PubMed:28838926 JSONTXT 28 Projects

A comprehensive functional assessment of carboxylesterase 1 nonsynonymous polymorphisms. Carboxylesterase 1 (CES1) is the predominant human hepatic hydrolase responsible for the metabolism of many clinically important medications. CES1 expression and activity vary markedly among individuals; and genetic variation is a major contributing factor to CES1 interindividual variability. In the present study, we comprehensively examined the functions of CES1 nonsynonymous single nucleotide polymorphisms (nsSNPs) and haplotypes using transfected cell lines and individual human liver tissues. The 20 candidate variants include CES1 nsSNPs with a minor allele frequency (MAF) > 0.5% in a given population or located in close proximity to the CES1 active site. Five nsSNPs including L40Ter (rs151291296), G142E (rs121912777), G147C (rs146456965), Y170D (rs148947808), and R171C (rs201065375) were found to be loss-of-function variants for metabolizing the CES1 substrates clopidogrel, enalapril, and sacubitril. Additionally, the A158V (rs202121317), R199H (rs2307243), E220G (rs200707504), and T290M (rs202001817) decreased CES1 activity to a lesser extent in a substrate-dependent manner. Several nsSNPs including the L40Ter (rs151291296), G147C (rs146456965), Y170D (rs148947808), and R171C (rs201065375) significantly reduced CES1 protein and/or mRNA expressions in the transfected cells. Functions of the common nonsynonymous haplotypes D203E-A269S and S75N-D203E-A269S were evaluated using cells stably expressing the haplotypes and a large set of human livers. Neither CES1 expression nor activity were affected by the two haplotypes. In sum, the study revealed several functional nsSNPs with impaired activity on the metabolism of CES1 substrate drugs. Clinical investigations are warranted to determine whether these nsSNPs can serve as biomarkers for the prediction of therapeutic outcomes of drugs metabolized by CES1.