Carboxylesterases: Pharmacological Inhibition Regulated Expression and Transcriptional Involvement of Nuclear Receptors and other Transcription Factors

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.

A pharmacokinetic–pharmacodynamic model based on multi-organ-on-a-chip for drug–drug interaction studies

“…The metabolism of CPT-11 to SN-38 would be decreased by the concomitant administration of SV, which is an inhibitor of carboxylesterase 2 (CES2). 18 We hypothesized that the concomitant administration of CPT-11 and RTV, which is an inhibitor of cytochrome P450 3A4 (CYP3A4), would not affect the amount of SN-38 in the MOoC because CYP3A4 expression in HepG2 cells is quite low. 19 The CPT-11 concentration was 15 μ M, whereas SV concentration was 1 μ M, which makes the CES2 expression 50%.…”

Viral target and metabolism‐based rationale for combined use of recently authorized small molecule COVID‐19 medicines: Molnupiravir, nirmatrelvir, and remdesivir

“…Carboxylesterases constitute a large class of serine hydrolases with high catalytic efficiency. In humans, CES1 and CES2 are two c arboxyl es terases with known pharmacological and toxicological significance 106–109 . These two carboxylesterases, on the other hand, differ in their substrate specificity and tissue distribution 110–112 .…”

The nucleoside antiviral prodrug remdesivir in treating COVID-19 and beyond with interspecies significance

“…In addition, remdesivir has been shown to irreversibly inhibit carboxylesterase-2 (CES2) (Shen et al 2021b ). This carboxylesterase is a major hydrolase with distinct substrate specificity, regulated expression and tissue distribution (Chen et al 2012 ; Shen et al 2019 ; Shen and Yan 2017 ; Shi et al 2006 ; Shi et al 2008 ; Tang et al 2006 ; Xiao et al 2012 ; Yang et al 2007 ; Yang et al 2009 ; Zhu et al 2000 ). Conceivably, irreversible inhibition of this hydrolase is a contributing factor to drug-drug interactions with potential pharmacological and toxicological significance.…”