Received for publication February 23, 2007.
Revised June 21, 2007.
Accepted for publication July 17, 2007.

Haplotypes and a novel defective allele of CES2 found in a Japanese population

Abstract

Human carboxylesterase 2 (hCE-2) is a member of the serine esterase superfamily and responsible for hydrolysis of a wide variety of xenobiotic and endogenous esters. hCE-2 also activates an anticancer drug, irinotecan (CPT-11), into its active metabolite, SN-38. In this study, a comprehensive haplotype analysis of the CES2 gene, which encodes hCE-2, in a Japanese population was conducted. Using 21 single nucleotide polymorphisms (SNPs), including 4 nonsynonymous SNPs, 100C>T (Arg34Trp, *2), 424G>A (Val142Met, *3), 1A>T (Met1Leu, *5), and 617G>A (Arg206His, *6), and a SNP at the splice acceptor site of intron 8 (IVS8-2A>G, *4), 20 haplotypes were identified in 262 Japanese subjects. In 176 Japanese cancer patients that received irinotecan, associations of CES2 haplotypes and changes in a pharmacokinetic parameter, (SN-38+SN-38G)/CPT-11 AUC ratio, were analyzed. No significant association was found among the major haplotypes of the *1 group lacking nonsynonymous or defective SNPs. However, patients with nonsynonymous SNPs, 100C>T (Arg34Trp) or 1A>T (Met1Leu), showed substantially reduced AUC ratios. In vitro functional characterization of the SNPs was conducted and showed that the 1A>T SNP affected translational, but not transcriptional, efficiency. These findings are useful for further pharmacogenetic studies on CES2-activated prodrugs.

Key words: carboxylesterases, pharmacokinetics, polymorphisms