Analysis of epigenetic regulation of drug-metabolizing enzymes catalyzing anticancer drugs

• Project/Area Number: 20790142
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Medical pharmacy
• Research Institution: Tohoku Pharmaceutical University
• Principal Investigator: SASAKI Takamitsu Tohoku Pharmaceutical University, 薬学部, 助手 (20382674)
• Project Period (FY): 2007 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2010: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2009: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2008: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: TPMT / エピジェネティクス / DHPLC / 抗癌剤代謝酵素 / 遺伝子多型 / 個人差 / マイクロRNA / iPS細胞 / DPD

Research Abstract

The purpose of this study was to investigate the regulatory mechanisms of TPMT gene expression and provide an information for future clinical studies regarding individual variations in drug efficacy and safety. We examined the relationship between TPMT activity and methylation of TPMT promoter or expression levels of microRNA. These results showed that TPMT activity was not significant effect on the regulatory mechanisms of methylation and microRNA. This study showed that individual variation of TPMT activity in human livers was associated with the present of genetic polymorphisms.

Research Products

• [Journal Article] Progression Alcoholic and Non-alcoholic Steatohepatitis : Common Metabolic Aspects of Innate Immune System and Oxidative Stress. (2011)
  • Author(s): S Sakaguchi, S Takahashi, T Sasaki, T Kumagai, K Nagata
  • Journal Title: Drug Metab.Pharmacokinet. 26 Pages: 30-46
  • NAID: 130004463160
  • Peer Reviewed
• [Journal Article] Progression Alcoholic and Non-alcoholic Steatohepatitis : Common Metabolic Aspects of Innate Immune System and Oxidative Stress. (2011)
  • Author(s): Shuhei Sakaguchi
  • Journal Title: Drug Metabolism and Pharmacokinetics Volume: 26 Pages: 30-46
  • Peer Reviewed
• [Journal Article] Functional characterization of genetic polymorphisms identified in the promoter region of the xanthine oxidase gene. (2010)
  • Author(s): M Kudo, T Sasaki, M Ishikawa, N Hirasawa, M Hiratsuka
  • Journal Title: Drug Metab.Pharmacokinet. 25 Pages: 599-604
  • NAID: 10027743970
  • Peer Reviewed
• [Journal Article] Kinetics of 6-thioxanthine metabolism by allelic variants of xanthine oxidase. (2010)
  • Author(s): M Kudo, T Sasaki, M Ishikawa, N Hirasawa, M Hiratsuka
  • Journal Title: Drug Metab.Pharmacokinet. 25 Pages: 361-366
  • NAID: 10027583274
  • Peer Reviewed
• [Journal Article] Functional characterization of 26 CYP2B6 allelic variants (CYP2B6.2-CYP2B6.28 expect CYP2B6.22). (2010)
  • Author(s): T Watanabe, K Sakuyama, T Sasaki, Y Ishii, M Ishikawa, N Hirasawa, M Hiratsuka
  • Journal Title: Pharmacogenet.Genomics. 20 Pages: 459-462
  • Peer Reviewed
• [Journal Article] Construction of a system that simultaneously evaluates CYP1A1 and CYP1A2 induction in a stable human-derived cell line using a dual reporter plasmid. (2010)
  • Author(s): W Sato, H Suzuki, T Sasaki, T Kumagai, S Sakaguchi, M Mizugaki, S Miyairi, Y Yamazoe, K Nagata
  • Journal Title: Drug Metab.Pharmacokinet. 25 Pages: 180-189
  • NAID: 10027582549
  • Peer Reviewed
• [Journal Article] Malondialdehyde-modified low density lipoprotein (MDA-LDL)-induced cell growth was suppressed by polycyclic aromatic hydrocarbons (PAHs). (2010)
  • Author(s): H Suzuki, T Sasaki, T Kumagai, S Sakaguchi, K Nagata
  • Journal Title: J.Toxicol.Sci. 35 Pages: 137-147
  • NAID: 10026193130
  • Peer Reviewed
• [Journal Article] Genetic Variations in the HGPRT, ITPA, IMPDH1, IMPDH2, and GMPS genes in Japanese Individuals. (2010)
