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来源，染料木素，作为逆转剂的多药耐药的有用性。已知染料木黄酮本身对乳腺癌具有抗癌活性。此外，各种豆制品，如味噌，豆腐等含有染料木素。已知多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如抗癌剂排出细胞。ABC外排转运蛋白涉及P-糖蛋白、MRP和BCRP。在本研究中，发现染料木黄酮对P-gp功能具有抑制效力，尽管它已被公认为抑制MRP。当染料木黄酮口服给药时，由于首过代谢，染料木黄酮的血液水平较低。因此，染料木黄酮在体内对P-gp的逆转活性不足。我们通过甲基化对染料木黄酮进行化学修饰，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，利用这些逆转剂，需要进一步研究，以找到有效而安全的逆转剂。

项目成果

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

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

Detoxication treatment for carbamazepine and lithium overdose

卡马西平和锂过量的解毒治疗

• 发表时间: 2008
• 期刊: Yakugaku Zasshi 128
• 作者: Unei;H.;et. al.
• 通讯作者: et. al.

Effects of Kaempferia parvifiora extracts and their flavone constituents on P-lcorotein function

小花山奈提取物及其黄酮成分对 P-lcorotein 功能的影响

• 发表时间: 2007
• 期刊: J Pharm Sci 96
• 作者: Patanasethanont;D.;et. al.
• 通讯作者: et. al.

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.