Regulation of Hepatic Uptake of Drugs and Xenobiotics

描述（由申请人提供）：细胞摄取是内源性化合物和外源物（如药物和环境污染物）引起细胞内生理、药理学和毒理学事件所需的基本现象。有人可能会认为，外源药物转运到肝实质细胞的机制会影响肝细胞的生物转化和胆汁排泄。有许多运输机制被认为负责肝窦吸收有机分子。这些机制包括由有机阴离子转运多肽（Oatps）介导的广泛的有机阴离子的钠独立转运。Oatp正弦转运体构成了一个重要的有机阴离子转运系统，我们假设该系统将受到经典酶诱导化学物质和胆汁酸的调节。尽管在克隆和鉴定燕麦方面取得了很大进展，但对燕麦的调控和功能的了解有限。这一缺陷，再加上小鼠基因组序列的出现和众多敲除小鼠模型的可用性，为我们研究和理解Oatp基因表达的调控提供了前所未有的机会。同时，我们新开发的Oatp4-null小鼠（第一个也是唯一一个Oatp4-null小鼠）为我们的实验室提供了一个独特的工具来检查这种重要的Oatp在体内的功能。因此，目前的提案代表了我们的计划：(1)确定肝脏中Oatp基因家族的组成和改变表达的分子调控机制，(2)表征肝脏特异性转运体Oatp4的体内功能。有关Oatps表达和调控的数据，以及来自oatp4缺失小鼠的功能数据，将极大地提高我们对Oatps在生理学、药理学和毒理学方面重要性的认识，最终不仅有助于科学界预测药物在人体中的疗效和安全性，而且允许开发肝脏特异性药物递送。

DESCRIPTION (provided by applicant): Cellular uptake is a fundamental phenomenon required for endogenous compounds and xenobiotics, such as drugs and environmental pollutants, to elicit physiological, pharmacological, and toxicological events within the cell. One might expect that the mechanism(s) by which xenobiotics are transported into hepatic parenchymal cells will affect hepatocellular biotransformation and biliary excretion. There are numerous transport mechanisms putatively responsible for hepatic sinusoidal uptake of organic molecules. These mechanisms include sodium-independent transport of a broad range of organic anions mediated by organic anion transporting polypeptides (Oatps). The Oatp sinusoidal transporters constitute an important organic anion transport system that we postulate will be regulated by classical enzyme inducing chemicals and bile acids. Despite much progress made in cloning and identifying Oatps, there is only a limited understanding of the regulation and function of Oatps. This deficiency, coupled with the emergence of the mouse genome sequence and the availability of numerous knockout mouse models, provides us an unprecedented opportunity to study and understand the regulation of Oatp gene expression. In parallel, our newly developed Oatp4-null mouse (the first and only Oatp-null mouse) gives our laboratory a unique tool to examine functions of this important Oatp in vivo. Therefore, the current proposal represents our plans to: (1) determine the molecular regulatory mechanisms responsible for both constitutive and altered expression of the Oatp gene family in liver, and (2) characterize the in vivo function of the liver-specific transporter Oatp4. The data generated regarding the expression and regulation of Oatps, as well as functional data from our Oatp4-null mouse will greatly advance our knowledge concerning the importance of Oatps in physiology, pharmacology, and toxicology, and ultimately not only aid the scientific community in predicting drug efficacy and safety in humans, but allow the development of liver-specific drug delivery.