  • Author(s): M Kudo, Y Saito, T Sasaki, H Akasaki, Y Yamaguchi, M Uehara, K Fujikawa, M Ishikawa, N Hirasawa, M Hiratsuka
  • Journal Title: Drug Metab.Pharmacokinet. 24 Pages: 557-564
  • NAID: 10027119756
  • Peer Reviewed
• [Journal Article] Functional characterization of genetic polymorphisms identified in the promoter region of the xanthine oxidase gene. (2010)
  • Author(s): Mutsumi Kudo
  • Journal Title: Drug Metabolism and Pharmacokinetics Volume: 25 Pages: 599-604
  • Peer Reviewed
• [Journal Article] Kinetics of 6-thioxanthine metabolism by allelic variants of xanthine oxidase. (2010)
  • Author(s): Mutsum Kudo
  • Journal Title: Drug Metabolism and Pharmacokinetics Volume: 25 Pages: 361-366
  • Peer Reviewed
• [Journal Article] Functional characterization of 26 CYP2B6 allelic variants (CYP2B6.2-CYP2B6.28 expect CYP2B6.22). (2010)
  • Author(s): Takashi Watanabe
  • Journal Title: Pharmacogenetics and Genomics Volume: 20 Pages: 459-462
  • Peer Reviewed
• [Journal Article] Construction of a system that simultaneously evaluates CYP1A1 and CYP1A2 induction in a stable human-derived cell line using a dual reporter plasmid. (2010)
  • Author(s): Wataru Sato
  • Journal Title: Drug Metabolism and Pharmacokinetics Volume: 25 Pages: 180-189
  • Peer Reviewed
• [Journal Article] Malondialdehyde-modified low density lipoprotein (MDA-LDL)-induced cell growth was suppressed by polycyclic aromatic hydrocarbons (PAHs). (2010)
  • Author(s): Hiroyuki Suzuki
  • Journal Title: Journal of Tocicology Science Volume: 37 Pages: 137-147
  • Peer Reviewed
• [Journal Article] Genetic Variations in the HGPRT, ITPA, IMPDH1, IMPDH2, and GMPS genes in Japanese Individuals (2009)
  • Author(s): Mutsumi Kudo
  • Journal Title: Drug Metabolism and Pharmacokinetics 24 Pages: 557-564
  • Peer Reviewed
• [Journal Article] Functional characterization of 17 CYP2D6 allelic variants (CYP2D6.2, 10, 14A-B, 18, 27, 36, 39, 47-51, 53-55, and 57). (2008)
  • Author(s): K Sakuyama, T Sasaki, S Ujiie, K Obata, M Mizugaki, M Ishikawa, M Hiratsuka
  • Journal Title: Drug Metab.Dispos. 36 Pages: 2460-2467
  • Peer Reviewed
• [Journal Article] Functional characterization of 23 allelic variants of thiopurine S-methyltransferase gene (TPMT*2-*24). (2008)
  • Author(s): S Ujiie, T Sasaki, M Mizugaki, M Ishikawa, M Hiratsuka
  • Journal Title: Pharmacogenet.Genomics 18 Pages: 887-893
  • NAID: 130005024445
  • Peer Reviewed
• [Journal Article] Possible relation between the risk of Japanese bladder cancer cases and CYP4B1 genotype (2008)
  • Author(s): T Sasaki, M Horikawa, K Orikasa, M Sato, Y Arai, Y Mitachi, M Mizugaki, M Ishikawa, M Hiratsuka
  • Journal Title: Jpn.J.Clin.Oncol. 38 Pages: 634-640
  • Peer Reviewed
• [Journal Article] Functional characterization of 17 CYP2D6 allelic variants (C YP2D6. 2, 10, 14A-B, 18, 27, 36, 39, 47-51, 53-55, and 57) (2008)
  • Author(s): Kanako Sakuyama
  • Journal Title: Drug Metabolism and Disposition 36 Pages: 2460-2467
  • Peer Reviewed
• [Journal Article] Possible relation between the risk of Japanese bladder cancer cases and CYP4B1 genotype (2008)
  • Author(s): Takamitsu Sasaki
  • Journal Title: Japanese Journal of Clinical Oncology 38 Pages: 634-640
  • Peer Reviewed
• [Journal Article] Functional characterization of 23 allelic variants of thiopu rine S-methvltransferase gene (TPMT*2-*24) (2008)
  • Author(s): Shuta Uiiie
  • Journal Title: Pharmacogenetics and Genomics 18 Pages: 887-893
  • Peer Reviewed
• [Presentation] CYP3A4転写活性に影響を与えるFBS中成分の同定 (2010)
  • Author(s): 福士素子
  • Organizer: 第49回日本薬学会東北支部大会
  • Place of Presentation: 福島
  • Year and Date: 2010-10-24
• [Presentation] MRP3における新規転写誘導機構の解明 (2010)
