Abstract
Carboxylesterases (CESs, E.C.3.1.1.1) constitute a large class of enzymes that determine the therapeutic efficacy and toxicity of ester/amide drugs. Without exceptions, all mammalian species studied express multiple forms of carboxylesterases. Two human carboxylesterases, CES1 and CES2, are major contributors to hydrolytic biotransformation. Recent studies have identified therapeutic agents that potently inhibit carboxylesterases-based catalysis. Some of them are reversible whereas others irreversible. The adrenergic antagonist carvedilol, for example, reversibly inhibits CES2 but this carboxylesterase is irreversibly inhibited by orlistat, a popular anti-obesity medicine. Kinetically, the inhibition occurs competitively, non-competitively or in combination, depending on a carboxylesterase. For example, the calcium channel blocker diltiazem competitively inhibits CES1 but non-competitively inhibits CES2. In addition to inhibited catalysis, several therapeutic agents or disease mediators have been shown to regulate the expression of carboxylesterases. For example, the antiepileptic drug phenobarbital induces both human and rodent carboxylesterases, whereas the antibiotic rifampicin induces human carboxylesterases only. Conversely, the proinflammatory cytokine interleukin-6 (IL-6) suppresses the expression of carboxylesterases across species, but depending on the concentrations of glucose in the culture medium. Transactivation, transrepression and altered mRNA stability contribute to the regulated expression. Several nuclear receptors are established to support the regulation including constitutive androstane receptor, glucocorticoid receptor and pregnane X receptor. In addition, non-ligand transcription factors are also involved in the regulation and exemplified by differentiated embryo chondrocyte-1, nuclear factor (erythroid-derived 2)-like 2 and tumor protein p53. These transcription factors coordinate the regulated expression of carboxylesterases, constituting a regulatory network for the hydrolytic biotransformation.
Highlights
Carboxylesterases (E.C.3.1.1.1) constitute a large class of hydrolytic enzymes that play critical roles in the metabolism of drugs, detoxification of insecticides and mobilization of lipids [1,2,3]
CES1 is encoded by two genes: CES1A1 and CES1A2 [1]
The CES1A1 and CES1A2 proteins differ by four amino acids, and they are located in the N-terminal signal peptide [4]
Summary
Carboxylesterases (E.C.3.1.1.1) constitute a large class of hydrolytic enzymes that play critical roles in the metabolism of drugs, detoxification of insecticides and mobilization of lipids [1,2,3]. These enzymes rapidly hydrolyze carboxylic acid esters, and to a less extent, amides and thioesters [3]. The anticancer prodrug irinotecan has a larger alcohol moiety (Top/Right of Fig. 1) and is hydrolyzed preferably by CES2 [9, 10]. In addition to inhibited catalysis, several therapeutic agents or disease mediators have been shown to induce or suppress the expression of carboxylesterases [2, 3]. The transcriptional network for the regulated expression is discussed in details
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