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      Human carboxylesterases: a comprehensive review

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          Abstract

          Mammalian carboxylesterases (CEs) are key enzymes from the serine hydrolase superfamily. In the human body, two predominant carboxylesterases (CES1 and CES2) have been identified and extensively studied over the past decade. These two enzymes play crucial roles in the metabolism of a wide variety of endogenous esters, ester-containing drugs and environmental toxicants. The key roles of CES in both human health and xenobiotic metabolism arouse great interest in the discovery of potent CES modulators to regulate endobiotic metabolism or to improve the efficacy of ester drugs. This review covers the structural and catalytic features of CES, tissue distributions, biological functions, genetic polymorphisms, substrate specificities and inhibitor properties of CES1 and CES2, as well as the significance and recent progress on the discovery of CES modulators. The information presented here will help pharmacologists explore the relevance of CES to human diseases or to assign the contribution of certain CES in xenobiotic metabolism. It will also facilitate medicinal chemistry efforts to design prodrugs activated by a given CES isoform, or to develop potent and selective modulators of CES for potential biomedical applications.

          Graphical abstract

          Human carboxylesterases (CES) play crucial roles in both endo- and xenobiotic metabolism, which arouse great interest in the discovery of potent CES modulators to regulate endobiotic metabolism or to improve the outcomes of ester drugs. This review covers the structural and catalytic features of human CES, tissue distributions, biological functions and substrate specificities of two predominant human CES, as well as the significance and recent progress on the discovery of human CES modulators.

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          Most cited references134

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          Structure-antioxidant activity relationships of flavonoids and phenolic acids.

          The recent explosion of interest in the bioactivity of the flavonoids of higher plants is due, at least in part, to the potential health benefits of these polyphenolic components of major dietary constituents. This review article discusses the biological properties of the flavonoids and focuses on the relationship between their antioxidant activity, as hydrogen donating free radical scavengers, and their chemical structures. This culminates in a proposed hierarchy of antioxidant activity in the aqueous phase. The cumulative findings concerning structure-antioxidant activity relationships in the lipophilic phase derive from studies on fatty acids, liposomes, and low-density lipoproteins; the factors underlying the influence of the different classes of polyphenols in enhancing their resistance to oxidation are discussed and support the contention that the partition coefficients of the flavonoids as well as their rates of reaction with the relevant radicals define the antioxidant activities in the lipophilic phase.
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            The role of human carboxylesterases in drug metabolism: have we overlooked their importance?

            Carboxylesterases are a multigene family of mammalian enzymes widely distributed throughout the body that catalyze the hydrolysis of esters, amides, thioesters, and carbamates. In humans, two carboxylesterases, hCE1 and hCE2, are important mediators of drug metabolism. Both are expressed in the liver, but hCE1 greatly exceeds hCE2. In the intestine, only hCE2 is present and highly expressed. The most common drug substrates of these enzymes are ester prodrugs specifically designed to enhance oral bioavailability by hydrolysis to the active carboxylic acid after absorption from the gastrointestinal tract. Carboxylesterases also play an important role in the hydrolysis of some drugs to inactive metabolites. It has been widely believed that drugs undergoing hydrolysis by hCE1 and hCE2 are not subject to clinically significant alterations in their disposition, but evidence exists that genetic polymorphisms, drug-drug interactions, drug-disease interactions and other factors are important determinants of the variability in the therapeutic response to carboxylesterase-substrate drugs. The implications for drug therapy are far-reaching, as substrate drugs include numerous examples from widely prescribed therapeutic classes. Representative drugs include angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, antiplatelet drugs, statins, antivirals, and central nervous system agents. As research interest increases in the carboxylesterases, evidence is accumulating of their important role in drug metabolism and, therefore, the outcomes of pharmacotherapy.
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              The mammalian carboxylesterases: from molecules to functions.

              Multiple carboxylesterases (EC 3.1.1.1) play an important role in the hydrolytic biotransformation of a vast number of structurally diverse drugs. These enzymes are major determinants of the pharmacokinetic behavior of most therapeutic agents containing ester or amide bonds. Carboxylesterase activity can be influenced by interactions of a variety of compounds either directly or at the level of enzyme regulation. Since a significant number of drugs are metabolized by carboxylesterase, altering the activity of this enzyme class has important clinical implications. Drug elimination decreases and the incidence of drug-drug interactions increases when two or more drugs compete for hydrolysis by the same carboxylesterase isozyme. Exposure to environmental pollutants or to lipophilic drugs can result in induction of carboxylesterase activity. Therefore, the use of drugs known to increase the microsomal expression of a particular carboxylesterase, and thus to increase associated drug hydrolysis capacity in humans, requires caution. Mammalian carboxylesterases represent a multigene family, the products of which are localized in the endoplasmic reticulum of many tissues. A comparison of the nucleotide and amino acid sequence of the mammalian carboxylesterases shows that all forms expressed in the rat can be assigned to one of three gene subfamilies with structural identities of more than 70% within each subfamily. Considerable confusion exists in the scientific community in regards to a systematic nomenclature and classification of mammalian carboxylesterase. Until recently, adequate sequence information has not been available such that valid links among the mammalian carboxylesterase gene family or evolutionary relationships could be established. However, sufficient basic data are now available to support such a novel classification system.
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                Author and article information

                Contributors
                Journal
                Acta Pharm Sin B
                Acta Pharm Sin B
                Acta Pharmaceutica Sinica. B
                Elsevier
                2211-3835
                2211-3843
                25 June 2018
                September 2018
                25 June 2018
                : 8
                : 5
                : 699-712
                Affiliations
                [a ]Institute of Interdisciplinary Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
                [b ]Dalian Medical University, Dalian 116044, China
                Author notes
                [* ]Corresponding author. geguangbo@ 123456dicp.ac.cn
                [†]

                These authors made equal contribution to this work.

                Article
                S2211-3835(18)30064-9
                10.1016/j.apsb.2018.05.005
                6146386
                30245959
                cc65fd1c-b4de-4463-aecf-e223b8fb7c4d
                © 2018 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 24 March 2018
                : 7 May 2018
                : 9 May 2018
                Categories
                Review

                human carboxylesterases,ces1,ces2,substrate preference,inhibitor spectra,inducer

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