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Human carboxylesterase

Xiaoze Bao, Shiqiang Wei, Xingkai Qian, Jingping Qu, Baomin Wang, Liwei Zou, Guangbo Ge
A catalytic asymmetric [3 + 2] cyclization of novel 4-isothiocyanato pyrazolones and isatin-derived ketimines was developed, delivering a wide range of intriguing dispirotriheterocyclic products in high yield with excellent diastereoselectivity and enantioselectivity. A chiral sulfoxide derivative of this dispirocyclic product was identified to be a promising hit of the human carboxylesterase 1 inhibitor, and the significant difference of the activity between two enantiomers emphasized the importance of this asymmetric process...
May 22, 2018: Organic Letters
Ahmed Samir, Ayano Kage, Ohura Kayoko, Teruko Imai
1. Loteprednol etabonate (LE) is a soft corticosteroid with two labile ester bonds at 17α- and 17β-positions. Its corticosteroidal activity disappears upon hydrolysis of either ester bond. Hydrolysis of both ester bonds produces the inactive metabolite, Δ1 -cortienic acid (Δ1 -CA). 2. The simple high performance liquid chromatography method using acetic acid gradient was developed for the simultaneous determination of LE and its acidic metabolites. 3. LE was hydrolyzed in rat plasma with a half-life of 9 minutes...
May 21, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Laura Hedges, Susan Brown, A Kenneth MacLeod, Audrey Vardy, Edward Doyle, Gina Song, Marjory Moreau, Miyoung Yoon, Thomas G Osimitz, Brian G Lake
1. The metabolism of the pyrethroids deltamethrin (DLM), cis-permethrin (CPM) and trans-permethrin (TPM) was studied in human expressed cytochrome P450 (CYP) and carboxylesterase (CES) enzymes. 2. DLM, CPM and TPM were metabolised by human CYP2B6 and CYP2C19, with the highest apparent intrinsic clearance (CLint ) values for pyrethroid metabolism being observed with CYP2C19. Other CYP enzymes contributing to the metabolism of one or more of the three pyrethroids were CYP1A2, CYP2C8, CYP2C9*1, CYP2D6*1, CYP3A4 and CYP3A5...
May 21, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Emily N Dunn, Teresa M Ferrara-Bowens, Mark E Chachich, Cary L Honnold, Cristin C Rothwell, Heidi M Hoard-Fruchey, Catherine A Lesyna, Erik A Johnson, Douglas M Cerasoli, John H McDonough, C Linn Cadieux
Mice and other rodents are typically utilized for chemical warfare nerve agent research. Rodents have large amounts of carboxylesterase in their blood, while humans do not. Carboxylesterase non-specifically binds to and detoxifies nerve agent. The presence of this natural bioscavenger makes mice and other rodents poor models for studies identifying therapeutics to treat humans exposed to nerve agents. To obviate this problem, a serum carboxylesterase knockout (Es1 KO) mouse was created. In this study, Es1 KO and wild type (WT) mice were assessed for differences in gene expression, nerve agent (soman; GD) median lethal dose (MLD) values, and behavior prior to and following nerve agent exposure...
May 16, 2018: Toxicology Mechanisms and Methods
Yuma Ishizaki, Tomomi Furihata, Yusuke Oyama, Kayoko Ohura, Teruko Imai, Masakiyo Hosokawa, Hidetaka Akita, Kan Chiba
Carboxylesterase 2 (CES2), which is a member of the serine hydrolase superfamily, is primarily expressed in the human small intestine, where it plays an important role in the metabolism of ester-containing drugs. Therefore, to facilitate continued progress in ester-containing drug development, it is crucial to evaluate how CES2-mediated hydrolysis influences its intestinal permeability characteristics. Human colon carcinoma Caco-2 cells have long been widely used in drug permeability studies as an enterocyte model...
