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Human carboxylesterase

Laura Hedges, Susan Brown, Audrey Vardy, Edward Doyle, Miyoung Yoon, Thomas G Osimitz, Brian G Lake
1. 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. 2. 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. 3. In human liver, DLM and TPM were mainly metabolised by CES enzymes, whereas CPM was metabolised by CYP and CES enzymes...
March 14, 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...
February 21, 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...
February 19, 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...
February 14, 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...
January 9, 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...
January 29, 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...
January 10, 2018: European Journal of Medicinal Chemistry
Lee C Mangum, Xiang Hou, Abdolsamad Borazjani, Jung Hwa Lee, Matthew K Ross, J Allen Crow
Macrophage foam cells store excess cholesterol as cholesteryl esters, which need to be hydrolyzed for cholesterol efflux. We recently reported that silencing expression of carboxylesterase 1 (CES1) in human THP-1 macrophages (CES1KD macrophages) reduced cholesterol uptake and decreased expression of CD36 and scavenger receptor-A in cells loaded with acetylated low-density lipoprotein (acLDL). Here, we report that CES1KD macrophages exhibit reduced transcription of cytochrome P450 27A1 ( CYP27A1 ) in non-loaded and acLDL-loaded cells...
January 10, 2018: Biochemical Journal
Yuuta Fujikawa, Taiki Nampo, Masaya Mori, Manami Kikkawa, Hideshi Inoue
Pi class glutathione S-transferase (GSTP1) is highly expressed in various cancerous cells and pre-neoplastic legions, where it is involved in apoptotic resistance or metabolism of several anti-tumour chemotherapeutics. Therefore, GSTP1 is a marker of malignant and pre-malignant cells and is a promising target for visualization and drug development. Here we demonstrate that fluorescein diacetate (FDA), a fluorescent probe used for vital staining, is a fluorescently activated by esterolytic activity of human GSTP1 (hGSTP1) selectively among various cytosolic GSTs...
March 1, 2018: Talanta
Amira Abdel-Daim, Kayoko Ohura, Teruko Imai
In the present study, we established a quantitative western blotting method to measure the expression level of recombinant serine hydrolases based on their catalytic mechanism. Fluorophosphonate (FP) biotin was selected as a universal probe to quantify their expression level, since FP moiety irreversibly inhibits serine hydrolases through strong stoichiometric binding to active serine residue. The linearity of detection using FP-biotin was assessed on three serine hydrolases; human carboxylesterase (CES) 1, butyrylcholinesterase and porcine liver esterases (PLE)...
December 28, 2017: European Journal of Pharmaceutical Sciences
Jin-Zi Ji, Bei-Bei Huang, Tong-Tong Gu, Ting Tai, Huan Zhou, Yu-Meng Jia, Qiong-Yu Mi, Meng-Ran Zhang, Hong-Guang Xie
Clopidogrel is predominantly hydrolyzed to clopidogrel carboxylic acid (CCA) by carboxylesterase 1, and subsequently CCA is glucuronidated to clopidogrel aryl glucuronide (CAG) by uridine diphosphate-glucuronosyltransferases (UGTs); however, the UGT isoenzymes glucuronidating CCA remain unidentified to date. In this study, the glucuronidation of CCA was screened with pooled human liver microsomes (HLMs) and 7 human recombinant UGT (rUGT) isoforms. Results indicated that rUGT2B7 exhibited the highest catalytical activity for the CCA glucuronidation as measured with a mean Vmax value of 120...
December 14, 2017: Biopharmaceutics & Drug Disposition
Li-Wei Zou, Qiang Jin, Dan-Dan Wang, Qing-Kai Qian, Da-Cheng Hao, Guang-Bo Ge, Ling Yang
Mammalian carboxylesterases are key serine hydrolases that catalyze the hydrolysis of a wide variety of ester compounds into the corresponding carboxylic acids and alcohols. In human, two major carboxylesterases, CES1 and CES2, have been identified and well-studied over the past decade. CES1 inhibitors have potential applications in the treatment of hypertriglyceridaemia, obesity and type 2 diabetes, owing to that this enzyme plays prominent role in the metabolism of cholesteryl esters. CES2 plays crucial roles in the metabolic activation of many prodrugs including anticancer agents capecitabine and CPT-11...
