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Drug Metabolism and Disposition Fast Forward
First published on July 20, 2005; DOI: 10.1124/dmd.105.005587

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Received for publication May 20, 2005.
Revised July 10, 2005.
Accepted for publication July 13, 2005.

Functional Characterization of Three Naturally Occurring Single Nucleotide Polymorphisms in the CES2 gene encoding carboxylesterase 2 (hCE-2)

Takashi Kubo 1, Su-Ryang Kim 1, Kimie Sai 1, Yoshiro Saito 1, Toshiharu Nakajima 2, Kenji Matsumoto 2, Hirohisa Saito 2, Kuniaki Shirao 3, Noboru Yamamoto 3, Hironobu Minami 4, Atsushi Ohtsu 4, Teruhiko Yoshida 5, Nagahiro Saijo 4, Yasuo Ohno 1, Shogo Ozawa 1*, Jun-ichi Sawada 1

1 National Institute of Health Sciences 2 National Research Institute for Child Health and Development 3 National Cancer Center Hospital 4 National Cancer Center Hospital East 5 National Cancer Center Research Institute

* Address correspondence to: E-mail: sozawa{at}nihs.go.jp

Abstract

Twelve single nucleotide polymorphisms (SNPs) in the human CES2 gene, which encodes a carboxylesterase, hCE-2, have been reported in the Japanese (Kim et al., Drug Metab Pharmacokinet 18:327-332, 2003). In this report, we have examined functional alterations of three SNPs, a nonsynonymous SNP (100C>T, R34W), an SNP at the splice acceptor site in intron 8 (IVS8-2A>G), and one newly discovered nonsynonymous SNP (424G>A, V142M). For the two nonsynonymous SNPs, the corresponding variant cDNAs were expressed in COS-1 cells. Both the R34W and V142M variants showed little esterase activities toward the anti-cancer agent irinotecan and 2 typical carboxylesterase substrates, p-nitrophenol acetate and 4-methylumbelliferyl acetate, although increased levels of cDNA-mediated protein expression were observed by Western blotting as compared with the wild-type. To investigate a possible splicing aberration in IVS8-2A>G, an in vitro splicing assay was utilized and transcripts derived from CES2 gene fragments of the wild-type and IVS8-2A>G were compared. Sequence analysis of the cloned transcripts revealed that IVS8-2A>G yielded mostly aberrantly spliced transcripts, including a deleted exon or a 32-bp deletion proximal to the 5'end of exon 9, which resulted in truncated hCE-2 proteins. These results suggested that 100C>T (R34W), 424G>A (V142M), and IVS8-2A>G are functionally deficient SNPs.


Key words: anticancer agents, carboxylesterases, drug efficacy, genetic polymorphism, microsomes, pharmacogenetics, site-directed mutagenesis


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