2018: Biological & Pharmaceutical Bulletin
Hiroyoshi Koide, Masayuki Tsujimoto, Yurie Katsube, Megumi Ochiai, Ayako Hojo, Taku Furukubo, Satoshi Izumi, Tomoyuki Yamakawa, Daisuke Shima, Tetsuya Minegaki, Kohshi Nishiguchi
PURPOSE: Pharmacokinetics and pharmacodynamics of irinotecan have been reported to be altered in cancer patients with end-stage kidney disease (ESKD). Carboxylesterase (CES) has an important role in metabolism of irinotecan to its active metabolite, SN-38, in human liver. The purpose of the present study was to investigate whether CES activity was altered in ESKD patients. METHODS: The present study investigated the effects of uremic serum, uremic toxins, and fatty acids on the hydrolysis of irinotecan and a typical CES substrate, p-nitrophenyl acetate (PNPA), in human liver microsomes...
April 24, 2018: Cancer Chemotherapy and Pharmacology
Mina Suh, Deborah Proctor, Grace Chappell, Julia Rager, Chad Thompson, Susan Borghoff, Lavorgie Finch, Robert Ellis-Hutchings, Karin Wiench
Lower alkyl acrylate monomers include methyl-, ethyl-, n-butyl-, and 2-ethylhexyl acrylate. These acrylates are used in the manufacture of acrylic polymers and copolymers for plastics, food packaging, adhesives, and cosmetic formulations. Although there is limited potential for human environmental exposure, occupational exposure can occur via inhalation and dermal contact. Recently, new genotoxicity data have been generated, along with in silico and in vitro read-cross analyses, for these acrylates. The availability of high-throughput screening (HTS) data through the ToxCast™/Tox21 databases allows for consideration of computational toxicology and organization of these data according to the ten key characteristics of carcinogens...
April 21, 2018: Toxicology
Momoko Ishimine, Hyeon-Cheol Lee, Hirofumi Nakaoka, Hajime Orita, Toshiyuki Kobayashi, Konomi Mizuguchi, Mikumi Endo, Ituro Inoue, Koichi Sato, Takehiko Yokomizo
Irinotecan (CPT-11) is an anticancer prodrug that is activated by the carboxylesterase CES2 and has been approved for the treatment of many types of solid tumors, including colorectal cancer. Recent studies with cell lines show that CES2 expression is regulated by the tumor suppressor protein p53. However, clinical evidence for this regulatory mechanism in cancer is lacking. In this study, we examined the relationship between TP53 gene status and CES2 expression in human colorectal cancer. Most colorectal cancer specimens (70%; 26 of 37) showed lower CES2 mRNA levels (≥1...
2018: Disease Markers
Xiao Yang, Juan Dai, Sujuan Zhao, Rong Li, Tim Goulette, Xianggui Chen, Hang Xiao
BACKGROUND: Organophosphate and carbamate pesticide residues in food and the environment pose a great threat to human health, and have made the easy and rapid detection of these pesticide residues an important task. Discovering new enzyme sources from plants can help reduce the cost of large-scale applications of rapid pesticide detection via enzyme inhibition. RESULTS: Plant esterase from kidney bean was purified. Kidney bean esterase is identified as a carboxylesterase by substrate and inhibitor specificity tests and mass spectrometry identification...
March 31, 2018: Journal of the Science of Food and Agriculture
Jing Xu, Jin-Chun Qiu, Xing Ji, Hong-Li Guo, Xuan Wang, Bo Zhang, Tengfei Wang, Feng Chen
Herbal products have grown steadily across the globe over the past 10 years and have increasingly been incorporated into western medicine for healthcare aims, thereby causing potential pharmacokinetic herb-drug interactions (HDI) through the inhibition or induction of drug-metabolizing enzymes and transporters. Human carboxylesterases 1 (CES1) and 2 (CES2) are versatile enzymes involvement in the metabolism of endogenous and exogenous compounds including many important therapeutic medications. Moreover, the growing number of CES substrate drugs also underscores the importance of CES1 and CES2...
