the metabolic stability of KO143 was very poor in human liver microsomes (HLM). Our further studies illustrated that the tert-butyl ester group in KO143 can be rapidly hydrolyzed and removed by carboxylesterase 1. This metabolic pathway was confirmed as a major pathway of KO143 metabolism in both HLM and mice...
March 6, 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28536421/assessment-of-tissue-specific-accumulation-elimination-and-toxic-effects-of-dichlorodiphenyltrichloroethanes-ddts-in-carp-through-aquatic-food-web
#11
Shanshan Di, Ruiquan Liu, Zhongnan Tian, Cheng Cheng, Li Chen, Wenjun Zhang, Zhiqiang Zhou, Jinling Diao
Microcosms containing DDT spiked-sediment, Tubifex tubifex and carp (Cyprinus carpio) were constructed to simulate a freshwater system. The accumulation, elimination and toxic effects of DDT (p,p'-DDT, o,p'-DDT), and its metabolites DDD (p,p'-DDD, o,p'-DDD) and DDE (p,p'-DDE, o,p'-DDE) were studied in T. tubifex and carp. Tissue/organ distributions of DDTs were also investigated in carp. The bioaccumulation and elimination of DDT differed in T. tubifex, carp and its tissues/organs. Unimodal or bimodal distributions were observed, and the concentrations of DDT metabolites (DDD and p,p'-DDE) increased over time...
May 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28532270/predominant-contributions-of-carboxylesterase-1-and-2-in-hydrolysis-of-anordrin-in-humans
#12
Jinfang Jiang, Xiaoyan Chen, Dafang Zhong
1. Anordrin (2α, 17α-diethynyl-A-nor-5α-androstane-2β, 17β-diol diproprionate) is post-coital contraceptive drug that is on the market in China for more than 30 years. This study aims to elucidate enzymes involved in anordrin hydrolysis, and to evaluate the significant role of carboxylesterases in anordrin hydrolysis in humans. 2. Human liver and intestinal microsomes, recombinant human carboxylesterase were selected as enzyme sources. In human liver microsomes, intrinsic clearance was 684 ± 83 μL/min/mg protein, which was considerably higher than the value of intestine microsomes (94...
June 7, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28473993/salvia-miltiorrhiza-roots-against-cardiovascular-disease-consideration-of-herb-drug-interactions
#13
REVIEW
Feng Chen, Li Li, Dan-Dan Tian
Salvia miltiorrhiza root (Danshen) is widely used in Asia for its cardiovascular benefits and contains both hydrophilic phenolic acids and lipophilic tanshinones, which are believed to be responsible for its therapeutic efficacy. This review summarized the effects of these bioactive components from S. miltiorrhiza roots on pharmacokinetics of comedicated drugs with mechanic insights regarding alterations of protein binding, enzyme activity, and transporter activity based on the published data stemming from both in vitro and in vivo human studies...
2017: BioMed Research International
https://www.readbyqxmd.com/read/28437488/the-novel-carboxylesterase-1-variant-c-662a-g-may-decrease-the-bioactivation-of-oseltamivir-in-humans
#14
Jaeseong Oh, SeungHwan Lee, Howard Lee, Joo-Youn Cho, Seo Hyun Yoon, In-Jin Jang, Kyung-Sang Yu, Kyoung Soo Lim
BACKGROUND: Human carboxylesterase 1 (CES1) is a serine esterase that hydrolyses various exogenous and endogenous compounds including oseltamivir, a prodrug used to treat influenza. A novel CES1 c.662A>G single nucleotide polymorphism (SNP) was predicted to decrease CES1 enzymatic activity in an in silico analysis. This study evaluated the effect of the c.662A>G SNP on the pharmacokinetics (PK) of oseltamivir in humans. METHODS: A single oral dose of oseltamivir at 75 mg was administered to 20 healthy subjects, 8 heterozygous c...
