Drug Toxicity Induced by Alteration of Transporter Activity

药物毒性是药物开发中的一个重要问题，因为药物或候选药物引起的毒性会导致药物退出市场或终止药物开发，即使化合物表现出良好的药理作用，为了评估药物或候选药物可能的毒性，有必要积累更多关于药物毒性发生机制的信息。转运蛋白是影响药物在细胞内浓度和药代动力学特征的重要因素，是药物作用的可能机制之一。在这里，我们研究了药物的转运机制，集中在几个组织，包括肠，肝，肾，脑，睾丸，肿瘤和血细胞。结果，我们成功地鉴定出SLCO 2B 1（OATP-B）是以功能性pH依赖性方式参与阴离子药物肠道吸收的转运蛋白。此外，我们研究了H1-拮抗剂的脑渗透性，药物穿过血脑屏障的渗透性受到转运蛋白如P-糖蛋白和分子未知阳离子转运蛋白的严格调节。在肾脏的情况下，研究了顶部和基底外侧表达的转运蛋白，如OCT和OCTN，并提出了其药理学相关性。接下来，我们评估了转运蛋白基因的遗传多态性对转运活性的影响。SLCO 1B 1（OATP-C）是一种对药物肝脏摄取很重要的肝脏转运蛋白，对于毒理学上重要的药物（如曲格列酮、伊立替康等），遗传变异体OATP-C^*15表现出比野生型更低的转运活性。此外，我们还以核受体FXR为研究对象，探讨了肝转运蛋白基因表达的调控机制。这些研究表明，影响转运蛋白表观活性的因素很多，临床上还需进一步研究。

Drug toxicity is a significant problem in developing drugs, because the toxicity induced by drugs or drug candidates will lead to the removal from the market or termination of drug development, even though the compound exhibits excellent pharmacological effect.To evaluate possible toxicity of drugs or drug candidates, it will be essential to accumulate more information on the mechanisms of occurrence of drug-induced toxicity. As one of possible mechanisms, transporter proteins should be involved, because transporters significantly affect the cellular concentration and the pharmacokinetic profiling of drugs. Here, we studied the transport mechanisms of drugs by focusing on several tissues, including intestine, liver, kidney, brain, testis, tumor, and blood cells. As the results, we succeeded to identify SLCO2B1(OATP-B) as the transporter involved in intestinal absorption of anionic drugs, in functionally pH dependent manners. Furthermore, we studied the brain penetration of H1-antagonists and the permeability of the drug across the blood-brain barrier was strictly regulated by transporters like P-glycoprotein and molecularly-unknown cation transporters. In the case of kidney, apically and basolaterally expressed transporters like OCTs and OCTNs were studied and their pharmacological relevance was suggested. Next, we evaluated the effect of genetic polymorphisms of transporter genes on the transport activity. SLCO1B1(OATP-C) is a hepatic transporter important for hepatic uptake of drugs and the genetic variants OATP-C^*15 exhibited lowered transport activity than wild one for toxicologically important drugs like troglitazone, irinotecan and others. Furthermore, we studied the regulation mechanism of the gene expression of hepatic transporters by focusing on nuclear receptor FXR. These studies clarified that there are many factors that affect apparent activity of transporter and we need to study further the clinical.