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Haplotypes and a Novel Defective Allele of CES2 Found in a Japanese Population

Project Team for Pharmacogenetics (S.-R.K., K.Sa., H.J., S.O., N.Kan., Y.S., J.S.), Division of Biosignaling (K.Sa.), Division of Environmental Chemistry and Exposure Assessment (T.T.-K., H.J.), Division of Pharmacology (S.O.), Division of Medicinal Safety Sciences (N.Kan.), Division of Biochemistry and Immunochemistry (Y.S., J.S.), National Institute of Health Sciences, Tokyo, Japan; Department of Allergy and Immunology, National Research Institute for Child Health and Development (K.M., H.S.), National Children's Medical Center (A.A.), National Center for Child Health and Development, Tokyo, Japan; Division of Genomic Medicine, Department of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan (N.Kam.); Division of Internal Medicine (K.Sh., N.Y.), National Cancer Center Hospital, Genetics Division (T.Y.), National Cancer Center Research Institute, Tokyo, Japan; and Division of Oncology/Hematology (H.M.), Division of GI Oncology/Digestive Endoscopy (A.O.), Deputy Director (N.S.), National Cancer Center Hospital East, Chiba, Japan

Human carboxylesterase 2 (hCE-2) is a member of the serine esterase superfamily and is responsible for hydrolysis of a wide variety of xenobiotic and endogenous esters. hCE-2 also activates an anticancer drug, irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin, CPT-11), into its active metabolite, 7-ethyl-10-hydroxycamptothecin (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 who received irinotecan, associations of CES2 haplotypes and changes in a pharmacokinetic parameter, (SN-38 + SN-38G)/CPT-11 area under the plasma concentration curve (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.