Wang_2018_Proteomics__e1800288

Carboxylesterase1 (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, we examined the activity and expression of each CES1 isoform using transfected cell lines and determined CES1 isoform composition and its impact on CES1 activity in human livers. In transfected cells, isoforms 3 and 4 showed mRNA and protein expressions comparable to isoforms 1 and 2, but had significantly impaired activity when hydrolyzing enalapril and clopidogrel. In individual human liver samples, isoforms 1 and 2 were the major forms, contributing 73%-90% of total CES1 protein expression. In addition, the protein expression ratios of isoforms 1 and 2 to isoforms 3 and 4 were positively associated with CES1 activity in the livers, 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 our understanding of CES1 variability and help develop a strategy to optimize the pharmacotherapy of many CES1 substrate medications. This article is protected by copyright. All rights reserved.