December 4, 2017: Current Medicinal Chemistry
Jinfang Jiang, Xiaoyan Chen, Dafang Zhong
Vicagrel, a structural analog of clopidogrel, is now being developed as a thienopyridine antiplatelet agent in a phase II clinical trial in China. Some studies have shown that vicagrel undergoes complete first-pass metabolism in human intestine, generating the hydrolytic metabolite 2-oxo-clopidogrel via carboxylesterase-2 (CES2) and subsequently the active metabolite H4 via CYP450s. This study aimed to identify hydrolases other than CES2 that are involved in the bioactivation of vicagrel in human intestine...
2017: Frontiers in Pharmacology
Ya-Li Wang, Jian-Chao Zhao, Jia-Hao Liang, Xiang-Ge Tian, Xiao-Kui Huo, Lei Feng, Jing Ning, Chao Wang, Bao-Jing Zhang, Gang Chen, Ning Li, Cheng-Peng Sun
A new protostane-type triterpenoid, 5β,29-dihydroxy alisol A (1) was isolated from Alisma plantago-aquatica subsp. orientale (Sam.) Sam. as well as 12-deoxyphorbol-13α-pentadecanoate (2). We first report the presence of compound 2 in the genus Alisma. Their structures were established on the basis of 1D and 2D NMR, and HRESIMS spectroscopic analyses. All the isolated compounds were assayed for their inhibitory effects against human carboxylesterase 2 (HCE-2). Compounds 1 and 2 displayed inhibitory activities against HCE-2 with IC50 values of 29...
November 28, 2017: Natural Product Research
Lili Wu, Muhammad Zubair Hafiz, Yu Guan, Shuangcheng He, Jing Xiong, Wei Liu, Bingfang Yan, Xiaoping Li, Jian Yang
In order to study the influence of estrogen on carboxylesterases, we investigated the effects of 17β-estradiol on CES1 (Ces1d) and CES2 (Ces1e) in human and mouse hepatocytes. After being treated with 17β-estradiol, the mRNA levels of CES1 and CES2 decreased by 29-39% and 28-55%, respectively, in the human hepatocytes from four donors. Consistently, the hydrolysis of para-nitrophenylacetate decreased markedly by 32% induced by 17β-estradiol. Moreover, 17β-estradiol decreased CES1 and CES2 by 45% and 47% respectively at protein levels...
January 15, 2018: European Journal of Pharmacology
David E Lenz, Douglas Cerasoli, Donald M Maxwell
Soman is a highly toxic organophosphorus chemical warfare compound that binds rapidly and irreversibility to a variety of serine active enzymes, i.e., butyryl- and acetyl-cholinesterases and carboxylesterase. The in vivo toxicity of soman has been reported to vary significantly in different animal species, such as rats and guinea pigs or non-human primates. This species variation makes it difficult to identify appropriate animal models for therapeutic drug development under the US Food and Drug Administration (FDA) Animal Rule...
February 2018: Toxicology Letters
Liana M Matson, Hilary S McCarren, C Linn Cadieux, Douglas M Cerasoli, John H McDonough
Genetics likely play a role in various responses to nerve agent exposure, as genetic background plays an important role in behavioral, neurological, and physiological responses to environmental stimuli. Mouse strains or selected lines can be used to identify susceptibility based on background genetic features to nerve agent exposure. Additional genetic techniques can then be used to identify mechanisms underlying resistance and sensitivity, with the ultimate goal of developing more effective and targeted therapies...
January 15, 2018: Toxicology
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