Development of reversing agent for multidrug resistance and new chemotherapy by utilizing genistein

利用金雀异黄素开发多药耐药逆转剂及新型化疗药物

• 批准号: 18590162
• 负责人: MURAKAMI Teruo
• 金额: $ 2.42万
• 依托单位: Hiroshima International University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590162/
• 关键词: ABC transporter; reversing agent for multidrug resistance; flavone; isoflavone; P-glycoprotein; MRP2; pharmacokinetics; natural products; 薬物動態解析; DDS; リボソーム; 多剤耐性; MRP; BCRP; リポソーム

In the present study, we examined the usefulness of natural products origin, genistein, as a reversing agent of multidrug resistance. Genistein itself is known to have an anticancer activity for breast cancer. Also, various soy products such as miso, tofu and so on contain genistein. Multidrug resistance of various cancer cells is known to be due to the induction of ABC efflux transporters that expel the substrate drugs such as anticancer agents out of cells. ABC efflux transporters involve P-glycoprotein, MRPs and BCRP. In the present study, genistein was found to have suppressing potency for P-gp function, though it has been recognized to suppress MRPs. When genistein was administered orally, the blood level of genistein was low, because of the first-pass metabolism. Thus, the reversing activity of genistein for P-gp in vivo was insufficient. We modified genistein chemically by methylation, but the water solubility became low. In studies with other natural products, some potent reversing agents for P-gp were found. By using them, further study is necessary to find potent but safer reversing agents.

在本研究中，我们研究了天然产物金雀异黄酮作为多药耐药性逆转剂的有用性。已知金雀异黄素本身对乳腺癌具有抗癌活性。另外，各种豆制品如味噌、豆腐等都含有染料木黄酮。已知各种癌细胞的多药耐药性是由于 ABC 外排转运蛋白的诱导，该转运蛋白将底物药物（例如抗癌药物）排出细胞外。 ABC 外排转运蛋白涉及 P-糖蛋白、MRP 和 BCRP。在本研究中，金雀异黄酮被发现对 P-gp 功能具有抑制作用，尽管它已被认为可以抑制 MRP。当口服金雀异黄酮时，由于首过代谢，金雀异黄酮的血液水平较低。因此，金雀异黄素在体内对P-gp的逆转活性不足。我们通过甲基化对金雀异黄素进行化学修饰，但水溶性变低。在对其他天然产物的研究中，发现了一些有效的 P-gp 逆转剂。通过使用它们，需要进一步研究以找到有效但更安全的逆转剂。

项目成果

Effects of Kaempferia parviflora extracts and their flavone constituents on P-glycoprotein function.

• DOI: 10.1002/jps.20769
• 发表时间: 2007
• 期刊: Journal of pharmaceutical sciences
• 影响因子: 3.8
• 作者: Denpong Patanasethanont;J. Nagai;R. Yumoto;T. Murakami;Khaetthareeya Sutthanut;B. Sripanidkulchai;C. Yenjai;M. Takano

Transporter-mediated intestinal absorption and secretion of immunosuppressants

转运蛋白介导的免疫抑制剂的肠道吸收和分泌

• 发表时间: 2008
• 作者: Yokooji;T.;et. al.;Takano M;Junyaprasert VB;Maeda Y;Yokooji T;Nagai J;村上 照夫;Murakami T
• 通讯作者: Murakami T

Characterization of intestinal absorption of mizoribine mediated by concentrative nucleoside transporters in rats

• DOI: 10.1016/j.ejphar.2008.02.043
• 发表时间: 2008-05-31
• 期刊: EUROPEAN JOURNAL OF PHARMACOLOGY
• 影响因子: 5
• 作者: Mori, Nobuhiro;Yokooji, Tomohara;Murakami, Teruo
• 通讯作者: Murakami, Teruo

Role of intestinal efilux transporters in the intestinal absorption of methotrexate in rats

肠道流出转运蛋白在大鼠甲氨蝶呤肠道吸收中的作用

• 发表时间: 2007
• 期刊: J Pharm Pharmacol 59
• 作者: Yokooji;T.;et. al.
• 通讯作者: et. al.

免疫抑制剤のトランスポーター介在性消化管吸収・分泌挙動

转运蛋白介导的免疫抑制剂胃肠道吸收和分泌行为

• 发表时间: 2008
• 作者: Yokooji;T.;et. al.;Takano M;Junyaprasert VB;Maeda Y;Yokooji T;Nagai J;村上 照夫
• 通讯作者: 村上 照夫