Effects of protein/protein interaction on activity of drug metabolizing enzymes

• Project/Area Number: 19790132
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Medical pharmacy
• Research Institution: The Institute of Physical and Chemical Research
• Principal Investigator: KIYOTANI Kazuma The Institute of Physical and Chemical Research, 遺伝情報解析チーム, 研究員 (30433642)
• Project Period (FY): 2007 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥3,710,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥510,000); Fiscal Year 2009: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2008: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2007: ¥1,500,000 (Direct Cost: ¥1,500,000)
• Keywords: チトクロームP450 / 相互作用 / 遺伝子多型 / 酵素活性 / SNP / 薬物代謝酵素

Research Abstract

Cytochrome P450 (CYP) is one of the most important drug-metabolizing enzymes. In this study, we investigated the effects of protein/protein interaction on the enzyme activity of CYPs. Mammalian two-hybrid system and immunoprecipitation assay revealed that CYP3A4 interacted with CYP3A4 or CYP3A5 in the cells transefected with expression plasmids for myc- or flag-tagged proteins. CYP3A4 also interacted with CYP2C isoforms. These results suggest the CYPs interact with each other in the cells, and possibly these interactions were associated with CYP expression or function.

Research Products

• [Journal Article] Significant Effect of Polymorphisms in CYP2D6 and ABCC2 on Clinical Outcomes of Adjuvant Tamoxifen TherEfapy for Breast Cancer Patients. (2010)
  • Author(s): Kazuma Kiyotani, Taisei Mushiroda, Chiyo K. Imamura, Naoya Hosono, Tatsuhiko Tsunoda, Michiaki Kubo, Yusuke Tanigawara, David A. Flockhart, Zeruesenay Desta, Todd C. Skaar, Fuminori Aki, Koichi Hirata, Yuichi Takatsuka, Minoru Okazaki, Shozo Ohsumi, Takashi Yamakawa, Mitsunori Sasa, Yusuke Nakamura, Hitoshi Zembutsu
  • Journal Title: J Clin Oncol 28 Pages: 1287-1293
  • Peer Reviewed
• [Journal Article] Significant Effect of Polymorphisms in CYP2D6 and ABCC2 on Clinical Outcomes of Adjuvant Tamoxifen Therapy for Breast Cancer Patients (2010)
  • Author(s): Kiyotani K, et al.
  • Journal Title: Journal of Clinical Oncology (in press)
  • Peer Reviewed
• [Journal Article] Two novel CYP2D6*10 haplotypes as possible causes of a poor metabolic phenotype in Japanese. (2009)
  • Author(s): Masayuki Matsunaga, Hiroshi Yamazaki, Kazuma Kiyotani, Shunsuke Iwano, Junji Saruwatari, Kazuko Nakagawa, Akiko Soyama, Shogo Ozawa, Jun-ichi Sawada, Eiji Kashiyama, Moritoshi Kinoshita, Tetsuya Kamataki
  • Journal Title: Drug Metab Dispos 37 Pages: 699-701
  • Peer Reviewed
• [Journal Article] Two novel CYP2D6*10 haplotypes as possible causes of a poor metabolic phenotype in Japanese (2009)
  • Author(s): Matsunaga M, et al
  • Journal Title: Drug Metab Dispos (in press)
  • Peer Reviewed
• [Journal Article] Impact of CYP2D6*10 on recurrence-free survival in breast cancer patients receiving adjuvant tamoxifen therapy. (2008)
