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 CESIA2 gene associates with the responsiveness to an angiotensin-converting enzyme (ACE) inhibitor, imiclapril, whose activity is achieved by CES1 To identify relevant functional polymorphisms, we re-sequenced the CES1A2 promoter region (similar to 1 kb) 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 Spl binding activities than the major haplotype, in vitro. 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 Spl binding site variation in the CESIA2 promoter is functional, and are good candidates for the pharmacogenetic studies of CES1-activated drugs. (c) 2008 Elsevier Inc. All rights reserved.