Haplotypes and a novel defective allele of CES2 found in a Japanese population.
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 (Arg(34)Trp, *2), 424G>A (Val(142)Met, *3), 1A>T (Met(1)Leu, *5), and 617G>A (Arg(206)His, *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 (Arg(34)Trp) or 1A>T (Met(1)Leu), 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.
Kim
Su-Ryang
SR
Project Team for Pharmacogenetics, National Institute of Health Sciences, Tokyo, Japan. kim@nihs.go.jp
Sai
Kimie
K
Tanaka-Kagawa
Toshiko
T
Jinno
Hideto
H
Ozawa
Shogo
S
Kaniwa
Nahoko
N
Saito
Yoshiro
Y
Akasawa
Akira
A
Matsumoto
Kenji
K
Saito
Hirohisa
H
Kamatani
Naoyuki
N
Shirao
Kuniaki
K
Yamamoto
Noboru
N
Yoshida
Teruhiko
T
Minami
Hironobu
H
Ohtsu
Atsushi
A
Saijo
Nagahiro
N
Sawada
Jun-ichi
J
D000483:Alleles; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D044466:Asian People / Q000235:genetics*; D019556:COS Cells; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D043182:Carboxylesterase / Q000235:genetics* / Q000378:metabolism; D002522:Chlorocebus aethiops; D006239:Haplotypes; D006801:Humans; D006967:Hypersensitivity / Q000235:genetics; D000077146:Irinotecan; D015810:Linkage Disequilibrium; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D011355:Prodrugs / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D017422:Sequence Analysis, DNA
D000972:Antineoplastic Agents, Phytogenic; D011355:Prodrugs; D012333:RNA, Messenger; D000077146:Irinotecan; C517204:CES2 protein, human; D043182:Carboxylesterase; D002166:Camptothecin