March 30, 2018: Current Drug Metabolism
Laura Hedges, Susan Brown, Audrey Vardy, Edward Doyle, Miyoung Yoon, Thomas G Osimitz, Brian G Lake
The metabolism of deltamethrin (DLM), cis-permethrin (CPM) and trans-permethrin (TPM) was studied in liver microsomes, liver cytosol and plasma from male Sprague-Dawley rats aged 15, 21 and 90 days and from adult humans. DLM and CPM were metabolised by rat hepatic microsomal cytochrome P450 (CYP) enzymes and to a lesser extent by microsomal and cytosolic carboxylesterase (CES) enzymes, whereas TPM was metabolised to a greater extent by CES enzymes. In human liver, DLM and TPM were mainly metabolised by CES enzymes, whereas CPM was metabolised by CYP and CES enzymes...
April 19, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Masato Takahashi, Tomohiro Ogawa, Hiroshi Kashiwagi, Fumiya Fukushima, Misaki Yoshitsugu, Masami Haba, Masakiyo Hosokawa
It is necessary to consider the affinity of prodrugs for metabolic enzymes for efficient activation of the prodrugs in the body. Although many prodrugs have been synthesized with consideration of these chemical properties, there has been little study on the design of a structure with consideration of biological properties such as substrate recognition ability of metabolic enzymes. In this report, chemical synthesis and evaluation of indomethacin prodrugs metabolically activated by human carboxylesterase 1 (hCES1) are described...
April 1, 2018: Bioorganic & Medicinal Chemistry Letters
Randall J Binder, M Jason Hatfield, Liying Chi, Philip M Potter
Recently, a series of selective human carboxylesterase inhibitors have been identified based upon the tanshinones, with biologically active molecules containing a 1,2-dione group as part of a naphthoquinone core. Unfortunately, the synthesis of such compounds is complex. Here we describe a novel method for the generation of 1,2-dione containing diterpenoids using a unified approach, by which boronic acids are joined to vinyl bromo-cyclohexene derivatives via Suzuki coupling, followed by electrocyclization and oxidation to the o-phenanthroquinones...
April 10, 2018: European Journal of Medicinal Chemistry
Jia-Nan Li, Yun-Feng Cao, Rong-Rong He, Guang-Bo Ge, Bin Guo, Jing-Jing Wu
Shikonin, a natural naphthoquinone compound derived from the herb Lithospermum erythrorhizon, is widely used for its various pharmacological activities. However, its potential interactions with other medications by inhibiting human carboxylesterases 2 (hCE2) remain unknown. In this study, the inhibitory effects of shikonin on the activity of hCE2 in human liver microsomes are investigated by using fluorescein diacetate (FD), N-(2-butyl-1,3-dioxo-2,3-dihydro-1H-phenalen-6-yl)-2-chloroacetamide (NCEN), and CPT-11 as substrates of hCE2...
February 22, 2018: Phytotherapy Research: PTR
Zongxi Sun, Yali Wu, Bing Yang, Baochen Zhu, Shaonan Hu, Yang Lu, Bo Zhao, Shouying Du
Herb-drug interactions are important safety concerns in clinical practice. The interactions occur firstly in the intestinal absorption for orally administered drugs. Aspirin and Panax notoginseng saponins (PNS)-based drugs are often combined in China to prevent larger-artery atherosclerosis. Here, we aimed to characterize the aspirin transport across Caco-2 cell monolayers, a model of the intestinal absorption, and further to evaluate the influence of PNS on aspirin hydrolysis and the relating mechanisms. Transcellular transport of aspirin and the influence of PNS were explored using Caco-2 cell monolayers...
February 18, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Kristina Forsch, Verena Schöning, Lucia Disch, Beate Siewert, Matthias Unger, Jürgen Drewe
ETHNOPHARMACOLOGICAL RELEVANCE: Pyrrolizidine alkaloids (PAs) are secondary plant ingredients formed in many plant species to protect against predators. PAs are generally considered acutely hepatotoxic, genotoxic and carcinogenic. Up to now, only few in vitro and in vivo investigations were performed to evaluate their relative toxic potential. AIM OF THE STUDY: The aim was to develop an in vitro screening method of their cytotoxicity. MATERIALS AND METHODS: Human and rodent hepatocyte cell lines (HepG2 and H-4-II-E) were used to assess cytotoxicity of the PA lasiocarpine...
