title: CES1 genetic variation affects the activation of angiotensin-converting enzyme inhibitors.
abstract: The aim of the study was to determine the effect of carboxylesterase 1 (CES1) genetic variation on the activation of angiotensin-converting enzyme inhibitor (ACEI) prodrugs. In vitro incubation study of human liver, intestine and kidney s9 fractions demonstrated that the ACEI prodrugs enalapril, ramipril, perindopril, moexipril and fosinopril are selectively activated by CES1 in the liver. The impact of CES1/CES1VAR and CES1P1/CES1P1VAR genotypes and diplotypes on CES1 expression and activity on enalapril activation was investigated in 102 normal human liver samples. Neither the genotypes nor the diplotypes affected hepatic CES1 expression and activity. Moreover, among several CES1 nonsynonymous variants studied in transfected cell lines, the G143E (rs71647871) was a loss-of-function variant for the activation of all ACEIs tested. The CES1 activity on enalapril activation in human livers with the 143G/E genotype was approximately one-third of that carrying the 143G/G. Thus, some functional CES1 genetic variants (for example, G143E) may impair ACEI activation, and consequently affect therapeutic outcomes of ACEI prodrugs.
authors.affiliation: Department of Clinical, Social, and Administrative sciences, University of Michigan, Ann Arbor, MI, USA.|The Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: The Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
authors.forename: G
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Clinical, Social, and Administrative sciences, University of Michigan, Ann Arbor, MI, USA.
authors.forename: J
authors.initials: J
authors.lastname: Shi
authors.affiliation: The Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
authors.forename: J
authors.initials: J
authors.lastname: Aa
authors.affiliation: Department of Clinical, Social, and Administrative sciences, University of Michigan, Ann Arbor, MI, USA.
authors.forename: R
authors.initials: R
authors.lastname: Comas
authors.affiliation: Department of Clinical, Social, and Administrative sciences, University of Michigan, Ann Arbor, MI, USA.|The Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Department of Clinical, Social, and Administrative sciences, University of Michigan, Ann Arbor, MI, USA.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Zhu
mesh_terms: D065767:Activation, Metabolic / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000378:metabolism*; D002265:Carboxylic Ester Hydrolases / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D005260:Female; D005838:Genotype; D006801:Humans; D006868:Hydrolysis; D007422:Intestines / Q000201:enzymology; D007668:Kidney / Q000201:enzymology; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D000071184:Pharmacogenomic Variants / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011355:Prodrugs / Q000378:metabolism*; D014162:Transfection; D055815:Young Adult
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D011355:Prodrugs; D002265:Carboxylic Ester Hydrolases; C474609:CES1 protein, human