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，即使化合物具有良好的药理作用。为了评估药物或候选药物可能的毒性，积累更多关于药物毒性发生机制的信息是至关重要的。作为可能的机制之一，转运蛋白应该参与其中，因为转运蛋白对药物的细胞浓度和药动学特征有重要影响。在这里，我们通过集中在几个组织，包括肠，肝，肾，脑，睾丸，肿瘤和血细胞来研究药物的转运机制。结果，我们成功地鉴定了SLCO2B1(OATP-B)是参与阴离子药物肠道吸收的转运蛋白，其作用依赖于pH。此外，我们还研究了H1-拮抗剂的脑渗透性，药物通过血脑屏障的通透性受到P-糖蛋白和分子未知阳离子转运体等转运体的严格调控。以肾脏为例，研究了OCTs和OCTns等顶端和基底表达的转运体，并提出了它们的药理学相关性。接下来，我们评估了转运蛋白基因的遗传多态性对转运蛋白活性的影响。SLCO1B1(OATP-C)是肝脏对药物摄取的重要转运体，其对曲格列酮、伊立替康等毒理学重要药物的转运活性低于野生型。此外，我们还重点研究了核受体FXR对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，临床尚需进一步研究。

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.