Mini reviewStructure, function and regulation of carboxylesterases
Introduction
The present review highlights the importance of structure in delineating overall function, substrate specificity, regulation and localization of mammalian carboxylesterases (CarbEs). They are α,β-hydrolase-fold protein and comprise a multigene superfamily [1]. Structural considerations emerge from the genes encoding the family. Diversity in the structure and ultimately function and cellular localization of the gene product is achieved through gene doubling, alternative mRNA processing and post-translational modification.
The expression of CarbEs is ubiquitous with high levels in various tissues. Some of the isozymes are destined for export into the plasma. Others are associated with cell membrane such as endoplasmic reticulum (ER) with its catalytic function directed extracellularly [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12].
Expression profiles of gene encoding CarbEs are highly regulated during development by nutritional status, hormonal factors and xenobiotics. Although the consequences of regulation of CarbEs by drugs and chemicals have been intensively studied [11], [13], [16], [17], relatively little is known about the mechanisms by which esterases are regulated by physiological factors. Recent developments have included more detailed biochemical characterization of mammalian CarbE enzymes and genes, leading to a better understanding of the biochemical significance and physiological role of CarbEs.
This review addresses the significant differences of molecular structure and function of recently identified CarbEs, and proposes a novel nomenclature for mammalian CarbE isozymes that is based on the nucleotide sequences of the genes encoding the individual CarbE isozymes.
Section snippets
Novel classification and nomenclature of mammalian CarbEs
According to the classification of esterases by Aldridge [18], the serine super family of esterases, i.e., acetylcholinesterase(AChE), butyrylcholinesterase and CarbE, fall into the B-esterase group. CarbE iszymes were initially classified by their substrate specificity and pI. However, this classification is ambiguous in overlapping substrate specificities. A single esterolytic reaction is frequently mediated by several kinds of enzymes. Recent studies on esterases, as with other enzymes
Structure–activity relationship of mammalian CarbEs
The CarbEs comprise a multigene superfamily, the gene products of which are localized in the endoplasmic reticulum (ER) of many tissues [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [23], [24]. These enzymes efficiently catalyze the hydrolysis of a variety of drugs or prodrugs containing ester- and amide-bonds to the respective free acids and alcohol. Since ester derivatives of therapeutic agents have been used as prodrugs, CarbEs are major determinants of the pharmacokinetic behavior of
Gene structure and regulation of CarbE isozymes
Both the murine [11] and human [4], [38], [46]CES1 genes span about 30 kb and contain 14 small exons. Recently, sequencing of the mouse and human genomes were completed, enabling detailed sequence comparisons. The previously published sequences of the individual exons, splice junctions, size of the introns and restriction sites within the murine and human CarbE genes are consistent with their respective genes sequenced by the mouse and human genome projects. Therefore, the organization of the
Drug metabolism
Drug-metabolizing enzymes that are present predominantly in the liver are involved in biotransformation of both endogenous and exogenous compounds to polar products to facilitate their elimination. These reactions are categorized into phases I and II reactions. CarbEs show ubiquitous tissue expression profiles with the highest levels of CarbE activity present in liver microsomes in many mammals [4], [5], [11]. CarbEs are categorized as phase-I drug-metabolizing enzymes that can hydrolyze a
Enzyme induction of CarbE
Much interest has been shown by both clinicians and reserchers in the induction of expression of drug-metabolizing enzymes by chemicals, including medical agents, since it is one of the main reasons for drug-drug interaction causing adverse effects and for the reduction in pharmacological potencies of drugs. As for CarbEs, it has been shown that rodent CarbE isozyme(s) was induced by phenobarbital [21], aminopyrine [32], peroxisome proliferators (clofibrate, di(2-ethylhexyl)phthalate, and
A novel biomarker of organophosphate insecticide exposure
Egasyn, an isozyme of CarbE, is an accessary protein of β-glucuronidase in the liver microsomes [4], [36], [84]. Egasyn-β-glucuronidase complexes are located at the luminal sites of liver microsomal endoplasmic reticulum membrane [85]. When the organophosphorus insecticides (OP) are incorporated into the liver microsomes, the OP is tightly bound to egasyn, and subsequently, β-glucuronidase is dissociated and released into the blood. Consequently, the increase of plasma BG activity is good
Conclusion
Multiple CarbEs play an important role in the hydrolytic biotransformation of a vast number of structurally diverse drugs. These enzymes are a major determinant of the pharmacokinetic behavior of most therapeutic agents containing an ester or amide bond. There are several factors that influence CarbE activity, either directly or at the level of enzyme regulation. In the clinical field, drug elimination is decreased and the incidence of drug–drug interactions increases when two or more drugs
Acknowledgements
The authors wish to acknowledge Professor Palmer Taylor, Univresity of California at San Diego, La Jolla, and Professor William Bosron, Indiana University, Indianapolis, Indiana for providing us with valuable suggestions. We also acknowledge the colleagues at the HAB Research laboratories for preparation of this manuscript.
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