Identification of regulatory variants of carboxylesterase 1 (CES1): A proof-of-concept study for the application of the Allele-Specific Protein Expression (ASPE) assay in identifying cis-acting regulatory genetic polymorphisms.

It is challenging to study regulatory genetic variants as gene expression is affected by both genetic polymorphisms and non-genetic regulators. The mRNA allele-specific expression (ASE) assay has been increasingly used for the study of cis-acting regulatory variants because cis-acting variants affect gene expression in an allele-specific manner. However, poor correlations between mRNA and protein expressions were observed for many genes, highlighting the importance of studying gene expression regulation at the protein level.

Developing a SWATH capillary LC-MS/MS method for simultaneous therapeutic drug monitoring and untargeted metabolomics analysis of neonatal plasma.

Most medications prescribed to neonatal patients are off-label uses. The pharmacokinetics and pharmacodynamics of drugs differ significantly between neonates and adults. Therefore, personalized pharmacotherapy guided by therapeutic drug monitoring (TDM) and drug response biomarkers are particularly beneficial to neonatal patients.

Effect of CES1 genetic variation on enalapril steady-state pharmacokinetics and pharmacodynamics in healthy subjects.

Aims: Enalapril is a prodrug and needs to be activated by carboxylesterase 1 (CES1). A previous in vitro study demonstrated the CES1 genetic variant, G143E (rs71647871), significantly impaired enalapril activation. Two previous clinical studies examined the impact of G143E on single-dose enalapril PK (10 mg); however, the results were inconclusive.

Impact of carboxylesterase 1 genetic polymorphism on trandolapril activation in human liver and the pharmacokinetics and pharmacodynamics in healthy volunteers.

Trandolapril, an angiotensin-converting enzyme inhibitor prodrug, needs to be activated by carboxylesterase 1 (CES1) in the liver to exert its intended therapeutic effect. A previous in vitro study demonstrated that the CES1 genetic variant G143E (rs71647871) abolished CES1-mediated trandolapril activation in cells transfected with the variant. This study aimed to determine the effect of the G143E variant on trandolapril activation in human livers and the pharmacokinetics (PKs) and pharmacodynamics (PDs) in human subjects.

FRACPRED-2D-PRM: A Fraction Prediction Algorithm-Assisted 2D Liquid Chromatography-Based Parallel Reaction Monitoring-Mass Spectrometry Approach for Measuring Low-Abundance Proteins in Human Plasma.

Multidimensional fractionation-based enrichment methods improve the sensitivity of proteomic analysis for low-abundance proteins. However, a major limitation of conventional multidimensional proteomics is the extensive labor and instrument time required for analyzing many fractions obtained from the first dimension separation. Here, a fraction prediction algorithm-assisted 2D LC-based parallel reaction monitoring-mass spectrometry (FRACPRED-2D-PRM) approach for measuring low-abundance proteins in human plasma is presented.

Carboxylesterase 1 and Precision Pharmacotherapy: Pharmacogenetics and Nongenetic Regulators.

Carboxylesterase (CES) 1 is the most abundant drug-metabolizing enzyme in human livers, comprising approximately 1% of the entire liver proteome. CES1 is responsible for 80%-95% of total hydrolytic activity in the liver and plays a crucial role in the metabolism of a wide range of drugs (especially ester-prodrugs), pesticides, environmental pollutants, and endogenous compounds. Expression and activity of CES1 vary markedly among individuals, which is a major contributing factor to interindividual variability in the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs metabolized by CES1.