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Malfunction of liver and intestine ion channels in mutant rats

突变大鼠肝脏和肠道离子通道功能障碍

基本信息

批准号：
05044155
负责人：
TAKEGUCHI Noriaki
金额：
$ 0.96万
依托单位：
Toyama Medical and Pharmaceutical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for international Scientific Research
财政年份：
1993
资助国家：
日本
起止时间：
1993 至无数据
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-05044155/
关键词：
Ion channel Multi-drug efflux pump Diarrhea Intestine Liver

项目摘要

Two different types of studies were undertaken by this joint program. For this study, Dr.Takeguchi and Dr.Sakai separately visited the University of Zurich, Institute of Veterinary Physiology, Zurich, Switzerland, and did experimental works. Dr.Diener at University Zurich visited Toyama Medical and Pharmaceutical University, Faculty of Pharmaceutical Sciences, Toyama, Japan, and did experimental works.1) We used a new rat mutant with chronic conjugated hyperbilirubinemia. Previously, it was reported that the secretary mechanism of organic anion was absent in hepatocytes of the rats by others. We found the function of multi-drug efflux pump in the hepatocytes was also impaired, although its gene-product is correctly expressed. The secretery rate of bile also decreased. The function of the cell volume regulatory mechanism upon hypotonic stress worked, however, its rate was decreased compared with normal rats. These results have shown that the mulfuctions are due to both genetic defect and deterioration of intracellular environments.2) A new antitumor drug CPT-11 was recently developed in Japan. Its phase II study has shown that this drug is very active against virtually all tumor types including non-small cell lung cancer, to which no active antitumor drug was known previously. This drug's dose-limiting is due to diarrhea and leukopenia. To solve the mechanism of this diarrhea is to increase the dose, which results in increased efficacy. In this joint study, we found that this cholera-like diarrhea was due to the production of thromboxanes by CPT-11 and its metabolite SN-38. The mechanism of diarrhea induced by thromboxane is new and not previously reported in animal models.

该联合方案进行了两种不同类型的研究。为了这项研究，Takeguchi博士和Sakai博士分别访问了瑞士苏黎世的苏黎世大学兽医生理学研究所，并进行了实验工作。苏黎世大学的Diener博士访问了日本富山的富山医科和药科大学药学部，并进行了实验工作。1）我们使用了一种新的患有慢性结合型高胆红素血症的大鼠突变体。以前，有人报道大鼠肝细胞中不存在有机阴离子的分泌机制。我们发现肝细胞中多药外排泵的功能也受损，尽管其基因产物正确表达。胆汁分泌率也下降。细胞体积调节机制在低渗应激时起作用，但其速率较正常大鼠降低。这些结果表明，这些缺陷是由于遗传缺陷和细胞内环境恶化。2）一种新的抗肿瘤药物CPT-11最近在日本开发。其II期研究表明，这种药物对几乎所有类型的肿瘤都非常有效，包括非小细胞肺癌，以前没有活性抗肿瘤药物。这种药物的剂量限制是由于腹泻和白细胞减少。解决这种腹泻的机制就是增加剂量，从而提高疗效。在这项联合研究中，我们发现这种霍乱样腹泻是由于CPT-11及其代谢产物SN-38产生血栓烷所致。血栓素引起腹泻的机制是新的，以前没有在动物模型中报道。