薬物代謝と生理活性脂質の生成に関与するシトクロームＰ－４５０の薬理遺伝学的解析

2015 Fiscal Year Annual Research Report

• Project/Area Number: 14F04092
• Research Institution: Shimane University
• Principal Investigator: 横田 一成 島根大学, 生物資源科学部, 教授 (90158361)
• Co-Investigator(Kenkyū-buntansha): ISLAM MOHAMMAD 島根大学, 生物資源科学部, 外国人特別研究員
• Project Period (FY): 2014-04-25 – 2016-03-31
• Keywords: クロピドグレル / 抗血小板作用 / シトクロームP-450酵素 / 遺伝子の多型 / CYP2C19 / P2Y12受容体 / ABCB1

Outline of Annual Research Achievements

クロピドグレルは、急性の冠動脈疾患、心筋梗塞、脳卒中などの虚血性の疾患の予防のための主要な経口投与による抗血小板作用の治療薬として使用されている。しかし、クロピドグレルの抗血小板作用には、患者間での著しい違いがある。クロピドグレルの活性化体への代謝変換は、小腸や肝臓での複数のシトクロームP-450酵素による代謝反応により行われる。今回の研究では、クロピドグレルの作用に関係ある蛋白質分子を暗号化する遺伝子の多型とバングラデシュの患者に血液に由来する血小板の凝集抑制作用との関連性について研究を行った。CYP2C19*2のGG、AG、およびAAの遺伝子型の比率は、それぞれ、46.7%、42.7%、そして10.7%と計算された。また、3つのグループの中での血小板のP2Y12受容体の阻害活性では、有意な違いが見出された。すなわち、GG、AG、およびAAの遺伝子型でのP2Y12受容体の阻害活性は、57.4%、37.6%、17.3%となった。従って、AGとAAの遺伝子型の阻害活性は、GGの遺伝子型よりも著しく低下しており、特に、AAの遺伝子型を持つ患者では、最も低い抗血小板作用であることがわかった。GとAの対立遺伝子を持つ患者の比率は、68%と32％であった。同様に、CYP2C19*3の遺伝子型の解析をした結果、GG、AG,AAの遺伝子型のうち、主要なものはGG型であり、AG型は5.3%であった。AG型の抗血小板作用は、GG型のものよりも低下していた。他に、ABCB1や P2Y12の遺伝子型の解析を行い、有用な知見を得た。
その他の関連研究として、乳癌におけるP-450関連酵素や他の関連細胞内因子の遺伝子多型の解析研究も行った。脂肪細胞の分化誘導や成熟化を制御するアラキドン酸代謝産物の作用にも関与した。また、さらに、心臓病における微量元素の研究論文の作成も行った。

