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Human carboxylesterase

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...
October 20, 2016: Environmental Research
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
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
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
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
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
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
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
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
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
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 (hydrolyzed) 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...
May 26, 2016: Basic & Clinical Pharmacology & Toxicology
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
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
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
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
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
Avinash M Veerappa, Prakash Padakannaya, Nallur B Ramachandra
Background and Objectives. Uridine diphospho-glucuronosyltransferase 2B (UGT2B) is a family of genes involved in metabolizing steroid hormones and several other xenobiotics. These UGT2B genes are highly polymorphic in nature and have distinct polymorphisms associated with specific regions around the globe. Copy number variations (CNVs) status of UGT2B17 in Indian population is not known and their disease associations have been inconclusive. It was therefore of interest to investigate the CNV profile of UGT2B genes...
2016: Journal of Nucleic Acids
Fernando Tecles, Asta Tvarijonaviciute, Carlos De Torre, José M Carrillo, Mónica Rubio, Montserrat García, Ramón Cugat, José J Cerón
Although saliva has esterase activity, this activity has not been characterized or studied in individuals subjected to physical stress. The aim of this report was to develop and validate an automated spectrophotometric assay for total esterase activity measurement in human saliva, as well as to study the contribution of different enzymes on this activity and its behaviour under physical stress in healthy subjects. The assay used 4-nitrophenyl acetate as substrate and was precise, accurate and provided low limits of detection and quantification...
July 2016: Scandinavian Journal of Clinical and Laboratory Investigation
Oliver H Wang, Nancy Azizian, Ming Guo, Michela Capello, Defeng Deng, Fenglin Zang, Jason Fry, Matthew H Katz, Jason B Fleming, Jeffrey E Lee, Robert A Wolff, Samir Hanash, Huamin Wang, Anirban Maitra
OBJECTIVES: MAP4K5 plays an important role in regulating a range of cellular responses and is involved in Wnt signaling in hematopoietic cells. However, its functions in human malignancies have not been studied. The major objectives of this study are to examine the expression, functions and clinical significance of MAP4K5 in pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS: The expression levels of MAP4K5, E-cadherin, vimentin, and carboxylesterase 2 (CES2) were examined by immunohistochemistry in 105 PDAC and matched non-neoplastic pancreas samples from our institution...
2016: PloS One
Sung S Choi, Byung Hoon Chi, In Ho Chang, Kyung Do Kim, Sang-Rae Lee, Seung U Kim, Hong J Lee
Bladder cancer is a significant clinical and economic problem. Despite intravesical chemotherapy and immunotherapy, up to 80% of patients with non-muscle-invasive bladder cancer develop recurrent tumors, of which 20% to 30% evolve into more aggressive, potentially lethal tumors. Recently, bladder cancer cells are considered to be mediators of resistance to current therapies and therefore represent strong candidates as biologic targets. No effective chemotherapy has yet been developed for advanced bladder cancer...
June 2016: Molecular Cancer Therapeutics
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