  • Author(s): Kazuma Kiyotani, Taisei Mushiroda, Mitsunori Sasa, Yoshimi Bando, Ikuko Sumitomo, Naoya Hosono, Michiaki Kubo, Yusuke Nakamura, Hitoshi Zembutsu
  • Journal Title: Cancer Sci 99 Pages: 995-999
  • NAID: 10024006283
  • Peer Reviewed
• [Journal Article] Association of genetic polymorphisms in SLCO1B3 and ABCC2 with docetaxel-induced leukopenia. (2008)
  • Author(s): Kazuma Kiyotani, Taisei Mushiroda, Michiaki Kubo, Hitoshi Zembutsu, Yuichi Sugiyama, Yusuke Nakamura
  • Journal Title: Cancer Sci 99 Pages: 967-972
  • NAID: 10024006132
  • Peer Reviewed
• [Journal Article] Association of genetic polymorphisms in SLCOIB3 and ABCC2 with docetaxel-induced leukopenia (2008)
  • Author(s): Kiyotani K, et. al.
  • Journal Title: Cancer Science (in press)
  • Peer Reviewed
• [Journal Article] Impact of CYP2D6*10 on recurrence-free survival in breast cancer patients received adjuvant tamoxifen therapy (2008)
  • Author(s): Kiyotani K, et. al.
  • Journal Title: Cancer Science (in press)
  • NAID: 10024006283
  • Peer Reviewed
• [Presentation] Association of polymorphisms of CYP2D6 and other PK-related genes on recurrence-free survival in Japanese breast cancer patients receiving adjuvant tamoxifen therapy. (2009)
  • Author(s): Kazuma Kiyotani, Taisei Mushiroda, Mitsunori Sasa, Takashi Yamakawa, Koichi Hirata, Minoru Okazaki, Shozo Ohsumi, Yuichi Takatsuka, Yoshimi Bando, Ikuko Sumitomo, Tatsuhiko Tsunoda, Naoya Hosono, Michiaki Kubo, Yusuke Nakamura, Hitoshi Zembutsu
  • Organizer: 59th Annual Meeting, the American society of Human Genetics
  • Place of Presentation: Honolulu
  • Year and Date: 2009-10-22
• [Presentation] CYP2D6 genotyping for functional gene dosage analysis by allele copy number detection. (2009)
  • Author(s): Naoya Hosono, Mamoru Kato, Kazuma Kiyotani, Taisei Mushiroda, Keiko Yamazaki, Tatsuhiko Tsunoda, Hitoshi Zembutsu, Yusuke Nakamura, Michiaki Kubo
  • Organizer: 59th Annual Meeting, the American society of Human Genetics
  • Place of Presentation: Honolulu
  • Year and Date: 2009-10-22
• [Presentation] Association of polymorphisms of CYP2D6 and other PK-related genes on recurrence-free survival in Japanese breast cancer patients receiving adjuvant tamoxifen therapy (2009)
  • Author(s): 清谷一馬, et al
  • Organizer: 59th Annual Meeting, the American society of Human Genetics
  • Place of Presentation: Honolulu
  • Year and Date: 2009-10-22
• [Presentation] 乳がん患者におけるタモキシフェンの再発予防効果と薬物代謝酵素の遺伝子型. (2009)
  • Author(s): 清谷一馬, 莚田泰誠, 笹三徳, 山川卓, 平田公一, 岡崎稔, 大住省三, 高塚雄一, 角田達彦, 細野直哉, 久保充明, 前佛均, 中村祐輔
  • Organizer: 日本人類遺伝学会第54回大会
  • Place of Presentation: 東京
  • Year and Date: 2009-09-24
• [Presentation] 乳がん患者におけるタモキシフェンの再発予防効果と薬物代謝酵素の遺伝子型 (2009)
  • Author(s): 清谷一馬, ら
  • Organizer: 日本人類遺伝学会 第54回年会
  • Place of Presentation: 東京
  • Year and Date: 2009-09-24
• [Presentation] Effects of polymorphisms in CYP2D6 and PK-related genes on clinical efficacy of adjuvant tamoxifen treatment in Japanese breast cancer patients (2009)
