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Randomized Controlled Trial
. 2016 Jun;72(6):681-7.
doi: 10.1007/s00228-016-2029-x. Epub 2016 Feb 26.

CES1P1 variant -816A>C is not associated with hepatic carboxylesterase 1 expression and activity or antihypertensive effect of trandolapril

Hao-Jie Zhu  1 , Taimour Y Langaee  2   3 , Yan Gong  2   3 , Xinwen Wang  1 , Carl J Pepine  4 , Rhonda M Cooper-DeHoff  2   3   4 , Julie A Johnson  2   3   4 , John S Markowitz  5   6
Affiliations
Randomized Controlled Trial

CES1P1 variant -816A>C is not associated with hepatic carboxylesterase 1 expression and activity or antihypertensive effect of trandolapril

Hao-Jie Zhu et al. Eur J Clin Pharmacol. 2016 Jun.

Abstract

Purpose: 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.

Keywords: Angiotensin-converting enzyme inhibitors; Carboxylesterase 1 (CES1); Drug metabolism; Hypertension; Pharmacogenomics; Trandolapril.

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Figures

Figure 1
Figure 1
Systolic blood pressure response to trandolapril by CES1 −816 A>C genotype in each race/ethnicity group. The p values were adjusted for age, gender, baseline systolic blood pressure and dose. Bars: adjusted blood pressure response; error bars: standard error of the mean.
Figure 2
Figure 2
Effect of the CES1P1 variant −816A>C on CES1 expression (A) and activity on trandolapril activation (B) in human liver samples (n=100). The data were categorized into three groups based on the −816A>C genotypes (i.e. AA, AC, CC). Horizontal bars represent mean values in each group.
Figure 3
Figure 3
Correlation analysis of CES1 expression and CES1 activity on trandolapril hydrolysis in human liver samples (n=100).
See this image and copyright information in PMC

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