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Carboxylesterase 1 (CES1) is involved in metabolic activation of a variety of prodrugs into active derivatives and plays an important role in pharmacokinetics. We previously reported that a single nucleotide polymorphism (SNP), -816A/C of the CES1A2 gene associates with the responsiveness to an angiotensin-converting enzyme (ACE) inhibitor, imidapril, whose activity is achieved by CES1. To identify relevant functional polymorphisms, we re-sequenced the CES1A2 promoter region ( approximately 1kb) in 100 Japanese hypertensive patients. Altogether 10 SNPs and one insertion/deletion (I/D) were identified, among which seven SNPs and one I/D residing between -62 and -32 were in almost complete linkage disequilibrium (D'=1.00, r2=0.97). They consisted a minor and a major haplotype, the allele frequencies of which were 22% and 74%, respectively. The minor haplotype possessed two putative Sp1 binding sites while the major haplotype did not have any Sp1 binding site. The minor haplotype had a higher transcription and Sp1 binding activities than the major haplotype, invitro. The original -816A/C was in high linkage disequilibrium with these haplotypes (D'=0.92, r2=0.85), and well agreed with the efficacy of imidapril medication. These results suggest that the Sp1 binding site variation in the CES1A2 promoter is functional, and are good candidates for the pharmacogenetic studies of CES1-activated drugs.

Imidapril is an angiotensin-converting enzyme inhibitor that is widely used in treating hypertension, although the responses vary among individuals. We investigated whether a single nucleotide polymorphism at position -816 of the carboxylesterase 1 (CES1) gene, which activates imidapril in the liver, is involved in the responsiveness to imidapril medication. A total of 105 Japanese hypertensives with systolic/diastolic blood pressures (SBP/DBP) of 140/90 mmHg or higher were prescribed 5-10 mg/day of imidapril. At baseline, blood pressure levels were not different between patients with and those without the -816C allele (AA vs. AC+ CC groups). After 8 weeks of treatment, we classified the responders and non-responders based on the decline in their blood pressures, and found that the responder rate was significantly higher in the AC+CC group than in the AA group (p=0.0331). Also, the reduction in SBP was significantly greater in the AC+CC group than in the AA group (24.7+/-11.8 vs. 17.6+/-16.8 mmHg, p=0.0184). Furthermore, an in vitro reporter assay revealed that the -816C construct had significantly higher promoter activity (p<0.0001). These findings suggest that the A(-816)C polymorphism affects the transcriptional activity, and that this may account for the responsiveness to imidapril.

We evaluated the effects of angiotensin-converting enzyme (ACE) inhibition on metabolic changes in myocardial organelles, myocardial hypertrophy, and interstitial fibrosis in the early stage of hypertension. An ACE inhibitor, imidapril (2.5 mg/kg per day), a calcium-channel blocker, diltiazem (30 mg/kg per day), or vehicle was given to spontaneously hypertensive rats (SHRs) from 10 to 18 weeks of age. Single myocytes were isolated enzymatically from the left ventricles of these SHRs and normotensive Wistar-Kyoto (WKY) controls at 18 weeks of age. In single ventricular myocytes, enzyme activities in the sarcoplasmic reticulum (SR) and the sarcolemma (SL) and the mitochondrial respiratory control ratio (RCR) were determined. In 18-week-old SHRs receiving vehicle, myocardial hypertrophy and interstitial fibrosis developed, and SR Ca2+ AT-Pase activity and the mitochondrial RCR were significantly lower and SL Na+, K(+)-ATPase activity was significantly higher than in age-matched WKYs. However, compared with diltiazem, imidapril was better able to prevent the development of myocardial hypertrophy and interstitial fibrosis, to improve SR Ca(2+)-ATPase activity and the mitochondrial RCR, and to increase SL Na+, K(+)-ATPase activity. These results suggest that ACE inhibition can prevent the development of morphologic changes associated with hypertension-induced left ventricular remodeling, such as myocardial hypertrophy and interstitial fibrosis, and can counteract ongoing dysfunction of organelle metabolism early in the development of hypertension.