Research Progress Status

27年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

27年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] Dhaka University(Bangladesh)
  • Country Name: Bangladesh
  • Counterpart Institution: Dhaka University
• [Journal Article] Breast cancer risk in relation to TP53 codon 72 and CDH1 gene polymorphisms in the Bangladeshi women. (2016)
  • Author(s): Shabnaz, S., Ahmed, M. U., Islam, M. S., Islam, M. R., Al-Mamun, M. M., Islam, M. S., Hasnat, A.
  • Journal Title: Tumour Biol. Volume: - Pages: in press
  • DOI: 10.1007/s13277-015-4612-7
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Pretreatment of cultured preadipocytes with arachidonic acid during the differentiation phase without a cAMP-elevating agent enhances fat storage after the maturation phase (2016)
  • Author(s): Khan, F., Seyda, P. K., Nartey, M. N. N., Rahman, M. S., Islam, M. S., Nishimura, K., Jisaka, M., Shono, F., and Yokota, K.
  • Journal Title: Prostaglandins Other Lipid Mediat. Volume: 123 Pages: 16-27
  • DOI: 10.1016/j.prostaglandins.2016.02.003.
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Low serum selenium concentration is associated with preeclampsia in pregnant women from Bangladesh (2016)
  • Author(s): Haque, M. M., Moghal, M. M., Sarwar, M. S., Anonna, S. N., Akter, M., Karmakar, P., Ahmed, S., Sattar, M. A., Islam, M. S.
  • Journal Title: J. Trace Elem. Med. Biol. Volume: 33 Pages: 21-25
  • DOI: doi:10.1016/j.jtemb.2015.08.002
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Stimulation of fat storage by prostacyclin and selective agonists of prostanoid IP receptor during the maturation phase of cultured adipocytes (2016)
  • Author(s): Khan, F., Syeda, P. K., Nartey, M. N. N., Rahman, M. S., Islam, M. S., Nishimura, K., Jisaka, M., Shono, F., and Yokota, K.
  • Journal Title: Cytotechnology Volume: - Pages: in press
  • DOI: 10.1007/s10616-016-9960-7
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Effect of GSTP1 and ABCC4 gene polymorphisms on response and toxicity of cyclophosphamide-epirubicin-5-fluorouracil-based chemotherapy in Bangladeshi breast cancer patients (2016)
  • Author(s): Islam, M. S., Islam, M. S., Parvin, S., Ahmed, M. U., Bin Sayeed, M. S., Uddin, M. M., Hussain, S. M., Hasnat, A.
  • Journal Title: Tumour Biol. Volume: 36 Pages: 5451-5457
  • DOI: 10.1007/s13277-015-3211-y
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Prostate cancer risk in relation to CYP3A4 and CYP3A5 genotypes in the Bangladeshi population (2015)
  • Author(s): Bellah, S. F., Ahmed, M. U., Rabbi, S. N. I., Uddin, M. M. N., Islam, M. S., Hasnat, A.
  • Journal Title: Dhaka Univ. J. Pharmaceut. Sci. Volume: 14 Pages: 179-185
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Effect of lipid peroxidation, antioxidants, macro minerals and trace elements on eczema (2015)
  • Author(s): Amin, M. N., Liza, K. F., Sarwar, M. S., Ahmed, J., Adnan, M. T., Chowdhury, M. I., Hossain, M. Z., Islam, M. S.
  • Journal Title: Arch. Dermatol. Res. Volume: 3017 Pages: 617-623
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Prevalence of CYP2C19 alleles, pharmacokinetic and pharmacodynamic variation of clopidogrel and prasugrel in Bangladeshi population (2015)
  • Author(s): Bin Sayeed, M. S., Hasan Apu, M. N., Munir, M. T., Ahmed, M. U., Islam, M. S., Haq, M. M., Ahsan, C. H., Rashid, M. A., Shin, J. G., Hasnat A.
  • Journal Title: Clin. Exp. Pharmacol. Physiol. Volume: 42 Pages: 451-457
  • DOI: 10.1111/1440-1681.12390
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Effect of DPYD and MTHFR gene polymorphisms on the response and toxicity of 5-fluorouracil based chemotherapy in the colorectal cancer patients (2015)
  • Author(s): Islam, M. S., Nahid, N. A., Ahmed, M. U., Islam, M. S., and Yokota, K
  • Organizer: The 53rd Annual Meeting of the Japan Society of Clinical Oncology
  • Place of Presentation: Kyoto (Kyoto International Congress Center)
  • Year and Date: 2015-10-29
• [Presentation] Effect of serum trace elements and macrominerals on myocardial infarction. (2015)
  • Author(s): Islam, M. S., Rahaman, M. Z., Uddin, S. M. N., Tammi, T. J., Sarwar, S., and Yokota, K.
  • Organizer: The 19th Japanese Heart Failure Society
  • Place of Presentation: Osaka (Convention Center, Grand Front Osaka)
  • Year and Date: 2015-10-24
• [Presentation] Breast cancer risk in relation to BRCA1, BRCA2, RAD51 and HER2 gene polymorphisms in the Bangladeshi population (2015)
  • Author(s): Islam, M. S., Parvin S., Islam, M. S., Ahmed, M. U., Yokota, K., Hasnat, A. H.
  • Organizer: The 74th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Nagoya (Nagoya Congress Center)
  • Year and Date: 2015-10-10
• [Presentation] Effect of P2RY12 and CYP2C9 gene polymorphisms on the anti-platelet response of clopidogrel in the Bangladeshi percutaneous coronary intervention patients (2015)
  • Author(s): Islam, M. S., Rahman, M. S., Nartey, M. N. N., and Yokota, K.
  • Organizer: 43th Annual Meeting of Chu-Shikoku Division in the Japan Society for Bioscience, Biotechnology, and Agrochemistry
  • Place of Presentation: Matsuyama (Faculty of Agriculture, Ehime University)
  • Year and Date: 2015-09-18
• [Presentation] Effect of PON1, ABCB1C1236T and ABCB1C3435T polymorphisms on the anti-platelet response of clopidogrel in the Bangladeshi percutaneous coronary intervention patients (2015)
  • Author(s): Islam, M. S., Islam, M. S., Apu, M. N. H., Nartey, M. N., Hasnat, A., Yokota, K.
  • Organizer: 42th Annual Meeting of Chu-Shikoku Division in the Japan Society for Bioscience, Biotechnology, and Agrochemistry
  • Place of Presentation: Totter (Faculty of Agriculture, Tottori University)
  • Year and Date: 2015-06-13
• [Presentation] Effect of VKORC1 and CYP2C9 genetic variations on warfarin dose requirement in Bangladeshi population (2015)
  • Author(s): Islam, M. S., Chowdhury, Z. S., Shahjin, F., Khan, F., Fatema, P. K. S. K., Hasnat, A., and Yokota, K.
  • Organizer: 56th Annual Meeting of Chugoku-Shikoku Division in the Japanese Biochemical Society
  • Place of Presentation: Matsue (Faculty of Life and Environmental Science, Shimane University)
  • Year and Date: 2015-05-30