2017: PloS One
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
#15
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/28394886/carboxylesterase-gene-amplifications-associated-with-insecticide-resistance-in-aedes-albopictus-geographical-distribution-and-evolutionary-origin
#16
Linda Grigoraki, Dimitra Pipini, Pierrick Labbé, Alexandra Chaskopoulou, Mylene Weill, John Vontas
BACKGROUND: Aedes albopictus is one of the most invasive human disease vectors. Its control has been largely based on insecticides, such as the larvicide temephos. Temephos resistance has been associated with the up-regulation, through gene amplification, of two carboxylesterase (CCE) genes closely linked on the genome, capable of sequestering and metabolizing temephos oxon, the activated form of temephos. PRINCIPAL FINDINGS: Here, we investigated the occurrence, geographical distribution and origin of the CCE amplicon in Ae...
April 2017: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/28379972/the-novel-nematicide-wact-86-interacts-with-aldicarb-to-kill-nematodes
#17
Andrew R Burns, Rachel Bagg, May Yeo, Genna M Luciani, Michael Schertzberg, Andy G Fraser, Peter J Roy
Parasitic nematodes negatively impact human and animal health worldwide. The market withdrawal of nematicidal agents due to unfavourable toxicities has limited the available treatment options. In principle, co-administering nematicides at lower doses along with molecules that potentiate their activity could mitigate adverse toxicities without compromising efficacy. Here, we screened for new small molecules that interact with aldicarb, which is a highly effective treatment for plant-parasitic nematodes whose toxicity hampers its utility...
April 2017: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/28345025/optimization-of-a-neural-stem-cell-mediated-carboxylesterase-irinotecan-gene-therapy-for-metastatic-neuroblastoma
#18
Margarita Gutova, Leanne Goldstein, Marianne Metz, Anahit Hovsepyan, Lyudmila G Tsurkan, Revathiswari Tirughana, Lusine Tsaturyan, Alexander J Annala, Timothy W Synold, Zesheng Wan, Robert Seeger, Clarke Anderson, Rex A Moats, Philip M Potter, Karen S Aboody
Despite improved survival for children with newly diagnosed neuroblastoma (NB), recurrent disease is a significant problem, with treatment options limited by anti-tumor efficacy, patient drug tolerance, and cumulative toxicity. We previously demonstrated that neural stem cells (NSCs) expressing a modified rabbit carboxylesterase (rCE) can distribute to metastatic NB tumor foci in multiple organs in mice and convert the prodrug irinotecan (CPT-11) to the 1,000-fold more toxic topoisomerase-1 inhibitor SN-38, resulting in significant therapeutic efficacy...
March 17, 2017: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/28331290/effects-of-dexamethasone-coadministered-with-oseltamivir-on-the-pharmacokinetics-of-oseltamivir-in-healthy-volunteers
#19
Kyungho Jang, Min-Kyoung Kim, Jaeseong Oh, SeungHwan Lee, Joo-Youn Cho, Kyung-Sang Yu, Tai Kiu Choi, Sang-Hyuk Lee, Kyoung Soo Lim
PURPOSE: Oseltamivir is widely used in the treatment and prophylaxis of influenza A and B viral infections. It is ingested as an oral prodrug that is rapidly metabolized by carboxylesterase 1 (CES1) to its active form, oseltamivir carboxylate. Dexamethasone is also used in the treatment of acute respiratory distress syndrome, a severe complication of influenza; however, its influence on the pharmacokinetics (PK) of oseltamivir is controversial. The aim of this study was to investigate the effects of coadministering oseltamivir and dexamethasone on the PK of oseltamivir in healthy volunteers...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/28318508/effects-of-novel-brominated-flame-retardant-tbph-and-its-metabolite-tbmehp-on-human-vascular-endothelial-cells-implication-for-human-health-risks
#20
Ping Xiang, Rong-Yan Liu, Hong-Jie Sun, Yun-Wen Yang, Xin-Yi Cui, Lena Q Ma
As a replacement for polybrominated diphenyl ethers, bis-(2-ethylhexyl) tetrabromophthalate (TBPH) is widely used as a novel flame retardant and has been detected in many environmental matrix including human blood. TBPH can be metabolized into mono-(2-ethyhexyl) tetrabromophthalate (TBMEHP) by carboxylesterase. However, their adverse effects on human vascular endothelium and their potential impacts on human cardiovascular disease are unknown. In this study, their adverse effects and associated molecular mechanisms on human vascular endothelial cells (HUVECs) were investigated...
July 2017: Environmental Research
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