title: CES1P1 variant -816A>C is not associated with hepatic carboxylesterase 1 expression and activity or antihypertensive effect of trandolapril.
abstract: OBJECTIVE
  The majority of angiotensin-converting enzyme inhibitors (ACEIs) are synthesized as ester prodrugs that must be converted to their active forms in vivo in order to exert therapeutic effects. Hepatic carboxylesterase 1 (CES1) is the primary enzyme responsible for the bioactivation of ACEI prodrugs in humans. The genetic variant -816A>C (rs3785161) is a common variant located in the promoter region of the CES1P1 gene. Previous studies report conflicting results with regard to the association of this variant and therapeutic outcomes of CES1 substrate drugs. The purpose of this study was to determine the effect of the variant -816A>C on the activation of the ACEI prodrug trandolapril in human livers and the blood pressure (BP)-lowering effect of trandolapril in hypertensive patients.
  
  
  METHODS
  The -816A>C genotypes and CES1 expression and activity on trandolapril activation were determined in 100 individual human liver samples. Furthermore, the association of the -816A>C variant and the BP lowering effect of trandolapril was evaluated in hypertensive patients who participated in the International Verapamil SR Trandolapril Study (INVEST).
  
  
  RESULTS
  Our in vitro study demonstrated that hepatic CES1 expression and activity did not differ among different -816A>C genotypes. Moreover, we were unable to identify a clinical association between the BP lowering effects of trandolapril and -816A>C genotypes.
  
  
  CONCLUSIONS
  We conclude that the -816A>C variant is not associated with interindividual variability in CES1 expression and activity or therapeutic response to ACEI prodrugs.
authors.affiliation: Department of Clinical Pharmacy, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Hao-Jie
authors.initials: HJ
authors.lastname: Zhu
authors.affiliation: Department of Pharmacotherapy and Translational Research, University of Florida, 1600 SW Archer Road, RM PG-23, Gainesville, FL, 32610-0486, USA.|Center for Pharmacogenomics, University of Florida, Gainesville, FL, USA.
authors.forename: Taimour Y
authors.initials: TY
authors.lastname: Langaee
authors.affiliation: Department of Pharmacotherapy and Translational Research, University of Florida, 1600 SW Archer Road, RM PG-23, Gainesville, FL, 32610-0486, USA.|Center for Pharmacogenomics, University of Florida, Gainesville, FL, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Department of Clinical Pharmacy, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Xinwen
authors.initials: X
authors.lastname: Wang
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Pepine
authors.affiliation: Department of Pharmacotherapy and Translational Research, University of Florida, 1600 SW Archer Road, RM PG-23, Gainesville, FL, 32610-0486, USA.|Center for Pharmacogenomics, University of Florida, Gainesville, FL, USA.|Division of Cardiovascular Medicine, Department of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Rhonda M
authors.initials: RM
authors.lastname: Cooper-DeHoff
authors.affiliation: Department of Pharmacotherapy and Translational Research, University of Florida, 1600 SW Archer Road, RM PG-23, Gainesville, FL, 32610-0486, USA.|Center for Pharmacogenomics, University of Florida, Gainesville, FL, USA.|Division of Cardiovascular Medicine, Department of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Johnson
authors.affiliation: Department of Pharmacotherapy and Translational Research, University of Florida, 1600 SW Archer Road, RM PG-23, Gainesville, FL, 32610-0486, USA. jmarkowitz@cop.ufl.edu.|Center for Pharmacogenomics, University of Florida, Gainesville, FL, USA. jmarkowitz@cop.ufl.edu.
authors.forename: John S
authors.initials: JS
authors.lastname: Markowitz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000494:pharmacology*; D002265:Carboxylic Ester Hydrolases / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D007211:Indoles; C052035:trandolapril; C121305:CES1P1 protein, human; D002265:Carboxylic Ester Hydrolases; C474609:CES1 protein, human
keywords: Angiotensin-converting enzyme inhibitors; Carboxylesterase 1 (CES1); Drug metabolism; Hypertension; Pharmacogenomics; Trandolapril