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Research ArticleArticle

FUNCTIONAL CHARACTERIZATION OF FIVE NOVEL CYP2C8 VARIANTS, G171S, R186X, R186G, K247R, AND K383N, FOUND IN A JAPANESE POPULATION

Hiroyuki Hichiya, Toshiko Tanaka-Kagawa, Akiko Soyama, Hideto Jinno, Satoru Koyano, Noriko Katori, Erika Matsushima, Shigehisa Uchiyama, Hiroshi Tokunaga, Hideo Kimura, Narihiro Minami, Masaaki Katoh, Kenji Sugai, Yu-ichi Goto, Tomohide Tamura, Noboru Yamamoto, Yuichiro Ohe, Hideo Kunitoh, Hiroshi Nokihara, Teruhiko Yoshida, Hironobu Minami, Nagahiro Saijo, Masanori Ando, Shogo Ozawa, Yoshiro Saito and Jun-ichi Sawada
Drug Metabolism and Disposition May 2005, 33 (5) 630-636; DOI: https://doi.org/10.1124/dmd.105.003830
Hiroyuki Hichiya
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Toshiko Tanaka-Kagawa
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Akiko Soyama
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Hideto Jinno
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Satoru Koyano
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Noriko Katori
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Erika Matsushima
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Shigehisa Uchiyama
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Hiroshi Tokunaga
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Hideo Kimura
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Narihiro Minami
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Masaaki Katoh
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Kenji Sugai
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Yu-ichi Goto
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Tomohide Tamura
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Noboru Yamamoto
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Yuichiro Ohe
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Hideo Kunitoh
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Hiroshi Nokihara
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Teruhiko Yoshida
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Masanori Ando
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Shogo Ozawa
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Yoshiro Saito
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Abstract

Cytochrome P450 2C8 is one of the primary enzymes responsible for the metabolism of a wide range of drugs such as paclitaxel, cerivastatin, and amiodarone. We have sequenced the CYP2C8 gene from 201 Japanese subjects and found five novel nonsynonymous single nucleotide polymorphisms (SNPs): 511G>A (G171S), 556C>T (R186X; X represents the translational stop codon), 556C>G (R186G), 740A>G (K247R), and 1149G>T (K383N), with the allele frequency of 0.0025. The CYP2C8 variants were heterologously expressed in COS-1 cells and functionally characterized in terms of expression level, paclitaxel 6α-hydroxylase activity, and intracellular localization. The prematurely terminated R186X variant was undetectable by Western blotting and inactive toward paclitaxel 6α-hydroxylation. The G171S, K247R, and K383N variants exhibited properties similar to those of the wild-type CYP2C8. Paclitaxel 6α-hydroxylase activity of the R186G transfectant was only 10 to 20% that of wild-type CYP2C8. Furthermore, the R186G variant displayed a lower level of protein expression in comparison to the wild type, which was restored by the addition of a proteasome inhibitor (MG-132; Z-Leu-Leu-Leu-aldehyde). The reduced CO-difference spectral analysis using recombinant proteins from an insect cell/baculovirus system revealed that the R186G variant has a minor peak at 420 nm in addition to the characteristic Soret peak at 450 nm, suggesting the existence of improperly folded protein. These results indicate that the novel CYP2C8 SNPs, 556C>T (R186X) and 556C>G (R186G), could influence the metabolism of CYP2C8 substrates such as paclitaxel and cerivastatin.

Footnotes

  • This study was supported in part by the Program for Promotion of Fundamental Studies in Health Sciences (MPJ-1, MPJ-2, and MPJ-6) of the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan.

  • Hiroyuki Hichiya, Toshiko Tanaka-Kagawa, and Akiko Soyama contributed equally to this article.

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

  • doi:10.1124/dmd.105.003830.

  • ABBREVIATIONS: P450, cytochrome P450; ECFP, enhanced cyan fluorescent protein; EYFP, enhanced yellow fluorescent protein; PCR, polymerase chain reaction; RT, reverse transcription; SNP, single nucleotide polymorphism; SRS, substrate recognition site; MG-132, Z-Leu-Leu-Leu-aldehyde.

    • Received January 26, 2005.
    • Accepted February 15, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 33 (5)
Drug Metabolism and Disposition
Vol. 33, Issue 5
1 May 2005
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Research ArticleArticle

FUNCTIONAL CHARACTERIZATION OF FIVE NOVEL CYP2C8 VARIANTS, G171S, R186X, R186G, K247R, AND K383N, FOUND IN A JAPANESE POPULATION

Hiroyuki Hichiya, Toshiko Tanaka-Kagawa, Akiko Soyama, Hideto Jinno, Satoru Koyano, Noriko Katori, Erika Matsushima, Shigehisa Uchiyama, Hiroshi Tokunaga, Hideo Kimura, Narihiro Minami, Masaaki Katoh, Kenji Sugai, Yu-ichi Goto, Tomohide Tamura, Noboru Yamamoto, Yuichiro Ohe, Hideo Kunitoh, Hiroshi Nokihara, Teruhiko Yoshida, Hironobu Minami, Nagahiro Saijo, Masanori Ando, Shogo Ozawa, Yoshiro Saito and Jun-ichi Sawada
Drug Metabolism and Disposition May 1, 2005, 33 (5) 630-636; DOI: https://doi.org/10.1124/dmd.105.003830

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Research ArticleArticle

FUNCTIONAL CHARACTERIZATION OF FIVE NOVEL CYP2C8 VARIANTS, G171S, R186X, R186G, K247R, AND K383N, FOUND IN A JAPANESE POPULATION

Hiroyuki Hichiya, Toshiko Tanaka-Kagawa, Akiko Soyama, Hideto Jinno, Satoru Koyano, Noriko Katori, Erika Matsushima, Shigehisa Uchiyama, Hiroshi Tokunaga, Hideo Kimura, Narihiro Minami, Masaaki Katoh, Kenji Sugai, Yu-ichi Goto, Tomohide Tamura, Noboru Yamamoto, Yuichiro Ohe, Hideo Kunitoh, Hiroshi Nokihara, Teruhiko Yoshida, Hironobu Minami, Nagahiro Saijo, Masanori Ando, Shogo Ozawa, Yoshiro Saito and Jun-ichi Sawada
Drug Metabolism and Disposition May 1, 2005, 33 (5) 630-636; DOI: https://doi.org/10.1124/dmd.105.003830
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