May 10, 2018: Journal of Ethnopharmacology
Zi-Miao Weng, Guang-Bo Ge, Tong-Yi Dou, Ping Wang, Ping-Kun Liu, Xin-Hui Tian, Nan Qiao, Yang Yu, Li-Wei Zou, Qi Zhou, Wei-Dong Zhang, Jie Hou
Human carboxylesterases (hCEs) are key enzymes from the serine hydrolase superfamily. Among all identified hCEs, human carboxylesterase 2 (hCE2) plays crucial roles in the metabolic activation of ester drugs including irinotecan and flutamide. Selective and potent hCE2 inhibitors could be used to alleviate the toxicity induced by hCE2-substrate drugs. In this study, more than fifty flavonoids were collected to assay their inhibitory effects against hCE2 using a fluorescence-based method. The results demonstrated that C3 and C6 hydroxy groups were essential for hCE2 inhibition, while O-glycosylation or C-glycosylation would lead to the loss of hCE2 inhibition...
April 2018: Bioorganic Chemistry
Morena Gabriele, Paola Puccini, Marco Lucchi, Anna Vizziello, Pier Giovanni Gervasi, Vincenzo Longo
Lungs are pharmacologically active organs and the pulmonary drug metabolism is of interest for inhaled drugs design. Carboxylesterases (CESs) are enzymes catalyzing the hydrolysis of many structurally different ester, amide and carbamate chemicals, including prodrugs. For the first time, the presence, kinetics, inhibition and inter-individual variations of the major liver CES isozymes (CES1 and CES2) were investigated in cytosol and microsomes of human lungs from 20 individuals using 4-nitrophenyl acetate (pNPA), 4-methylumbelliferyl acetate (4-MUA), and fluorescein diacetate (FD) as substrates the rates of hydrolysis (Vmax ) for pNPA and 4-MUA, unlike FD, were double in microsomes than in cytosol...
April 2018: Biochemical Pharmacology
Peter R Bradshaw, Ian D Wilson, Rachel Upcott Gill, Philip J Butler, Clive Dilworth, Toby J Athersuch
The release of aromatic amines from drugs and other xenobiotics resulting from the hydrolysis of metabolically labile amide bonds presents a safety risk through several mechanisms, including geno-, hepato- and nephrotoxicity. Whilst multiple in vitro systems used for studying metabolic stability display serine hydrolase activity, responsible for the hydrolysis of amide bonds, they vary in their efficiency and selectivity. Using a range of amide-containing probe compounds (0.5-10 µM), we have investigated the hydrolytic activity of several rat, minipig and human-derived in vitro systems - including Supersomes, microsomes, S9 fractions and hepatocytes - with respect to their previously observed human in vivo metabolism...
February 5, 2018: Scientific Reports
Yu-Zhuo Wu, Hua-Wei Zhang, Zhao-Hui Sun, Jun-Gui Dai, You-Cai Hu, Rui Li, Peng-Cheng Lin, Gui-Yang Xia, Ling-Yan Wang, Bo-Lin Qiu, Jing-Fang Zhang, Guang-Bo Ge, Sheng Lin
Bysspectin A (1), a polyketide-derived octaketide dimer with a novel carbon skeleton, and two new precursor derivatives, bysspectins B and C (2 and 3), were obtained from an organic extract of the endophytic fungus Byssochlamys spectabilis that had been isolated from a leaf tissue of the traditional Chinese medicinal plant Edgeworthia chrysantha, together with a known octaketide, paecilocin A (4). Their structures were determined by HRMS, 1D and 2D NMR spectroscopic analysis. A plausible route for their biosynthetic pathway is proposed...
February 10, 2018: European Journal of Medicinal Chemistry
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