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Research ArticleArticle

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
Drug Metabolism and Disposition October 2005, 33 (10) 1482-1487; DOI: https://doi.org/10.1124/dmd.105.005587
Takashi Kubo
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Su-Ryang Kim
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Kimie Sai
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Yoshiro Saito
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Toshiharu Nakajima
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Kenji Matsumoto
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Hirohisa Saito
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Kuniaki Shirao
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Noboru Yamamoto
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Hironobu Minami
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Atsushi Ohtsu
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Teruhiko Yoshida
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Nagahiro Saijo
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Yasuo Ohno
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Shogo Ozawa
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Jun-ichi Sawada
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Abstract

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.

Footnotes

  • T.K. and S.-R.K. contributed equally to this study. This study was supported by the Program for the Promotion of Fundamental Studies in Health Sciences (MPJ-1, -5, and -6) of the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.105.005587.

  • ABBREVIATIONS: hCE-2, human carboxylesterase 2 (EC 3.1.1.1); SNP, single nucleotide polymorphism; RT, reverse transcriptase; PCR, polymerase chain reaction; AUC, area under the plasma concentration curve; CES2, the human carboxylesterase 2 gene; SN-38, 7-ethyl-10-hydroxycamptothecin; SN-38G, glucuronide conjugate of SN-38; HPLC, high-performance liquid chromatography; bp, base pair(s).

    • Received May 20, 2005.
    • Accepted July 13, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 33 (10)
Drug Metabolism and Disposition
Vol. 33, Issue 10
1 Oct 2005
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Research ArticleArticle

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
Drug Metabolism and Disposition October 1, 2005, 33 (10) 1482-1487; DOI: https://doi.org/10.1124/dmd.105.005587

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Research ArticleArticle

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
Drug Metabolism and Disposition October 1, 2005, 33 (10) 1482-1487; DOI: https://doi.org/10.1124/dmd.105.005587
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