Functional Study of Carboxylesterase 1 Protein Isoforms

Abstract

Carboxylesterase 1 (CES1) is a primary human hepatic hydrolase involved in hydrolytic biotransformation of numerous medications. Considerable interindividual variability in CES1 expression and activity has been consistently reported. Four isoforms of the CES1 protein are produced by alternative splicing (AS). In the current study, the activity and expression of each CES1 isoform are examined using transfected cell lines, and CES1 isoform composition and its impact on CES1 activity in human livers are determined. In transfected cells, isoforms 3 and 4 show mRNA and protein expressions comparable to isoforms 1 and 2, but have significantly impaired activity when hydrolyzing enalapril and clopidogrel. In individual human liver samples, isoforms 1 and 2 are the major forms, contributing 73–90% of the total CES1 protein expression. In addition, the protein expression ratios of isoforms 1 and 2 to isoforms 3 and 4 are positively associated with CES1 activity in the liver, suggesting that CES1 isoform composition is a factor contributing to the variability in hepatic CES1 function. Further investigations of the regulation of CES1 AS would improve the understanding of CES1 variability and help develop a strategy to optimize the pharmacotherapy of many CES1 substrate medications.

Quantitative mass spectrometry-based proteomics in the era of model-informed drug development: Applications in translational pharmacology and recommendations for best practice

“…however, a proportion of these proteins is expected to be lost into the cytosol during sample processing and therefore these proteins are quantified more accurately in S9 fractions (consisting of microsomes and cytosol) provided the target proteins are sufficiently abundant (Prasad et al, 2018;X. Wang, Shi, & Zhu, 2019).…”

“…The QconCAT-MRM workflow has been successfully used to quantify hepatic drug-metabolizing enzymes (Achour, Russell, et al, 2014;Shi et al, 2018;H. Wang et al, 2015;X. Wang et al, 2019) as well as transporters in liver (Wegler et al, 2017), intestine (Harwood, Achour, et al, 2016a;Harwood et al, 2015) and brain microvessels (Al-Majdoub et al, 2019;Al Feteisi et al, 2018).…”

“…Abundance is commonly used as a surrogate for activity; correlation between protein abundance and activity was demonstrated for various hepatic and renal drug-metabolizing enzymes, such as CYPs, UGTs, carboxylesterase 1, aldehyde oxidase 1, flavin-containing monooxygenases and sulfotransferases (Achour, Dantonio, et al, 2017;Y. Chen et al, 2016;Fu et al, 2013;Knights et al, 2016;Margaillan et al, 2015;Ohtsuki et al, 2012;Venkatakrishnan et al, 2000;X. Wang et al, 2019;Xie et al, 2017).…”

Genome-Wide Identification and Functional Analysis of Carboxylesterase and Methylesterase Gene Families in Peach (Prunus persica L. Batsch)

“…In the presence of water, CXEs catalyze the hydrolysis of a carboxylic ester to an alcohol and a carboxylic acid anion. However, compared to the broad ranges of functions established in mammals, insects, and microorganisms (Levisson et al, 2009; Wang et al, 2018; Wang et al, 2019), the biological roles of CXEs in plants are poorly understood. It is known that hydrolysis of natural compounds often alters their biological activity and transport and it has been suggested that CXEs play important roles in plants.…”

Electromembrane extraction and mass spectrometry for liver organoid drug metabolism studies

“…related to the key liver enzymes [56][57][58][59][60] hCES1 (9 peptides identified) and hCES2 (4 peptides identified) in the organoids differentiated from the iPSC cell line AG27…”