Abstract
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.
Footnotes
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doi:10.1124/dmd.107.015339.
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This study was supported in part by the Program for the Promotion of Fundamental Studies in Health Sciences from the National Institute of Biomedical Innovation and by a Health and Labour Science Research Grant from the Ministry of Health, Labour and Welfare of Japan.
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ABBREVIATIONS: hCE-1, human carboxylesterase 1; hCE-2, human carboxylesterase 2 (EC 3.1.1.1); irinotecan, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin, CPT-11; SN-38, 7-ethyl-10-hydroxycamptothecin; SN-38G, SN-38 glucuronide; SNP, single nucleotide polymorphisms; PCR, polymerase chain reaction; LD, linkage disequilibrium; 5-FU, 5-fluorouracil; MMC, mitomycin C; AUC, area under plasma concentration curve; RT, reverse transcriptase; UTR, untranslated region; ORF, open reading frame.
- Received February 23, 2007.
- Accepted July 17, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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