Malfunction of liver and intestine ion channels in mutant rats

这个联合项目进行了两种不同类型的研究。在这项研究中，武口博士和酒井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医科大学药学院，并进行了实验工作。1)我们使用了一种患有慢性结合性高胆红素血症的新突变大鼠。此前有报道称，有机阴离子的分泌机制在大鼠肝细胞中缺失。我们发现，尽管其基因产物得到正确表达，但肝细胞中多药外排泵的功能也受到了损害。胆汁分泌率也有所下降。细胞体积调节机制对低渗应激起作用，但其发生率较正常大鼠有所降低。这些结果表明，这种多功能是由于遗传缺陷和细胞内环境的恶化所致。2)日本最近开发了一种新的抗肿瘤药物CPT-11。它的第二阶段研究表明，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，以前对这些肿瘤还没有有效的抗肿瘤药物。这种药物的剂量限制是由于腹泻和白细胞减少所致。解决这种腹泻的机制是增加剂量，从而增加疗效。在这项联合研究中，我们发现这种霍乱样腹泻是由于CPT-11及其代谢物SN-38产生血栓烷所致。血栓烷引起腹泻的机制是新的，在动物模型中未见报道。

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.