Molecular mechanisms of transcriptional regulation of the intestinal and renal drug transporters in the normal and disease states.

我们展示了肾有机阴离子转运蛋白1 （OAT1）等三种药物转运蛋白的基本转录机制。研究发现，在胆汁淤积时，肾脏OAT3上调，并负责肾脏胆汁酸的分泌。我们在启动子区域发现了一个影响H^+/有机阳离子反转运蛋白（MATE1）启动子活性的SNP。Mate1敲除小鼠是新开发的，我们明确了Mate1在体内的药代动力学作用。临床药代动力学研究表明，杂合的MATE变异不影响二甲双胍在糖尿病患者中的配置。这些信息应该有助于考虑病理生理作用和应用药物转运体的个性化药物治疗

We demonstrated the basal transcriptional mechanisms of three kinds of drug transporters such as renal organic anion transporter 1 (OAT1). It was found that renal OAT3 is up-regulated during cholestasis, and is responsible for renal secretion of bile acids. We identified a SNP in the promoter region that affecting the promoter activity of H^+/organic cation antiporter (MATE1). Mate1 knockout mice were newly developed, and we clarified the pharmacokinetic roles of MATE1 in vivo. Heterozygous MATE variants could not influence the disposition of metformin in diabetic patients by the clinical pharmacokinetic study. These information should be useful to consider the pathophysiological roles and to apply the personalized pharmacotherapy of drug transporters