  • Author(s): 沼田喜弘
  • Organizer: 第49回日本薬学会東北支部大会
  • Place of Presentation: 福島
  • Year and Date: 2010-10-24
• [Presentation] 薬物代謝酵素遺伝子多型と肺がんリスクとの関連 (2010)
  • Author(s): 田巻祐一郎
  • Organizer: 第49回日本薬学会東北支部大会
  • Place of Presentation: 福島
  • Year and Date: 2010-10-24
• [Presentation] タモキシフェン代謝におけるCYP2D6バリアント酵素の機能解析 (2009)
  • Author(s): 作山佳奈子
  • Organizer: 第30回日本臨床薬理学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2009-12-03
• [Presentation] キサンチンオキシダーゼ活性の個人差に影響を及ぼす遺伝子多型 (2009)
  • Author(s): 工藤睦
  • Organizer: 第30回日本臨床薬理学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2009-12-03
• [Presentation] タモキシフェンの薬効発現に影響を及ぼすCYP2D6バリアント酵素のinvitro (2009)
  • Author(s): 作山佳奈子
  • Organizer: 第48回日本薬学会東北支部大会
  • Place of Presentation: 仙台
  • Year and Date: 2009-10-18
• [Presentation] キサンチンオキシダーゼ活性の個人差に影響を及ぼす遺伝子多型 (2009)
  • Author(s): 工藤睦
  • Organizer: 第48回日本薬学会東北支部大会
  • Place of Presentation: 仙台
  • Year and Date: 2009-10-18
• [Presentation] CYP1A1, CYP1A2誘導スクリーニングのためのin vitro同時評価系の構築 (2009)
  • Author(s): 佐藤渉
  • Organizer: 第48回日本薬学会東北支部大会
  • Place of Presentation: 仙台
  • Year and Date: 2009-10-18
• [Presentation] アデノウイルスベクターを用いた薬物代謝・毒性評価系の確立 (2009)
  • Author(s): 高橋昌悟
  • Organizer: 第48回日本薬学会東北支部大会
  • Place of Presentation: 仙台
  • Year and Date: 2009-10-18
• [Presentation] 多環芳香族炭化水素類によるCYP3A4転写活性化分子機構の解析 (2009)
  • Author(s): 庄司理恵
  • Organizer: 第48回日本薬学会東北支部大会
  • Place of Presentation: 仙台
  • Year and Date: 2009-10-18
• [Presentation] タモキシフェンの薬効発現に影響を及ぼすCYP2D6バリアント酵素のin vitro解析 (2009)
  • Author(s): 作山佳奈子
  • Organizer: 第48回日本薬学会東北支部大会
  • Place of Presentation: 仙台
  • Year and Date: 2009-10-18
• [Presentation] チオプリンS-メチルトランスフェラーゼ(TPMT)遺伝子多型によるバリアント酵素の機能解析 (2009)
  • Author(s): 佐々木崇光
  • Organizer: 第4回東北薬科大学ハイテク・リサーチ・シンポジウム
  • Place of Presentation: 仙台
  • Year and Date: 2009-05-29
• [Presentation] チオプリンS-メチルトランスフェラーゼ(TPMT)における発現調節因子の解析 (2009)
  • Author(s): 佐々木崇光
  • Organizer: 第4回東北薬科大学ハイテク・リサーチ・シンポジウム
  • Place of Presentation: 仙台
  • Year and Date: 2009-05-29
• [Presentation] Xanthine oxidase遺伝子プロモーター領域の遺伝子多型解析 (2009)
  • Author(s): 工藤睦
  • Organizer: 第129回日本薬学会
  • Place of Presentation: 京都
  • Year and Date: 2009-03-28
• [Presentation] 塩酸セレギリンを用いたCYP2B6バリアントの酵素速度論的解析 (2009)
  • Author(s): 渡邊卓嗣
  • Organizer: 第129回日本薬学会
  • Place of Presentation: 京都
  • Year and Date: 2009-03-28
• [Presentation] 6-mercaptopurine代謝に関与する酵素群の遺伝子多型解析 (2009)
  • Author(s): 齋藤友香
  • Organizer: 第129回日本薬学会
  • Place of Presentation: 京都
  • Year and Date: 2009-03-28
• [Presentation] 塩酸セレギリンを用いたCYP286バリアントの酵素速度論的解析 (2009)
  • Author(s): 渡邊卓嗣
  • Organizer: 第129回日本薬学会
  • Place of Presentation: 京都
  • Year and Date: 2009-03-28
• [Presentation] 日本人におけるCYP2D6バリアント酵素の機能解析 (2008)
  • Author(s): 作山佳奈子
  • Organizer: 第29回日本臨床薬理学会
  • Place of Presentation: 東京
  • Year and Date: 2008-12-04
• [Presentation] FUNCTIONAL CHARACTERIZATION OF HUMAN CYTOCHROME P450 2B6 ALLELIC VARIANTS (2008)
  • Author(s): 渡邊卓嗣
  • Organizer: 第23回日本薬物動態学会
  • Place of Presentation: 熊本
  • Year and Date: 2008-10-31
• [Presentation] Functional characterization of 23 allelic variants of thiopurine Smethyltransferase gene (TPMT*2-*24) (2008)
  • Author(s): 氏家秀太
  • Organizer: 第23回日本薬物動態学会
  • Place of Presentation: 熊本
  • Year and Date: 2008-10-31
• [Presentation] Functional characterization of 23 allelic variants of thiopu rine S-methyltransferase gene (TPMT*2-*24) (2008)
  • Author(s): 氏家秀太
  • Organizer: 第23回日本薬物動態学会
  • Place of Presentation: 熊本
  • Year and Date: 2008-10-31
• [Book] 創薬研究のストラテジー上 (2011)
  • Author(s): 佐々木崇光、永田清
  • Publisher: 金芳堂
• [Book] 創薬研究のストラテジー上 (2011)
  • Author(s): 佐々木崇光
  • Publisher: 金芳堂