PT  - JOURNAL ARTICLE
AU  - Su-Ryang Kim
AU  - Kimie Sai
AU  - Toshiko Tanaka-Kagawa
AU  - Hideto Jinno
AU  - Shogo Ozawa
AU  - Nahoko Kaniwa
AU  - Yoshiro Saito
AU  - Akira Akasawa
AU  - Kenji Matsumoto
AU  - Hirohisa Saito
AU  - Naoyuki Kamatani
AU  - Kuniaki Shirao
AU  - Noboru Yamamoto
AU  - Teruhiko Yoshida
AU  - Hironobu Minami
AU  - Atsushi Ohtsu
AU  - Nagahiro Saijo
AU  - Jun-ichi Sawada
TI  - Haplotypes and a Novel Defective Allele of <em>CES2</em> Found in a Japanese Population
AID  - 10.1124/dmd.107.015339
DP  - 2007 Oct 01
TA  - Drug Metabolism and Disposition
PG  - 1865--1872
VI  - 35
IP  - 10
4099  - http://dmd.aspetjournals.org/content/35/10/1865.short
4100  - http://dmd.aspetjournals.org/content/35/10/1865.full
SO  - Drug Metab Dispos2007 Oct 01; 35
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics