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

0090-9556/05/3310-1482-1487$20.00
DMD 33:1482-1487, 2005

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FUNCTIONAL CHARACTERIZATION OF THREE NATURALLY OCCURRING SINGLE NUCLEOTIDE POLYMORPHISMS IN THE CES2 GENE ENCODING CARBOXYLESTERASE 2 (HCE-2)

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

Project Team for Pharmacogenetics (T.K., S.-R.K., K.Sa., Y.S., S.O., J.I.S.), Division of Xenobiotic Metabolism and Disposition (K.Sa.), Division of Biochemistry and Immunochemistry (Y.S., J.I.S.), Division of Pharmacology (S.O.), and Deputy Director (Y.O.), National Institute of Health Sciences, Tokyo, Japan; Department of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo, Japan (T.N., K.M., H.S.); Division of Internal Medicine (K.Sh., N.Y.), National Cancer Center Hospital, Tokyo, Japan; Genetics Division (T.Y.), National Cancer Center Research Institute, Tokyo, Japan; and Division of Oncology Hematology (H.M.), Division of Gastrointestinal Oncology Digestive Endoscopy (A.O.), and Deputy Director (N.S.), National Cancer Center Hospital East, Chiba, Japan

Twelve single nucleotide polymorphisms (SNPs) in the human CES2 gene, which encodes a carboxylesterase, hCE-2 [human carboxylesterase 2 (EC 3.1.1.1)], have been reported in the Japanese [S. R. Kim, T. Nakamura, Y. Saito, K. Sai, T. Nakajima, H. Saito, K. Shirao, H. Minami, A. Ohtsu, T. Yoshida, et al. (2003) Drug Metab Pharmacokinet 18:327–332). 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 anticancer agent irinotecan and two 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.

Address correspondence to: Dr. Shogo Ozawa, Division of Pharmacology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan. E-mail: sozawa{at}nihs.go.jp




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