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

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 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 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, activity or therapeutic response to ACEI prodrugs.

Functional Study of Carboxylesterase 1 Protein Isoforms

“…As the predominant hepatic hydrolase, CES1 plays a critical role in the activation/deactivation of various medications. Importantly, previous studies have shown hepatic CES1 expression and activity to vary among individuals by 11.3‐fold and 47.8‐fold, respectively. Additionally, significant interindividual variability has been consistently reported in responses to CES1 substrate medications, which is in part associated with CES1 genetic polymorphisms .…”

“…Additionally, we recently conducted a comprehensive functional study of CES1 nonsynonymous variants and revealed a few CES1 SNPs which impaired CES1 activity in the hydrolysis of enalapril, clopidogrel, and sacubitril; these include L40Ter (rs151291296), A158V (rs202121317), R199H (rs2307243), E220G (rs200707504), and T290M (rs202001817) . Aside from nonsynonymous variants, two SNPs ‐816A>C (rs3785161) and ‐75T>G (rs3815583), located in the promoter regions of CES1P1 and CES1 , respectively, have been reported to be associated with responses to CES1 substrates, such as imidapril, clopidogrel, and methylphenidate, although not all studies have supported this association . Taken together, these findings have established an important role for CES1 genetic polymorphisms in regulating CES1 function; however, it is worth noting that a substantial portion of CES1 variability remains unexplained.…”

Dabigatran etexilate activation is affected by the CES1 genetic polymorphism G143E (rs71647871) and gender

“…In addition to the G143E, other CES1 variations such as the −816A>C (rs3785161) and functional CES1 gene copy numbers were suggested by several clinical studies to be associated with the metabolism of some CES1 substrate drugs [30-32]. However, our recent in vitro CES1 pharmacogenetic studies utilizing individual human livers demonstrated that neither CES1 expression nor activity was affected by the −816AA>C and functional CES1 gene copy variants [22, 33]. Pare and associates conducted a genome-wide association study in RE-LY study participants, and reported that the CES1 SNPs rs2244613 and rs8192935 were associated with lower plasma concentrations of DAB, and the rs2244613 was also associated with a lower risk of bleeding [4].…”

Carboxylesterase 1 and Precision Pharmacotherapy: Pharmacogenetics and Nongenetic Regulators

“…Zhu et al (2014) also performed a retrospective pharmacogenetic analysis of the INternational VErapamil SR Trandolapril study (n 5 486) and did not find an association between -816A.C and the blood pressure-lowering effect of trandolapril. The follow-up in vitro study also showed -816A.C genotype was not significantly associated with CES1 protein expression and trandolapril activation in human liver samples (n 5 100) (Zhu et al, 2016). Other researchers also noted that the CES1P1 VAR gene, which contains -816A.C, is considered functionally insignificant because of its low transcription efficiency (Tanimoto et al, 2007;Hosokawa et al, 2008).…”