  • Author(s): 清谷一馬, et al
  • Organizer: Cold Spring Harbor Laboratory Pharmacogenomics meeting
  • Place of Presentation: London
  • Year and Date: 2009-09-13
• [Presentation] Effects of polymorphisms in CYP2D6 and PK-related genes on clinical efficacy of adjuvant tamoxifen treatment in Japanese breast cancer patients. (2009)
  • Author(s): Kazuma Kiyotani, Hitoshi Zembutsu, Taisei Mushiroda, Mitsunori Sasa, Takashi Yamakawa, Koichi Hirata, Minoru Okazaki, Shozo Ohsumi, Yuichi Takatsuka, Yoshimi Bando, Ikuko Sumitomo, Tatsuhiko Tsunoda, Naoya Hosono, Michiaki Kubo, Yusuke Nakamura
  • Organizer: Cold Spring Harbor Laboratory Pharmacogenomics meeting
  • Place of Presentation: London
• [Presentation] 乳がん患者におけるタモキシフェンの再発予防効果に及ぼすCYP2D6遺伝子型の影響 (2008)
  • Author(s): 清谷一馬, ら
  • Organizer: 日本臨床薬理学会 第29回年会
  • Place of Presentation: 新宿
  • Year and Date: 2008-12-05
• [Presentation] Effects of CYP2D6*10 on recurrence-free survival in breast cancer patients receiving adjuvant tamoxifen therapy (2008)
  • Author(s): Kiyotani K, et al
  • Organizer: 58^<th> Annual Meeting, the American society of Human Genetics
  • Place of Presentation: Philadelphia
  • Year and Date: 2008-11-12
• [Presentation] Clinical Outcome with Adjuvant Tamoxifen Relative to Patient CYP2D6 Genotypes (2008)
  • Author(s): 清谷一馬, ら
  • Organizer: 日本薬物動態学会 第23回年会
  • Place of Presentation: 熊本
  • Year and Date: 2008-10-31
• [Presentation] ドセタキセルの副作用に関連するSLCO1B3およびABCC2遺伝子多型 (2008)
  • Author(s): 清谷一馬, ら
  • Organizer: 日本人類遺伝学会 第53回年会
  • Place of Presentation: 横浜
  • Year and Date: 2008-09-29
• [Presentation] 乳がん患者におけるタモキシフェンの再発予防効果に及ぼすCYP2D6遺伝子型の影響. (2008)
  • Author(s): 清谷一馬, 前佛均, 莚田泰誠, 中村祐輔
  • Organizer: 第29回日本臨床薬理学会年会
  • Place of Presentation: 東京
• [Presentation] mPCR-RETINAおよびリアルタイムPCRを用いたCYP2D6ジェノタイピング方法の確立. (2008)
  • Author(s): 細野直哉, 久保充明, 加藤護, 角田達彦, 莚田泰誠, 清谷一馬, 佐藤寛子, 網谷花枝, 高田定暁, 前佛均, 中村祐輔
  • Organizer: 日本人類遺伝学会第53回大会
  • Place of Presentation: 横浜
• [Presentation] ドセタキセルの副作用に関連するSLCO1B3およびABCC2遺伝子多型. (2008)
  • Author(s): 清谷一馬, 莚田泰誠, 久保充明, 前佛均, 杉山雄一, 中村祐輔
  • Organizer: 日本人類遺伝学会第53回大会
  • Place of Presentation: 横浜
• [Presentation] Clinical outcome with Adjuvant tamoxifen relative to patient CYP2D6 genotypes. (2008)
  • Author(s): Kazuma Kiyotani, Hitoshi Zembutsu, Taisei Mushiroda, Mitsunori Sasa, Koichi Hirata, Minoru Okazaki, Yuichi Takatsuka, Yoshimi Bando, Ikuko Sumitomo, Naoya Hosono, Michiaki Kubo, Yusuke Nakamura
  • Organizer: 日本薬物動態学会第23回年会
  • Place of Presentation: 熊本
• [Presentation] Effects of CYP2D6*10 on recurrence-free survival in breast cancer patients receiving adjuvant tamoxifen therapy. (2008)
  • Author(s): Kazuma Kiyotani, Hitoshi Zembutsu, Taisei Mushiroda, Mitsunori Sasa, Koichi Hirata, Minoru Okazaki, Yuichi Takatsuka, Yoshimi Bando, Ikuko Sumitomo, Naoya Hosono, Michiaki Kubo, Yusuke Nakamura
  • Organizer: The American Society of Human Genetics 58th Annual Meeting (ASHG2008)
  • Place of Presentation: Philadelphia