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

  • Pharmacogenetics
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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.

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Acknowledgments

The research reported in this publication was supported in part by the National Institute on Aging (R21AG048500) (Hao-Jie Zhu), the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number 2UL1TR000433 (Hao-Jie Zhu), and the American Association of Colleges of Pharmacy (AACP) 2015 New Investigator Award (Hao-Jie Zhu).

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Authors and Affiliations

  1. Department of Clinical Pharmacy, University of Michigan, Ann Arbor, MI, USA

    Hao-Jie Zhu & Xinwen Wang

  2. Department of Pharmacotherapy and Translational Research, University of Florida, 1600 SW Archer Road, RM PG-23, Gainesville, FL, 32610-0486, USA

    Taimour Y. Langaee, Yan Gong, Rhonda M. Cooper-DeHoff, Julie A. Johnson & John S. Markowitz

  3. Center for Pharmacogenomics, University of Florida, Gainesville, FL, USA

    Taimour Y. Langaee, Yan Gong, Rhonda M. Cooper-DeHoff, Julie A. Johnson & John S. Markowitz

  4. Division of Cardiovascular Medicine, Department of Medicine, University of Florida, Gainesville, FL, USA

    Carl J. Pepine, Rhonda M. Cooper-DeHoff & Julie A. Johnson

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  1. Hao-Jie Zhu
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Correspondence to John S. Markowitz.

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Zhu, HJ., Langaee, T.Y., Gong, Y. et al. CES1P1 variant −816A>C is not associated with hepatic carboxylesterase 1 expression and activity or antihypertensive effect of trandolapril. Eur J Clin Pharmacol 72, 681–687 (2016). https://doi.org/10.1007/s00228-016-2029-x

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  • DOI: https://doi.org/10.1007/s00228-016-2029-x

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